INTRODUCTION: in 2007 the National Institute of Health and Clinical Excellence (NICE) restricted the use of acetylcholinesterase inhibitors and memantine. METHODS: we conducted a health technology assessment (HTA) of the effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of AD to re-consider and up-date the evidence base used to inform the 2007 NICE decision. The systematic review of effectiveness targeted randomised controlled trials. A comprehensive search, including MEDLINE, Embase and the Cochrane Library, was conducted from January 2004 to March 2010. All key review steps were done by two reviewers. Random effects meta-analysis was conducted. The cost-effectiveness was assessed using a cohort-based model with three health states: pre-institutionalised, institutionalised and dead. The perspective was NHS and Personal Social Services and the cost year 2009. RESULTS: confidence about the size and statistical significance of the estimates of effect of galantamine, rivastigmine and memantine improved on function and global impact in particular. Cost-effectiveness also changed. For donepezil, galantamine and rivastigmine, the incremental cost per quality-adjusted life year (QALY) in 2004 was above £50,000; in 2010 the same drugs 'dominated' best supportive care (improved clinical outcome at reduced cost). This was primarily because of changes in the modelled costs of introducing the drugs. For memantine, the cost-effectiveness also improved from a range of £37-53,000 per QALY gained to a base-case of £32,000. CONCLUSION: there has been a change in the evidence base between 2004 and 2010 consistent with the change in NICE guidance. Further evolution in cost-effectiveness estimates is possible particularly if there are changes in drug prices.

BACKGROUND: Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included the Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: the clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, the model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: the additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

BACKGROUND: Breast cancer (BC) accounts for one-third of all cases of cancer in women in the UK. Current strategies for the detection of BC recurrence include computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy. Positron emission tomography (PET) and, more recently, positron emission tomography/computed tomography (PET/CT) are technologies that have been shown to have increasing relevance in the detection and management of BC recurrence. OBJECTIVE: to review the accuracy of PET and PET/CT for the diagnosis of BC recurrence by assessing their value compared with current practice and compared with each other. DATA SOURCES: MEDLINE and EMBASE were searched from inception to May 2009. STUDY SELECTION: Studies were included if investigations used PET or PET/CT to diagnose BC recurrence in patients with a history of BC and if the reference standard used to define the true disease status was histological diagnosis and/or long-term clinical follow-up. Studies were excluded if a non-standard PET or PET/CT technology was used, investigations were conducted for screening or staging of primary breast cancer, there was an inadequate or undefined reference standard, or raw data for calculation of diagnostic accuracy were not available. STUDY APPRAISAL: Quality assessment and data extraction were performed independently by two reviewers. Direct and indirect comparisons were made between PET and PET/CT and between these technologies and methods of conventional imaging, and meta-analyses were carried out. Analysis was conducted separately on patient- and lesion-based data. Subgroup analysis was conducted to investigate variation in the accuracy of PET in certain populations or contexts and sensitivity analysis was conducted to examine the reliability of the primary outcome measures. RESULTS: of the 28 studies included in the review, 25 presented patient-based data and 7 presented lesion-based data for PET and 5 presented patient-based data and 1 presented patient- and lesion-based data for PET/CT; 16 studies conducted direct comparisons with 12 comparing the accuracy of PET or PET/CT with conventional diagnostic tests and 4 with MRI. For patient-based data (direct comparison) PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] and significantly higher specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 67% to 92%, relative specificity 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with conventional imaging tests (CITs)--test performance did not appear to vary according to the type of CIT tested. For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, p = 0.015), but the increase in specificity was not significant (89%, 95% CI 69% to 97% vs 77%, 95% CI 50% to 92%, relative specificity 1.15, 95% CI 0.95 to 1.41, p = 0.157). For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with PET (96%, 95% CI 90% to 98% vs 85%, 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 to 1.18, p = 0.006), but the increase in specificity was not significant (89%, 95% CI 74% to 96% vs 82%, 95% CI 64% to 92%, relative specificity 1.08, 95% CI 0.94 to 1.20, p = 0.267). For patient-based data there were no significant differences in the sensitivity or specificity of PET when compared with MRI, and, in the one lesion based study, there was no significant differences in the sensitivity or specificity of PET/CT when compared with MRI. LIMITATIONS: Studies reviewed were generally small and retrospective and this may have limited the generalisability of findings. Subgroup analysis was conducted on the whole set of studies investigating PET and was not restricted to comparative studies. Conventional imaging studies that were not compared with PET or PET/CT were excluded from the review. CONCLUSIONS: Available evidence suggests that for the detection of BC recurrence PET, in addition to conventional imaging techniques, may generally offer improved diagnostic accuracy compared with current standard practice. However, uncertainty remains around its use as a replacement for, rather than an add-on to, existing imaging technologies. In addition, PET/CT appeared to show clear advantage over CT and PET alone for the diagnosis of BC recurrence. FUTURE WORK: Future research should include: prospective studies with patient populations clearly defined with regard to their clinical presentation; a study of diagnostic accuracy of PET/CT compared with conventional imaging techniques; a study of PET/CT compared with whole-body MRI; studies investigating the possibility of using PET/CT as a replacement for rather than an addition to CITs; and using modelling of the impact of PET/CT on patient outcomes to inform the possibility of conducting large-scale intervention trials.

OBJECTIVES: to identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. DATA SOURCES: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. REVIEW METHODS: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. RESULTS: of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance. CONCLUSIONS: for primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia.

Introduction Although the new generation of cardiac
troponin assays have revolutionised the diagnosis of
myocardial infarction (MI), their application in triaging
patients with suspected acute coronary syndrome
requires further investigation. The objectives of the current
systematic review are to evaluate the diagnostic accuracy
of contemporary and high-sensitivity cardiac troponin
assays used in serial testing, versus single-sample testing
as a comparator, to identify patients with non-ST-segmentelevation
MI in the emergency department.
Methods and analysis We will conduct systematic
searches of MEDLINE, EMBASE, Science Citation Index,
the Cochrane Database of Systematic Reviews and the
CENTRAL database covering the period from 1 January 2006
to present, with no restrictions on language or publication
status. Two review authors will independently screen studies
for inclusion, extract data from eligible studies and assess
their methodological quality using Quality Assessment
of Diagnostic Accuracy Studies version 2. Studies will be
included if they evaluate contemporary or high-sensitivity
cardiac troponin assays used in serial testing, in patients
presenting to the ED with suspicion of MI. Estimates of
sensitivity and specificity from each study will be presented
in forest plots and in the receiver-operating characteristics
space. If appropriate, we will pool the results using Bayesian
hierarchical models that allow correction for imperfect
reference standard. We will obtain summary estimates of
sensitivity and specificity of alternative testing protocols and
compare their accuracy. We will also investigate the impact
of prespecified sources of heterogeneity and methodological
quality items. If pooling of results is considered inappropriate,
we will present our findings in tables and diagrams and will
describe them narratively.
Ethics and dissemination No formal ethical approval will
be sought, but we will report on the ethical approval of the
included studies. Dissemination of findings will be through
publications in peer-reviewed journals, presentations at
conferences and the websites of the universities.

Abstract
. Background
Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early.
Methods
Our objective was to estimate the effect of LDCT lung cancer screening on mortality in high risk populations.
A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. RCTs of CXR screening were additionally included in the network meta-analyses. Bibliographic sources including MEDLINE, Embase, Web of Science and the Cochrane Library were searched to January 2017, and then further extended to November 2021. All key review steps were done by two persons. Quality assessment used the Cochrane Risk of Bias tool. Meta-analyses were performed.
Results
Nine RCTs, with up to 12.3 years of follow-up from randomisation, were included in the direct meta-analysis, which showed that LDCT screening was associated with a statistically significant decrease in lung cancer mortality (pooled relative risk (RR) 0.87, 95% confidence interval [CI] 0.77 to 0.96). There was a statistically non-significant decrease in all-cause mortality (pooled RR 0.98, 95% CI 0.95 to 1.01). The statistical heterogeneity for both outcomes was minimal. Network meta-analysis including the nine RCTs in the direct meta-analysis plus two further RCTs comparing CXR with usual care confirmed the size of the effect of LDCT on lung cancer mortality and that this was very similar irrespective of whether the comparator was usual care or CXR screening.
Conclusions
LDCT screening is effective in reducing lung cancer mortality in high risk populations. The uncertainty of its effect on lung cancer mortality observed in 2018 has been much reduced with new trial results and updates to existing trials, emphasising the importance of up-dating systematic reviews. Although there are still a number of RCTs unreported or in progress, we predict that further evolution of summary mortality estimates is unlikely. The focus for debate now moves to resolving uncertainty about the cost-effectiveness of LDCT screening taking into account the balance between benefits and harms which occur in all screening programmes.

Background: the ordering of thyroid function tests (TFTs) is increasing but there is not a similar increase in thyroid disorders in the general population, leading some to query whether inappropriate testing is taking place. Inconsistent clinical practice is thought to be a cause of this, but there is little evidence of the views of general practitioners, practice nurses or practice managers on the reasons for variation in the ordering of TFTs.Aim: to find out the reasons for variation in ordering of TFTs from the perspective of primary healthcare professionals Methods: Fifteen semi-structured interviews were carried out with primary healthcare professionals (general practitioners, practice nurses, practice managers) that used one laboratory of a general hospital in South West England for TFTs. Framework Analysis was used to analyse views on test ordering variation at the societal, practice, individual practitioner and patient level.Results: a number of reasons for variation in ordering across practices were suggested. These related to: primary healthcare professionals awareness of and adherence to national policy changes; practices having different protocols on TFTs ordering; the set-up and use of computer systems in practices; the range of practice healthcare professionals able to order TFTs; greater risk-aversion amongst general practitioners and changes in their training and finally how primary healthcare staff responded to patients who were perceived to seek help more readily than in the past.Conclusion: the reasons for variation in TFTs ordering are complex and interdependent. Interventions to reduce variation in TFTs ordering need to consider multiple behavioural and contextual factors to be most effective.

AbstractObjectivesTo identify which international HTA agencies are undertaking evaluations of medical tests, summarise commonalities and differences in methodological approach, and highlight examples of best practice.MethodsA methodological review incorporating: systematic identification of HTA guidance documents mentioning evaluation of tests; identification of key contributing organisations and abstraction of approaches to all essential HTA steps; summary of similarities and differences between organisations; and identification of important emergent themes which define the current state of the art and frontiers where further development is needed.ResultsSeven key organisations were identified from 216 screened. The main themes were: elucidation of claims of test benefits; attitude to direct and indirect evidence of clinical effectiveness (including evidence linkage); searching; quality assessment; and health economic evaluation. With the exception of dealing with test accuracy data, approaches were largely based on general approaches to HTA with few test-specific modifications. Elucidation of test claims and attitude to direct and indirect evidence are where we identified the biggest dissimilarities in approach.ConclusionsThere is consensus on some aspects of HTA of tests, such as dealing with test accuracy, and examples of good practice which HTA organisations new to test evaluation can emulate. The focus on test accuracy contrasts with universal acknowledgement that it is not a sufficient evidence base for test evaluation. There are frontiers where methodological development is urgently required, notably integrating direct and indirect evidence and standardising approaches to evidence linkage.

Background: Anaemia is a common side-effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions (RBCTs) to improve cancer treatment-induced anaemia (CIA).
Methods: the clinical effectiveness review followed principles published by NHS CRD. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care (BSC), placebo, or other ESA. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL), and adverse events (AEs) were evaluated. Where appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment to no ESA treatment. The model has two components: one evaluating short-term costs and QALYs (while patients are anaemic); and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% pa. Probabilistic and univariate deterministic sensitivity analyses were performed.
Results: Twenty-three studies assessing ESAs within their licensed indication (based on start dose administered) were included. None of the RCTs were completely aligned with current EU licenses. Results suggest that there is clinical benefit from ESAs for anaemia-related outcomes. Data suggest improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain; although point estimates are lower confidence intervals are wide and not statistically significant. Base case incremental cost-effectiveness ratios (ICERs) for ESA treatment versus no ESA treatment ranged from £19,429–£35,018 per quality-adjusted life year (QALY) gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost.
Conclusions: ESAs could be cost-effective when used closer to licence but there is considerable uncertainty mainly due to unknown impacts on overall survival.

OBJECTIVES: to identify which international health technology assessment (HTA) agencies are undertaking evaluations of medical tests, summarize commonalities and differences in methodological approach, and highlight examples of good practice. METHODS: a methodological review incorporating: systematic identification of HTA guidance documents mentioning evaluation of tests; identification of key contributing organizations and abstraction of approaches to all essential HTA steps; summary of similarities and differences between organizations; and identification of important emergent themes which define the current state of the art and frontiers where further development is needed. RESULTS: Seven key organizations were identified from 216 screened. The main themes were: elucidation of claims of test benefits; attitude to direct and indirect evidence of clinical effectiveness (including evidence linkage); searching; quality assessment; and health economic evaluation. With the exception of dealing with test accuracy data, approaches were largely based on general approaches to HTA with few test-specific modifications. Elucidation of test claims and attitude to direct and indirect evidence are where we identified the biggest dissimilarities in approach. CONCLUSIONS: There is consensus on some aspects of HTA of tests, such as dealing with test accuracy, and examples of good practice which HTA organizations new to test evaluation can emulate. The focus on test accuracy contrasts with universal acknowledgment that it is not a sufficient evidence base for test evaluation. There are frontiers where methodological development is urgently required, notably integrating direct and indirect evidence and standardizing approaches to evidence linkage.

OBJECTIVES: to systematically review the accuracy of artificial intelligence (AI)-based systems for grading of fundus images in diabetic retinopathy (DR) screening. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and the ClinicalTrials.gov from 1st January 2000 to 27th August 2021. Accuracy studies published in English were included if they met the pre-specified inclusion criteria. Selection of studies for inclusion, data extraction and quality assessment were conducted by one author with a second reviewer independently screening and checking 20% of titles. Results were analysed narratively. RESULTS: Forty-three studies evaluating 15 deep learning (DL) and 4 machine learning (ML) systems were included. Nine systems were evaluated in a single study each. Most studies were judged to be at high or unclear risk of bias in at least one QUADAS-2 domain. Sensitivity for referable DR and higher grades was ≥85% while specificity varied and was

OBJECTIVE: to quantify use of shorthand description of research design in the titles and abstracts of diagnostic test accuracy studies, comparing 2012 and 2019. STUDY DESIGN AND SETTING: Joint examination, using pre-specified criteria, by two investigators of 320 randomly sampled articles indexed as "diagnostic (test) accuracy studies" in EMBASE in 2012 and 2019. RESULTS: the percentage of abstracts with shorthand descriptions of study design was 11% in 2012 and 15% in 2019, a difference of 4% (95% CI -3, 12). Although use of the term accuracy in the abstract did increase (58% in 2012 to 74% in 2019, difference 16% (95% CI 5, 26)), accuracy was only used to convey purpose or design in 49% (95% CI 43, 56) of abstracts where accuracy appeared (2012+2019). CONCLUSION: it is difficult to identify the study design of test evaluations from information in the title and abstract. This is important because bias is associated with different study designs. Developing a limited number of standardised, widely understood study design descriptions could greatly improve clarity of the only freely available information on many pieces of medical research. It may be helpful that the fact that a study addresses test accuracy be part of shorthand descriptions.

ObjectivesWe aimed to assess the diversity and practices of existing studies on several assays and algorithms for serial measurements of high-sensitivity cardiac troponin (hs-cTn) for risk stratification and the diagnosis of myocardial infarction (MI) and 30-day outcomes in patients suspected of having non-ST-segment elevation MI (NSTEMI).MethodsWe searched multiple databases including MEDLINE, EMBASE, Science Citation Index, the Cochrane Database of Systematic Reviews and the CENTRAL databases for studies published between January 2006 and November 2021. Studies that assessed the diagnostic accuracy of serial hs-cTn testing in patients suspected of having NSTEMI in the emergency department (ED) were eligible. Data were analysed using the scoping review method.ResultsWe included 86 publications, mainly from research centres in Europe, North America and Australasia. Two hs-cTn assays, manufactured by Abbott (43/86) and Roche (53/86), dominated the evaluations. The studies most commonly measured the concentrations of hs-cTn at two time points, at presentation and a few hours thereafter, to assess the two-strata or three-strata algorithm for diagnosing or ruling out MI. Although data from 83 studies (97%) were prospectively collected, 0%–90% of the eligible patients were excluded from the analysis due to missing blood samples or the lack of a final diagnosis in 53 studies (62%) that reported relevant data. Only 19 studies (22%) reported on head-to-head comparisons of alternative assays.ConclusionEvidence on the accuracy of serial hs-cTn testing was largely derived from selected research institutions and relied on two specific assays. The proportions of the eligible patients excluded from the study raise concerns about directly applying the study findings to clinical practice in frontline EDs.PROSPERO registration numberCRD42018106379.

The objective of this exploratory modelling study was to estimate the effects of second-trimester, ultrasound-based antenatal detection strategies for vasa praevia (VP) in a hypothetical cohort of pregnant women. For this, a decision-analytic tree model was developed covering four discrete detection pathways/strategies: no screening; screening targeted at women undergoing in-vitro fertilisation (IVF); screening targeted at women with low-lying placentas (LLP); screening targeted at women with velamentous cord insertion (VCI) or a bilobed or succenturiate (BL/S) placenta. Main outcome measures were the number of referrals to transvaginal sonography (TVS), diagnosed and undiagnosed cases of VP, overdetected cases of VCI, and VP-associated perinatal mortality. The greatest number of referrals to TVS occurred in the LLP-based (2,083) and VCI-based screening (1,319) pathways. These two pathways also led to the highest proportions of pregnancies diagnosed with VP (VCI-based screening: 552 [78.9% of all pregnancies]; LLP-based: 371 [53.5%]) and the lowest proportions of VP leading to perinatal death (VCI-based screening: 100 [14.2%]; LLP-based: 196 [28.0%]). In contrast, the IVF-based pathway resulted in 66 TVS referrals, 50 VP diagnoses (7.1% of all VP pregnancies), and 368 (52.6%) VP-associated perinatal deaths which was comparable to the no screening pathway (380 [54.3%]). The VCI-based pathway resulted in the greatest detection of VCI (14,238 [99.1%]), followed by the IVF-based pathway (443 [3.1%]); no VCI detection occurred in the LLP-based or no screening pathways. In conclusion, the model results suggest that a targeted LLP-based approach could detect a substantial proportion of VP cases, while avoiding VCI overdetection and requiring minimal changes to current clinical practice. High-quality data is required to explore the clinical and cost-effectiveness of this and other detection strategies further. This is necessary to provide a robust basis for future discussion about routine screening for VP.

Artificial intelligence (AI) could have the potential to accurately classify mammograms according to the presence or absence of radiological signs of breast cancer, replacing or supplementing human readers (radiologists). The UK National Screening Committee's assessments of the use of AI systems to examine screening mammograms continues to focus on maximising benefits and minimising harms to women screened, when deciding whether to recommend the implementation of AI into the Breast Screening Programme in the UK. Maintaining or improving programme specificity is important to minimise anxiety from false positive results. When considering cancer detection, AI test sensitivity alone is not sufficiently informative, and additional information on the spectrum of disease detected and interval cancers is crucial to better understand the benefits and harms of screening. Although large retrospective studies might provide useful evidence by directly comparing test accuracy and spectrum of disease detected between different AI systems and by population subgroup, most retrospective studies are biased due to differential verification (ie, the use of different reference standards to verify the target condition among study participants). Enriched, multiple-reader, multiple-case, test set laboratory studies are also biased due to the laboratory effect (ie, radiologists' performance in retrospective, laboratory, observer studies is substantially different to their performance in a clinical environment). Therefore, assessment of the effect of incorporating any AI system into the breast screening pathway in prospective studies is required as it will provide key evidence for the effect of the interaction of medical staff with AI, and the impact on women's outcomes.

Objectives: This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:. To determine the diagnostic accuracy of biomarkers for detecting acute appendicitis in hospitalised adults with suspected acute appendicitis. Secondary objectives to determine (if possible) the diagnostic accuracy of biomarkers for detecting: uncomplicated and complicated (gangrenous or perforated) acute appendicitis; acute appendicitis in males and females; acute appendicitis in women of reproductive age; acute appendicitis in pregnancy; acute appendicitis at different time intervals from onset of pain.

BACKGROUND: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES: to determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

For many users of the biomedical literature, abstracts may be the only source of information about a study. Hence, abstracts should allow readers to evaluate the objectives, key design features, and main results of the study. Several evaluations have shown deficiencies in the reporting of journal and conference abstracts across study designs and research fields, including systematic reviews of diagnostic test accuracy studies. Incomplete reporting compromises the value of research to key stakeholders. The authors of this article have developed a 12 item checklist of preferred reporting items for journal and conference abstracts of systematic reviews and meta-analyses of diagnostic test accuracy studies (PRISMA-DTA for Abstracts). This article presents the checklist, examples of complete reporting, and explanations for each item of PRISMA-DTA for Abstracts.

BACKGROUND: Low rectal cancers could be treated using restorative (anterior resection, AR) or non-restorative procedures with an end/permanent stoma (Hartmann's, HE; or abdominoperineal excision, APE). Although the surgical choice is determined by tumour and patient factors, quality of life (QoL) will also influence the patient's future beyond cancer. This systematic review of the literature compared postoperative QoL between the restorative and non-restorative techniques using validated measurement tools. METHODS: the review was registered on PROSPERO (CRD42020131492). Embase and MEDLINE, along with grey literature and trials websites, were searched comprehensively for papers published since 2012. Inclusion criteria were original research in an adult population with rectal cancer that reported QoL using a validated tool, including the European Organization for Research and Treatment of Cancer QLQ-CR30, QLQ-CR29, and QLQ-CR38. Studies were included if they compared AR with APE (or HE), independent of study design. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Outcomes of interest were: QoL, pain, gastrointestinal (GI) symptoms (stool frequency, flatulence, diarrhoea and constipation), and body image. RESULTS: Nineteen studies met the inclusion criteria with a total of 6453 patients; all papers were observational and just four included preoperative evaluations. There was no identifiable difference in global QoL and pain between the two surgical techniques. Reported results regarding GI symptoms and body image documented similar findings. The ROBINS-I tool highlighted a significant risk of bias across the studies. CONCLUSION: Currently, it is not possible to draw a firm conclusion on postoperative QoL, pain, GI symptoms, and body image following restorative or non-restorative surgery. The included studies were generally of poor quality, lacked preoperative evaluations, and showed considerable bias in the data.

OBJECTIVES: (1) to identify and classify comparative diagnostic test accuracy (DTA) study designs; (2) to describe study design labels used by authors of comparative DTA studies. METHODS: We performed a methodological review of 100 comparative DTA studies published between 2015 and 2017, randomly sampled from studies included in 238 comparative DTA systematic reviews indexed in MEDLINE in 2017. From each study report, we extracted six design elements characterizing participant flow and the labels used by authors. RESULTS: We identified a total of 46 unique combinations of study design features in our sample, based on six design elements characterizing participant flow. We classified the studies into five study design categories based on how participants were allocated to receive each index test: 'fully paired' (n=79), 'partially paired, random subset' (n=0), 'partially paired, nonrandom subset' (n=2), 'unpaired randomized' (n=1) and 'unpaired nonrandomized' (n=3). The allocation method used in 15 studies was unclear. Sixty-one studies reported, in total, 29 unique study design labels but only four labels referred to specific design features of comparative studies. CONCLUSION: Our classification scheme can help systematic review authors define study eligibility criteria, assess risk of bias, and communicate the strength of the evidence. A standardized labelling scheme could be developed to facilitate communication of specific design features.

BACKGROUND: Cow's milk protein allergy (CMPA) is an immune-mediated allergic response to proteins in milk that is common in infants. Broad CMPA symptoms make diagnosis a challenge, particularly in primary care. Symptom scores may improve a clinician's awareness of symptoms, indicating a need for further testing. This systematic review examined the development and evaluation of such symptom scores for use in infants. METHODS: CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched from inception to 3 December 2019 (Updated 14 November 2020) for diagnostic accuracy studies, randomised controlled trials, observational studies, economic evaluations, qualitative studies and studies reporting development of the tools. Data were not suitable for meta-analysis due to clinical and methodological heterogeneity, so were narratively synthesised. RESULTS: We found two symptom scores evaluated in one and fourteen studies, respectively. Estimated sensitivity and specificity ranged from 37% to 98% and 38% to 93%. The evaluations of each tool were at high risk of bias or failed to address issues such as clinical and cost-effectiveness. CONCLUSIONS: Estimates of accuracy of symptom scores for CMPA offered so far should be interpreted cautiously. Rigorous, conflict-free research based on well-defined roles for the tools is urgently required.

Gaps in the translation of research findings to clinical management have been recognized for decades. They exist for the diagnosis as well as the management of cancer. The international standards for cancer diagnosis are contained within the World Health Organization (WHO) Classification of Tumours, published by the International Agency for Research on Cancer (IARC) and known worldwide as the WHO Blue Books. In addition to their relevance to individual patients, these volumes provide a valuable contribution to cancer research and surveillance, fulfilling an important role in scientific evidence synthesis and international standard setting. However, the multidimensional nature of cancer classification, the way in which the WHO Classification of Tumours is constructed, and the scientific information overload in the field pose important challenges for the translation of research findings to tumour classification and hence cancer diagnosis. To help address these challenges, we have established the International Collaboration for Cancer Classification and Research (IC3 R) to provide a forum for the coordination of efforts in evidence generation, standard setting and best practice recommendations in the field of tumour classification. The first IC3 R meeting, held in Lyon, France, in February 2019, gathered representatives of major institutions involved in tumour classification and related fields to identify and discuss translational challenges in data comparability, standard setting, quality management, evidence evaluation and copyright, as well as to develop a collaborative plan for addressing these challenges.

OBJECTIVES: the objective of this study was to clarify a difference between two approaches while evaluating the diagnostic accuracy of medical tests, labeled here as "pragmatic" vs. "explanatory" studies. METHODS: Using the definitions and characteristics described by Schwartz and Lellouch for randomized trials of interventions, and Schwartz' more general distinction between a pragmatic and an explanatory approach in medical research, we define a similar continuum for diagnostic accuracy studies. Explanatory studies aim to better understand the behavior of a test; pragmatic ones are done to support recommendations or decisions about using the test in clinical practice. RESULTS: Pragmatic test accuracy studies differ from explanatory test accuracy studies in several ways. The difference in aims has implications for key elements of study design, such as the study eligibility criteria, the recruitment of patients, the reference standard, and the choice of the statistical analysis. Explanatory accuracy studies are often designed to test a hypothesis. They are typically selective in recruitment, may include "healthy controls," with a small sample size, often recruited at a single center. They ignore testing failures in the analysis and more often present their results as ROC curves. By contrast, pragmatic studies are designed to guide decision making. They ideally will recruit a single, large, and representative group of patients at multiple sites and will more often present their results as estimates of sensitivity and specificity or predictive values at a prespecified threshold. CONCLUSION: Distinguishing between a pragmatic and an explanatory approach can help in the design, analysis, and interpretation of diagnostic accuracy studies. It can clarify debates about the appropriateness of design features to the study purpose and about the validity and applicability of study findings.

Background: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity. Methods: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites. Results: of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from − 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset. Conclusions: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.

Abstract
.
. Background
. Tools based on diagnostic prediction models are available to help general practitioners (GP) diagnose colorectal cancer. It is unclear how well they perform and whether they lead to increased or quicker diagnoses and ultimately impact on patient quality of life and/or survival. The aim of this systematic review is to evaluate the development, validation, effectiveness, and cost-effectiveness, of cancer diagnostic tools for colorectal cancer in primary care.
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.
. Methods
. Electronic databases including Medline and Web of Science were searched in May 2017 (updated October 2019). Two reviewers independently screened titles, abstracts and full-texts. Studies were included if they reported the development, validation or accuracy of a prediction model, or assessed the effectiveness or cost-effectiveness of diagnostic tools based on prediction models to aid GP decision-making for symptomatic patients presenting with features potentially indicative of colorectal cancer. Data extraction and risk of bias were completed by one reviewer and checked by a second. A narrative synthesis was conducted.
.
.
. Results
. Eleven thousand one hundred thirteen records were screened and 23 studies met the inclusion criteria. Twenty-studies reported on the development, validation and/or accuracy of 13 prediction models: eight for colorectal cancer, five for cancer areas/types that include colorectal cancer. The Qcancer models were generally the best performing.
. Three impact studies met the inclusion criteria. Two (an RCT and a pre-post study) assessed tools based on the RAT prediction model. The third study looked at the impact of GP practices having access to RAT or Qcancer.
. Although the pre-post study reported a positive impact of the tools on outcomes, the results of the RCT and cross-sectional survey found no evidence that use of, or access to, the tools was associated with better outcomes. No study evaluated cost effectiveness.
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.
. Conclusions
. Many prediction models have been developed but none have been fully validated. Evidence demonstrating improved patient outcome of introducing the tools is the main deficiency and is essential given the imperfect classification achieved by all tools. This need is emphasised by the equivocal results of the small number of impact studies done so far.
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Abstract
Background
A systematic review of economic evaluations for lung cancer identified no economic models of the UK setting based on disease natural history. We first sought to develop a new model of natural history for population screening, then sought to explore the cost-effectiveness of multiple alternative potential programmes.

Methods
An individual patient model (ENaBL) was constructed in MS Excel® and calibrated against data from the US National Lung Screening Trial. Costs were taken from the UK Lung Cancer Screening Trial and took the perspective of the NHS and PSS. Simulants were current or former smokers aged between 55 and 80 years and so at a higher risk of lung cancer relative to the general population. Subgroups were defined by further restricting age and risk of lung cancer as predicted by patient self-questionnaire. Programme designs were single, triple, annual and biennial arrangements of LDCT screens, thereby examining number and interval length. Forty-eight distinct screening strategies were compared to the current practice of no screening. The primary outcome was incremental cost-effectiveness of strategies (additional cost per QALY gained).

Results
LDCT screening is predicted to bring forward the stage distribution at diagnosis and reduce lung cancer mortality, with decreases versus no screening ranging from 4.2 to 7.7% depending on screen frequency. Overall healthcare costs are predicted to increase; treatment cost savings from earlier detection are outweighed by the costs of over-diagnosis. Single-screen programmes for people 55–75 or 60–75 years with ≥ 3% predicted lung cancer risk may be cost-effective at the £30,000 per QALY threshold (respective ICERs of £28,784 and £28,169 per QALY gained). Annual and biennial screening programmes were not predicted to be cost-effective at any cost-effectiveness threshold.

Limitations
LDCT performance was unaffected by lung cancer type, stage or location and the impact of a national screening programme of smoking behaviour was not included.

Conclusion
Lung cancer screening may not be cost-effective at the threshold of £20,000 per QALY commonly used in the UK but may be cost-effective at the higher threshold of £30,000 per QALY.

OBJECTIVE: the objective of this study was to examine methodological and reporting characteristics of systematic reviews and meta-analyses which compare diagnostic test accuracy (DTA) of multiple index tests, identify good practice, and develop guidance for better reporting. STUDY DESIGN AND SETTING: Methodological survey of 127 comparative or multiple tests reviews published in 74 different general medical and specialist journals. We summarized methods and reporting characteristics that are likely to differ between reviews of a single test and comparative reviews. We then developed guidance to enhance reporting of test comparisons in DTA reviews. RESULTS: of 127 reviews, 16 (13%) reviews restricted study selection and test comparisons to comparative accuracy studies while the remaining 111 (87%) reviews included any study type. Fifty-three reviews (42%) statistically compared test accuracy with only 18 (34%) of these using recommended methods. Reporting of several items-in particular the role of the index tests, test comparison strategy, and limitations of indirect comparisons (i.e. comparisons involving any study type)-was deficient in many reviews. Five reviews with exemplary methods and reporting were identified. CONCLUSION: Reporting quality of reviews which evaluate and compare multiple tests is poor. The guidance developed, complemented with the exemplars, can assist review authors in producing better quality comparative reviews.

Systematic reviews of diagnostic test accuracy (DTA) studies are fundamental to the decision making process in evidence based medicine. Although such studies are regarded as high level evidence, these reviews are not always reported completely and transparently. Suboptimal reporting of DTA systematic reviews compromises their validity and generalisability, and subsequently their value to key stakeholders. An extension of the PRISMA (preferred reporting items for systematic review and meta-analysis) statement was recently developed to improve the reporting quality of DTA systematic reviews. The PRISMA-DTA statement has 27 items, of which eight are unmodified from the original PRISMA statement. This article provides an explanation for the 19 new and modified items, along with their meaning and rationale. Examples of complete reporting are used for each item to illustrate best practices.

An evaluation of a rapid portable gold-nanotechnology measuring SARS-CoV-2 IgM, IgA and IgG antibody concentrations against spike 1 (S1), spike 2 (S) and nucleocapsid (N) was conducted using serum samples from 74 patients tested for SARS-CoV-2 RNA on admission to hospital, and 47 historical control patients from March 2019. 59 patients were RNA(+) and 15 were RNA(-). A serum (±) classification was derived for all three antigens and a quantitative serological profile was obtained. Serum(+) was identified in 30% (95% CI 11-48) of initially RNA(-) patients, in 36% (95% CI 17-54) of RNA(+) patients before 10 days, 77% (95% CI 67-87) between 10 and 20 days and 95% (95% CI 86-100) after 21 days. The patient-level diagnostic accuracy relative to RNA(±) after 10 days displayed 88% sensitivity (95% CI 75-95) and 75% specificity (95% CI 22-99), although specificity compared with historical controls was 100% (95%CI 91-100). This study provides robust support for further evaluation and validation of this novel technology in a clinical setting and highlights challenges inherent in assessment of serological tests for an emerging disease such as COVID-19.

IntroductionTo identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i).Research design and methodsWe assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation.ResultsGenital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; &lt;1 year before initiation (HR 4.38; 3.73 to 5.13), 1–5 years (HR 3.04; 2.64 to 3.51), and &gt;5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21–1.80) and DPP4i (HR 1.58; 1.21–2.07).ConclusionsFemale sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i.

OBJECTIVES: Comparative diagnostic test accuracy systematic reviews (DTA reviews) assess the accuracy of two or more tests and compare their diagnostic performance. We investigated how comparative DTA reviews assessed the risk of bias (RoB) in primary studies that compared multiple index tests. STUDY DESIGN AND SETTING: This is an overview of comparative DTA reviews indexed in MEDLINE from January 1st to December 31st, 2017. Two assessors independently identified DTA reviews including at least two index tests and containing at least one statement in which the accuracy of the index tests was compared. Two assessors independently extracted data on the methods used to assess RoB in studies that directly compared the accuracy of multiple index tests. RESULTS: We included 238 comparative DTA reviews. Only two reviews (0.8%, 95% confidence interval 0.1 to 3.0%) conducted RoB assessment of test comparisons undertaken in primary studies; neither used an RoB tool specifically designed to assess bias in test comparisons. CONCLUSION: Assessment of RoB in test comparisons undertaken in primary studies was uncommon in comparative DTA reviews, possibly due to lack of existing guidance on and awareness of potential sources of bias. Based on our findings, guidance on how to assess and incorporate RoB in comparative DTA reviews is needed.

Abstract
Background
Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early.

Methods
Our objective was to estimate the effect of LDCT lung cancer screening on mortality in high-risk populations. A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. RCTs of CXR screening were additionally included in the network meta-analysis. Bibliographic sources including MEDLINE, Embase, Web of Science and the Cochrane Library were searched to January 2017. All key review steps were done by two persons. Quality assessment used the Cochrane Risk of Bias tool. Meta-analyses were performed.

Results
Four RCTs were included. More will provide data in the future. Meta-analysis demonstrated that LDCT screening with up to 9.80 years of follow-up was associated with a statistically non-significant decrease in lung cancer mortality (pooled relative risk (RR) 0.94, 95% confidence interval (CI) 0.74 to 1.19; p = 0.62). There was a statistically non-significant increase in all-cause mortality. Given the considerable heterogeneity for both outcomes, the results should be treated with caution.
Network meta-analysis including the four original RCTs plus two further RCTs assessed the relative effectiveness of LDCT, CXR and usual care. The results showed that in terms of lung cancer mortality reduction LDCT was ranked as the best screening strategy, CXR screening as the worst strategy and usual care intermediate.

Conclusions
LDCT screening may be effective in reducing lung cancer mortality but there is considerable uncertainty: the largest of the RCTs compared LDCT with CXR screening rather than no screening; there is imprecision of the estimates; and there is important heterogeneity between the included study results. The uncertainty about the effect on all-cause mortality is even greater. Maturing trials may resolve the uncertainty.

Identifying dementia in general practice remains a considerable challenge, with mild to moderate stages of dementia potentially underdiagnosed in 30-50% of cases. The primary aim of this PhD thesis was to address the question “how can we improve the accuracy of brief cognitive assessments when used as part of the process for identifying dementia in general practice?”. This was carried out via a combination of secondary research through three evidence syntheses, and primary research via a survey of general practitioners with results triangulated with existing research and thesis findings.
Through the conduct of a rapid review of clinical practice guidelines (CPGs),I found a lack of consistent recommendations for general practice regarding selection and application of brief cognitive assessment (BCA) tools There was also a paucity of guidance given within the identified CPGs on tailoring BCA choice and use for specific populations. The rapid review indicates that greater clarity and consistency is needed from CPGs relating specifically to the use of BCAs as part of the process for identifying dementia in general practice. The systematic review and overview identified an absence of existing evidence. Where evidence exists, BCAs performed inconsistently and were broadly inadequate as a tool for use in general practice dementia care. Other factors beyond diagnostic accuracy render established tests ill-suited for general practice such as administration time, cost and acceptability for clinicians and patients. A number of areas are identified both in cognitive testing and research methods where progress can be made relatively simply.
This thesis demonstrates that many assumptions underlying current practice are without robust foundations, with severe implications for general practice and patient care at a time of scarce resource and growing demand. These assumptions need revising as a priority. What is needed is clear, specific, well-designed primary research to begin to unpick these complexities and realistically address the challenges presented by the identification of dementia within general practice and primary care. I provide explicit recommendations for the design and conduct of a primary comparative accuracy study alongside a trial of effectiveness and cost-effectiveness of using brief cognitive assessments as part of the process of identifying dementia in general practice in order to objectively and systematically assess the suitability of brief cognitive assessments as a tool for use in this population and setting.

BACKGROUND: a variety of study designs are available to evaluate the accuracy of tests, but the terms used to describe these designs seem to lack clarity and standardization. We investigated if this was the case in the diagnostic guidance of the National Institute of Care and Health Excellence (NICE), an influential source of advice on the value of tests. OBJECTIVES: to describe the range of study design terms and labels used to distinguish study designs in NICE Diagnostic Guidance and the underlying evidence reports. METHODS: We carefully examined all NICE Diagnostic Guidance that has been developed from inception in 2011 until 2018 and the corresponding diagnostic assessment reports that summarized the evidence, focusing on guidance where tests were considered for diagnosis. We abstracted labels used to describe study designs and investigated what labels were used when studies were weighted differently because of their design (in terms of validity of evidence), in relevant sections. We made a descriptive analysis to assess the range of labels and also categorized labels by design features. RESULTS: from a total of 36 pieces of guidance, 20 (56%) were eligible and 17 (47%) were included in our analysis. We identified 53 unique design labels, of which 19 (36%) were specific to diagnostic test accuracy designs. These referred to a total of 12 study design features. Labels were used in assigning different weights to studies in seven of the reports (41%) but never in the guidance documents. CONCLUSION: Our study confirms a lack of clarity and standardization of test accuracy study design terms. There seems to be scope to reduce and harmonize the number of terms and still capture the design features that were deemed influential by those compiling the evidence reports. This should help decision makers in quickly identifying subgroups of included studies that should be weighted differently because their designs are more susceptible to bias.

The identification of surgical patients at higher risk of infection enables targeted allocation of critical care resources to improve patient mortality. The Complement cascade of the innate immune system is known to increase risk of infection if compromised and can be tested in vitro as a potential method for stratification of high-risk patients.
Existing assays of Complement function are laboratory bound and require trained personnel to operate and interpret. This thesis describes the development of novel immunoassays for C3, C5a, TCC and TNFα, based on a multiplex biosensor platform with a duty cycle of 0.05) from the serum data of 22 volunteers. The model and cohort data provide an initial estimate of effect size for future clinical studies investigating the ability of these Complement activation phenotypes to identify high-risk surgical patients or identify the onset of infection.

BACKGROUND: a previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment (MCI). OBJECTIVES: to update the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease (AD) dementia at follow-up. METHODS: a systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies. RESULTS: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56-100%, specificity 24-100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies. CONCLUSION: Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18F-FDG PET in people with MCI is needed.

AIMS/HYPOTHESIS: Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years. METHODS: This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate. RESULTS: a total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years' follow-up without treatment, p = 0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m2) at the time of genetic diagnosis, compared with individuals (n = 23/36) with an HbA1c >58 mmol/mol (>7.5%) (or 69 mmol/mol (>8.5%) at the time of genetic diagnosis. CONCLUSIONS/INTERPRETATION: in participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA1c.

BACKGROUND: Decisions about which subgroup of chronic hepatitis C (CHC) patients should be treated with direct acting anti-viral agents (DAAs) have economic importance due to high drug prices. Treat-all DAA strategies for CHC have gained acceptance despite high drug acquisition costs. However, there are also costs associated with the surveillance of CHC to determine a subgroup of patients with significant impairment. The aim of this systematic review was to describe the modelling methods used and summarise results in cost-effectiveness analyses (CEAs) of both CHC treatment with DAAs and surveillance of liver disease. METHODS: Electronic databases including Embase and Medline were searched from inception to May 2015. Eligible studies included models predicting costs and/or outcomes for interventions, surveillance, or management of people with CHC. Narrative and quantitative synthesis were conducted. Quality appraisal was conducted using validated checklists. The review was conducted following principles published by NHS Centre for Research and Dissemination. RESULTS: Forty-one CEAs met the eligibility criteria for the review; 37 evaluated an intervention and four evaluated surveillance strategies for targeting DAA treatment to those likely to gain most benefit. Included studies were of variable quality mostly due to reporting omissions. of the 37 CEAs, eight models that enabled comparative analysis were fully appraised and synthesized. These models provided non-unique cost-effectiveness estimates in a specific DAA comparison in a specific population defined in terms of genotype, prior treatment status, and presence or absence of cirrhosis. Marked heterogeneity in cost-effectiveness estimates was observed despite this stratification. Approximately half of the estimates suggested that DAAs were cost-effective considering a threshold of US$30,000 and 73% with threshold of US$50,000. Two models evaluating surveillance strategies suggested that treating all CHC patients regardless of the staging of liver disease could be cost-effective. CONCLUSIONS: CEAs of CHC treatments need to better account for variability in their estimates. This analysis suggested that there are still circumstances where DAAs are not cost-effective. Surveillance in place of a treat-all strategy may still need to be considered as an option for deploying DAAs, particularly where acquisition cost is at the limit of affordability for a given health system.

BACKGROUND: Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms. AIMS: We sought to evaluate the diagnostic accuracy of calprotectin to distinguish IBD from functional gut disorder in young adults in whom general practitioners (GPs) suspected IBD; including patients reporting gastrointestinal alarm symptoms. We hypothesised that calprotectin would reduce secondary care referrals and healthcare costs. METHODS: We undertook a prospective cohort study of 789 young adults (18-46 years old) presenting with gastrointestinal symptoms to 49 local general practices that had undergone calprotectin testing (1053 tests: between Jan 2014 and May 2016) because of suspected IBD. We considered calprotectin levels of ≥100 μg/g positive. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard. RESULTS: Overall, 39% (308/789) patients reported gastrointestinal alarm symptoms and 6% (50/789) tested patients were diagnosed with IBD. The positive and negative predictive values of calprotectin testing for distinguishing IBD from functional gut disorder in patients with gastrointestinal alarm symptoms were 50% (95% CI 36%-64%) and 98% (96%-100%): and in patients without gastrointestinal alarm symptoms were 27% (16%-41%) and 99% (98%-100%), respectively. We estimate savings of 279 referrals and £160 per patient. CONCLUSIONS: Calprotectin testing of young adults with suspected IBD in primary care accurately distinguishes IBD from functional gut disorder, even in patients with gastrointestinal alarm symptoms and reduces secondary care referrals and diagnostic healthcare costs.

IMPORTANCE: Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. OBJECTIVE: to develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. DESIGN: Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. FINDINGS: the systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. CONCLUSIONS AND RELEVANCE: the 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.

OBJECTIVE: This study reviewed the news media coverage of statins, seeking to identify specific trends or differences in viewpoint between media outlets and examine common themes. DESIGN: the study is a content analysis of the frequency and content of the reporting of statins in a selection of the British newsprint media. It involved an assessment of the number, timing and thematic content of articles followed by a discourse analysis examining the underlying narratives. The sample was the output of four UK newspapers, covering a broad-spectrum readership, over a six month timeframe 1 October 2013 to 31 March 2014. RESULTS: a total of 67 articles included reference to statins. The majority (39, 58%) were reporting or responding to publication of a clinical study. The ratio of negative to positive coverage was greater than 2:1 overall. In the more politically right-leaning newspapers, 67% of coverage was predominantly negative (30/45 articles); 32% in the more left-leaning papers (7/22 articles). Common themes were the perceived 'medicalisation' of the population; the balance between lifestyle modification and medical treatments in the primary prevention of heart disease; side effects and effectiveness of statins; pharmaceutical sponsorship and implications for the reliability of evidence; trust between the public and government, institutions, research organisations and the medical profession. CONCLUSIONS: Newsprint media coverage of statins was substantially influenced by the publication of national guidance and by coverage in the medical journals of clinical studies and comment. Statins received a predominantly negative portrayal, notably in the more right-leaning press. There were shared themes: concern about the balance between medication and lifestyle change in the primary prevention of heart disease; the adverse effects of treatment; and a questioning of the reliability of evidence from research institutions, scientists and clinicians in the light of their potential allegiances and funding.

BACKGROUND: a systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for identifying Lynch syndrome in patients with colorectal cancer (CRC). Unlike previous reviews, this was based on assessing MSI testing against best practice for the reference standard, and included CRC populations that were unselected, age-limited or high-risk for Lynch syndrome. METHODS: Single- and two-gate diagnostic test accuracy studies, or similar, were identified, assessed for inclusion, data extracted and quality appraised by two reviewers according to a pre-specified protocol. Sensitivity of MSI testing was estimated for all included studies. Specificity, likelihood ratios and predictive values were estimated for studies that were not based on high-risk samples. Narrative synthesis was conducted. RESULTS: Nine study samples were included. When MSI-Low results were considered to be negative, sensitivity estimates ranged from 67% (95% CI 47, 83) to 100% (95% CI 94, 100). Three studies contributed to estimates of both sensitivity and specificity, with specificity ranging from 61% (95% CI 57, 65), to 93% (95% CI 89, 95). Good sensitivity was achieved at the expense of specificity. When MSI-L was considered to be positive (effectively lowering the threshold for a positive index test result) sensitivity increased and specificity decreased. Between-study heterogeneity in both the MSI and reference standard testing, combined with the low number of studies contributing to both sensitivity and specificity estimates, precluded pooling by meta-analysis. CONCLUSIONS: MSI testing is an effective screening test for Lynch syndrome. However, there is significant uncertainty surrounding what balance of sensitivity and specificity will be achieved in clinical practice and how this relates to specific characteristics of the test (such as the panel of markers used or the thresholds used to denote a positive test).

BACKGROUND: Liver-related mortality has been increasing worldwide. We aimed to estimate the age-standardized mortality rates from viral hepatitis in Brazil. METHODS: the Brazilian National Death Registry was analyzed from 2008 to 2014. Viral hepatitis deaths were defined by the following ICD-10 codes in the death certificate: hepatitis a [B15.0; B15.9]; hepatitis B [B16.2; B16.9; B18.1]; hepatitis C [B17.1; B18.2]; hepatitis Delta [B16.0; B16.1; B18.0; B17.0] and other viral hepatitis [B17.2; B17.8; B18.8; B18.9; B19.0; B19.9]. Crude mortality rates were calculated by the ratio between total number of deaths and estimated population. Mortality rates were age-standardized by the direct method using the WHO standard population. RESULTS: Thirty four thousand ,nine hundred seventy eight deaths had viral hepatitis mentioned in their death certificate [65% male, aged 58 years, 73% associated with hepatitis C]. Age-standardized mortality rate (95% CI) due to viral hepatitis was 2.695 (2.667-2.724) deaths per 100,000 inhabitants: South region had the higher rates [3.997 (3.911-4.085)]. Mortality rates associated with hepatitis a and Delta were 0.032 (0.029-0.035) and 0.028 (0.025-0.031), respectively. Hepatitis C mortality rates were 4-fold higher than those associated with hepatitis B [1.964 (1.940-1.989) vs 0.500 (0.488-0.512)]. South region had the higher rates for hepatitis C [3.163 (3.087-3.241)] and North had the higher rates for hepatitis a [0.066 (0.049-0.087)], B [0.986 (0.918-1.058)] and Delta [0.220 (0.190-0.253)]. CONCLUSION: Viral hepatitis remains a major public health issue in Brazil. Mortality rates were not homogeneous across the country, suggesting that health policies should be customized according to geographical location.

BACKGROUND: Expert opinion is often sought to complement available information needed to inform model-based economic evaluations in health technology assessments. In this context, we define expert elicitation as the process of encoding expert opinion on a quantity of interest, together with associated uncertainty, as a probability distribution. When availability for face-to-face expert elicitation with a facilitator is limited, elicitation can be conducted remotely, overcoming challenges of finding an appropriate time to meet the expert and allowing access to experts situated too far away for practical face-to-face sessions. However, distance elicitation is associated with reduced response rates and limited assistance for the expert during the elicitation session. The aim of this study was to inform the development of a remote elicitation tool by exploring the influence of mode of elicitation on elicited beliefs. METHODS: an Excel-based tool (EXPLICIT) was developed to assist the elicitation session, including the preparation of the expert and recording of their responses. General practitioners (GPs) were invited to provide expert opinion about population alcohol consumption behaviours. They were randomised to complete the elicitation by either a face-to-face meeting or email. EXPLICIT was used in the elicitation sessions for both arms. RESULTS: Fifteen GPs completed the elicitation session. Those conducted by email were longer than the face-to-face sessions (13 min 30 s vs 10 min 26 s, p = 0.1) and the email-elicited estimates contained less uncertainty. However, the resulting aggregated distributions were comparable. CONCLUSIONS: EXPLICIT was useful in both facilitating the elicitation task and in obtaining expert opinion from experts via email. The findings support the opinion that remote, self-administered elicitation is a viable approach within the constraints of HTA to inform policy making, although poor response rates may be observed and additional time for individual sessions may be required.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

This is an economic model, developed in Microsoft Excel, for evaluating the cost-effectiveness (cost-utility) of different immunosuppressive regimens for adult kidney transplant recipients. This is the Assessment Group economic evaluation for the National Institute for Health and Care Excellence (NICE) Technology Appraisal guidance in development: Kidney transplantation (adults) - immunosuppressive therapy (review of TA 85) [ID456]. It produces the deterministic base case analysis for the model, and the probabilistic sensitivity analysis (PSA) as reported to NICE and in the monograph [Jones-Hughes T, Snowsill T, Haasova M, et al. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic evaluation. Health Technology Assessment 2016;20(62)]. It includes the specific PSA dataset upon which the results were based, but can be used to generate a new PSA dataset.

OBJECTIVES: to evaluate the accuracy of reduced-dose CT scans reconstructed using a new generation of model-based iterative reconstruction (MBIR) in the imaging of urinary tract stone disease, compared with a standard-dose CT using 30% adaptive statistical iterative reconstruction. METHODS: This single-institution prospective study recruited 125 patients presenting either with acute renal colic or for follow-up of known urinary tract stones. They underwent two immediately consecutive scans, one at standard dose settings and one at the lowest dose (highest noise index) the scanner would allow. The reduced-dose scans were reconstructed using both ASIR 30% and MBIR algorithms and reviewed independently by two radiologists. Objective and subjective image quality measures as well as diagnostic data were obtained. RESULTS: the reduced-dose MBIR scan was 100% concordant with the reference standard for the assessment of ureteric stones. It was extremely accurate at identifying calculi of 3 mm and above. The algorithm allowed a dose reduction of 58% without any loss of scan quality. CONCLUSIONS: a reduced-dose CT scan using MBIR is accurate in acute imaging for renal colic symptoms and for urolithiasis follow-up and allows a significant reduction in dose. KEY POINTS: • MBIR allows reduced CT dose with similar diagnostic accuracy • MBIR outperforms ASIR when used for the reconstruction of reduced-dose scans • MBIR can be used to accurately assess stones 3 mm and above.

BACKGROUND: Eradication of hepatitis C virus (HCV) using direct-acting agents (DAA) has been associated with a financial burden to health authorities worldwide. We aimed to evaluate the guideline-based treatment costs by DAAs from the perspective of the Brazilian Ministry of Health (BMoH). METHODS: the activity based costing method was used to estimate the cost for monitoring/treatment of genotype-1 (GT1) HCV patients by the following strategies: peg-interferon (PEG-IFN)/ribavirin (RBV) for 48 weeks, PEG-IFN/RBV plus boceprevir (BOC) or telaprevir (TEL) for 48 weeks, and sofosbuvir (SOF) plus daclastavir (DCV) or simeprevir (SIM) for 12 weeks. Costs were reported in United States Dollars without (US$) and with adjustment for purchasing power parity (PPP$). Drug costs were collected at the National Database of Health Prices and an overview of the literature was performed to assess effectiveness of SOF/DCV and SOF/SIM regimens in real-world cohorts. RESULTS: Treatment costs of GT1-HCV patients were PPP$ 43,176.28 (US$ 24,020.16) for PEG-IFN/RBV, PPP$ 71,196.03 (US$ 39,578.23) for PEG-IFN/RBV/BOC and PPP$ 86,250.33 (US$ 47,946.92) for PEG-IFN/RBV/TEL. Treatment by all-oral interferon-free regimens were the less expensive approach: PPP$ 19,761.72 (US$ 10,985.90) for SOF/DCV and PPP$ 21,590.91 (US$ 12,002.75) for SOF/SIM. The overview reported HCV eradication in up to 98% for SOF/DCV and 96% for SOF/SIM. CONCLUSION: Strategies with all oral interferon-free might lead to lower costs for management of GT1-HCV patients compared to IFN-based regimens in Brazil. This occurred mainly because of high discounts over international DAA prices due to negotiation between BMoH and pharmaceutical industries.

BACKGROUND: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. OBJECTIVES: to investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. REVIEW METHODS: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. RESULTS: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. LIMITATIONS: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. CONCLUSIONS: Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033879. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

© 2017 Elsevier B.V.Objectives to determine the diagnostic accuracy of lung nodule detection in thoracic CT using 2 reduced dose protocols comparing 3 available CT reconstruction algorithms (filtered back projection-FBP, adaptive statistical reconstruction-ASIR and model-based iterative reconstruction-MBIR) in a western population. Materials and methods a prospective single-center study recruited 98 patients with written consent. Standard dose (STD) thoracic CT followed by 2 reduced-dose protocols using automatic tube current modulation (RD1) and fixed tube current (RD2) were performed and reconstructed with FBP, ASIR and MBIR with subsequent diagnostic accuracy analysis for nodule detection. Results 108 solid nodules, 47 subsolid nodules and 89 purely calcified nodules were analyzed. RD1 was superior to RD2 for assessment of solid nodules ≤4 mm, and subsolid nodules ≤5 mm (p < 0.05). Deterioration of RD2 is correlated to patient's body mass index and least affected by MBIR. For solid nodules ≤4 mm, MBIR area under curve (AUC) for RD1 was 0.935/0.913 and AUC for RD2 was 0.739/0.739, for rater 1/rater2 respectively. For subsolid nodules ≤5 mm, MBIR AUC for RD1 was 0.971/0.986 and AUC for RD2 was 0.914/0.914, for rater 1/rater2 respectively. For calcified nodules excellent detection accuracy was maintained regardless of reconstruction algorithms with AUC >0.97 for both readers across all dose and reconstruction algorithms. Conclusions Diagnostic performance of lung nodule is affected by nodule size, protocol, reconstruction algorithm and patient's body habitus. The protocol in this study showed that RD1 was superior to RD2 for assessment of solid nodules ≤4 mm, and subsolid nodules ≤5 mm and deterioration of RD2 is related to patient's body mass index.

BACKGROUND: the most rigorous method for evaluating the effectiveness of diagnostic tests is through randomised trials that compare test-treatment interventions: complex interventions comprising episodes of testing, decision-making and treatment. The multi-staged nature of these interventions, combined with the need to relay diagnostic decision-making and treatment planning, has led researchers to hypothesise that test-treatment strategies may be very challenging to document. However, no reviews have yet examined the reporting quality of interventions used in test-treatment RCTs. In this study we evaluate the completeness of intervention descriptions in a systematically identified cohort of test-treatment RCTs. METHODS: We ascertained all test-treatment RCTs published 2004-2007, indexed in CENTRAL. Included trials randomized patients to diagnostic tests and measured patient outcomes after treatment. Two raters examined the completeness of test-treatment intervention descriptions in four components: 1) the test, 2) diagnostic decision-making, 3) management decision-making, 4) treatments. RESULTS: One hundred and three trials compared 105 control with 119 experimental interventions, most commonly in cardiovascular medicine (35, 34%), obstetrics and gynecology (17%), gastroenterology (14%) or orthopedics (10%). A broad range of tests were evaluated, including imaging (50, 42%), biochemical assays (21%) and clinical assessment (12%). Only five (5%) trials detailed all four components of experimental and control interventions, none of which also provided a complete care pathway diagram. Experimental arms were missing descriptions of tests, diagnostic-decision making, management planning and treatments (36%, 51%, 55% and 79% of trials respectively); control arms were missing the same details in 61%, 66%, 67% and 84% of trials. CONCLUSION: Reporting of test-treatment interventions is very poor, inadequate for understanding the results of these trials, and for comparing or translating results into clinical practice. Reporting needs to improve, with greater emphasis on describing the decision-making components of care pathways in both pragmatic and explanatory trials. Please see the companion paper to this article: http://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-016-0287-z.

Many abstracts of diagnostic accuracy studies are currently insufficiently informative. We extended the STARD (Standards for Reporting Diagnostic Accuracy) statement by developing a list of essential items that authors should consider when reporting diagnostic accuracy studies in journal or conference abstracts. After a literature review of published guidance for reporting biomedical studies, we identified 39 items potentially relevant to report in an abstract. We then selected essential items through a two round web based survey among the 85 members of the STARD Group, followed by discussions within an executive committee. Seventy three STARD Group members responded (86%), with 100% completion rate. STARD for Abstracts is a list of 11 quintessential items, to be reported in every abstract of a diagnostic accuracy study. We provide examples of complete reporting, and developed template text for writing informative abstracts.

Background Although health economic evaluations (HEEs) are increasingly common for therapeutic interventions, they appear to be rare for the use of risk prediction models (PMs). Objectives to evaluate the current state of HEEs of PMs by performing a comprehensive systematic review. Methods Four databases were searched for HEEs of PM-based strategies. Two reviewers independently selected eligible articles. A checklist was compiled to score items focusing on general characteristics of HEEs of PMs, model characteristics and quality of HEEs, evidence on PMs typically used in the HEEs, and the specific challenges in performing HEEs of PMs. Results After screening 791 abstracts, 171 full texts, and reference checking, 40 eligible HEEs evaluating 60 PMs were identified. In these HEEs, PM strategies were compared with current practice (n = 32; 80%), to other stratification methods for patient management (n = 19; 48%), to an extended PM (n = 9; 23%), or to alternative PMs (n = 5; 13%). The PMs guided decisions on treatment (n = 42; 70%), further testing (n = 18; 30%), or treatment prioritization (n = 4; 7%). For 36 (60%) PMs, only a single decision threshold was evaluated. Costs of risk prediction were ignored for 28 (46%) PMs. Uncertainty in outcomes was assessed using probabilistic sensitivity analyses in 22 (55%) HEEs. Conclusions Despite the huge number of PMs in the medical literature, HEE of PMs remains rare. In addition, we observed great variety in their quality and methodology, which may complicate interpretation of HEE results and implementation of PMs in practice. Guidance on HEE of PMs could encourage and standardize their application and enhance methodological quality, thereby improving adequate use of PM strategies.

BACKGROUND: There is a growing recognition for the need to expand our evidence base for the clinical effectiveness of diagnostic tests. Many international bodies are calling for diagnostic randomized controlled trials to provide the most rigorous evidence of impact to patient health. Although these so-called test-treatment RCTs are very challenging to undertake due to their methodological complexity, they have not been subjected to a systematic appraisal of their methodological quality. The extent to which these trials may be producing biased results therefore remains unknown. We set out to address this issue by conducting a methodological review of published test-treatment trials to determine how often they implement adequate methods to limit bias and safeguard the validity of results. METHODS: We ascertained all test-treatment RCTs published 2004-2007, indexed in CENTRAL, including RCTs which randomized patients to diagnostic tests and measured patient outcomes after treatment. Tests used for screening, monitoring or prognosis were excluded. We assessed adequacy of sequence generation, allocation concealment and intention-to-treat, appropriateness of primary analyses, blinding and reporting of power calculations, and extracted study characteristics including the primary outcome. RESULTS: One hundred three trials compared 105 control with 119 experimental interventions, and reported 150 primary outcomes. Randomization and allocation concealment were adequate in 57 and 37% of trials. Blinding was uncommon (patients 5%, clinicians 4%, outcome assessors 21%), as was an adequate intention-to-treat analysis (29%). Overall 101 of 103 trials (98%) were at risk of bias, as judged using standard Cochrane criteria. CONCLUSION: Test-treatment trials are particularly susceptible to attrition and inadequate primary analyses, lack of blinding and under-powering. These weaknesses pose much greater methodological and practical challenges to conducting reliable RCT evaluations of test-treatment strategies than standard treatment interventions. We suggest a cautious approach that first examines whether a test-treatment intervention can accommodate the methodological safeguards necessary to minimize bias, and highlight that test-treatment RCTs require different methods to ensure reliability than standard treatment trials. Please see the companion paper to this article: http://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-016-0286-0.

BACKGROUND: When data needed to inform parameters in decision models are lacking, formal elicitation of expert judgement can be used to characterise parameter uncertainty. Although numerous methods for eliciting expert opinion as probability distributions exist, there is little research to suggest whether one method is more useful than any other method. This study had three objectives: (i) to obtain subjective probability distributions characterising parameter uncertainty in the context of a health technology assessment; (ii) to compare two elicitation methods by eliciting the same parameters in different ways; (iii) to collect subjective preferences of the experts for the different elicitation methods used. METHODS: Twenty-seven clinical experts were invited to participate in an elicitation exercise to inform a published model-based cost-effectiveness analysis of alternative treatments for prostate cancer. Participants were individually asked to express their judgements as probability distributions using two different methods - the histogram and hybrid elicitation methods - presented in a random order. Individual distributions were mathematically aggregated across experts with and without weighting. The resulting combined distributions were used in the probabilistic analysis of the decision model and mean incremental cost-effectiveness ratios and the expected values of perfect information (EVPI) were calculated for each method, and compared with the original cost-effectiveness analysis. Scores on the ease of use of the two methods and the extent to which the probability distributions obtained from each method accurately reflected the expert's opinion were also recorded. RESULTS: Six experts completed the task. Mean ICERs from the probabilistic analysis ranged between £162,600-£175,500 per quality-adjusted life year (QALY) depending on the elicitation and weighting methods used. Compared to having no information, use of expert opinion decreased decision uncertainty: the EVPI value at the £30,000 per QALY threshold decreased by 74-86 % from the original cost-effectiveness analysis. Experts indicated that the histogram method was easier to use, but attributed a perception of more accuracy to the hybrid method. CONCLUSIONS: Inclusion of expert elicitation can decrease decision uncertainty. Here, choice of method did not affect the overall cost-effectiveness conclusions, but researchers intending to use expert elicitation need to be aware of the impact different methods could have.

BACKGROUND: Identification of permanent hearing impairment at the earliest possible age is crucial to maximise the development of speech and language. Universal newborn hearing screening identifies the majority of the 1 in 1000 children born with a hearing impairment, but later onset can occur at any time and there is no optimum time for further screening. A universal but non-standardised school entry screening (SES) programme is in place in many parts of the UK but its value is questioned. OBJECTIVES: to evaluate the diagnostic accuracy of hearing screening tests and the cost-effectiveness of the SES programme in the UK. DESIGN: Systematic review, case-control diagnostic accuracy study, comparison of routinely collected data for services with and without a SES programme, parental questionnaires, observation of practical implementation and cost-effectiveness modelling. SETTING: Second- and third-tier audiology services; community. PARTICIPANTS: Children aged 4-6 years and their parents. MAIN OUTCOME MEASURES: Diagnostic accuracy of two hearing screening devices, referral rate and source, yield, age at referral and cost per quality-adjusted life-year. RESULTS: the review of diagnostic accuracy studies concluded that research to date demonstrates marked variability in the design, methodological quality and results. The pure-tone screen (PTS) (Amplivox, Eynsham, UK) and HearCheck (HC) screener (Siemens, Frimley, UK) devices had high sensitivity (PTS ≥ 89%, HC ≥ 83%) and specificity (PTS ≥ 78%, HC ≥ 83%) for identifying hearing impairment. The rate of referral for hearing problems was 36% lower with SES (Nottingham) relative to no SES (Cambridge) [rate ratio 0.64, 95% confidence interval (CI) 0.59 to 0.69; p 

AIM: to assess the diagnostic accuracy of computed tomography coronary angiography (CTCA) using a combination of high-definition CT (HD-CTCA) and high level of reader experience, with invasive coronary angiography (ICA) as the reference standard, in high-risk patients for the investigation of coronary artery disease (CAD). MATERIALS AND METHODS: Three hundred high-risk patients underwent HD-CTCA and ICA. Independent experts evaluated the images for the presence of significant CAD, defined primarily as the presence of moderate (≥ 50%) stenosis and secondarily as the presence of severe (≥ 70%) stenosis in at least one coronary segment, in a blinded fashion. HD-CTCA was compared to ICA as the reference standard. RESULTS: No patients were excluded. Two hundred and six patients (69%) had moderate and 178 (59%) had severe stenosis in at least one vessel at ICA. The sensitivity, specificity, positive predictive value, and negative predictive value were 97.1%, 97.9%, 99% and 93.9% for moderate stenosis, and 98.9%, 93.4%, 95.7% and 98.3%, for severe stenosis, on a per-patient basis. CONCLUSION: the combination of HD-CTCA and experienced readers applied to a high-risk population, results in high diagnostic accuracy comparable to ICA. Modern generation CT systems in experienced hands might be considered for an expanded role.

OBJECTIVES: to evaluate the effectiveness of behaviour changing interventions targeting ordering of thyroid function tests. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Database up to May 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included studies evaluating the effectiveness of behaviour change interventions aiming to reduce ordering of thyroid function tests. Randomised controlled trials (RCTs), non-randomised controlled studies and before and after studies were included. There were no language restrictions. STUDY APPRAISAL AND SYNTHESIS METHODS: 2 reviewers independently screened all records identified by the electronic searches and reviewed the full text of any deemed potentially relevant. Study details were extracted from the included papers and their methodological quality assessed independently using a validated tool. Disagreements were resolved through discussion and arbitration by a third reviewer. Meta-analysis was not used. RESULTS: 27 studies (28 papers) were included. They evaluated a range of interventions including guidelines/protocols, changes to funding policy, education, decision aids, reminders and audit/feedback; often intervention types were combined. The most common outcome measured was the rate of test ordering, but the effect on appropriateness, test ordering patterns and cost were also measured. 4 studies were RCTs. The majority of the studies were of poor or moderate methodological quality. The interventions were variable and poorly reported. Only 4 studies reported unsuccessful interventions but there was no clear pattern to link effect and intervention type or other characteristics. CONCLUSIONS: the results suggest that behaviour change interventions are effective particularly in reducing the volume of thyroid function tests. However, due to the poor methodological quality and reporting of the studies, the likely presence of publication bias and the questionable relevance of some interventions to current day practice, we are unable to draw strong conclusions or recommend the implementation of specific intervention types. Further research is thus justified. TRIAL REGISTRATION NUMBER: CRD42014006192.

BACKGROUND: Peripheral venous cannulation is an everyday practice in hospitals, which many adults find painful. However, anaesthesia for cannulation is usually only offered to children. Inadequate pain relief is not only unpleasant for patients but may cause anxiety about further treatment and deter patients from seeking medical care in the future. The aim of this study is to discover the most effective local anaesthetic for adult peripheral venous cannulation and to find out how the pain of local anaesthetic application compares with that of unattenuated cannulation. METHODS: These aims are addressed through a systematic review, network meta-analysis and random-effects meta-analysis. Searching covered 12 databases including MEDLINE and EMBASE from 1990 to August 2015. The main included study design was RCTs. The primary outcome measure is self-reported pain, measured on a 100 mm visual analogue scale. RESULTS: the systematic review found 37 includable studies, 27 of which were suitable for network meta-analysis and two for random-effects meta-analysis. The results of the network meta-analysis indicate that none of the 17 anaesthetic considered had a very high probability of being the most effective when compared to each other; 2 % lidocaine had the highest probability (44 %). When the anaesthetics were compared to no treatment, the network meta-analysis showed that again 2 % lidocaine was estimated to be the most effective (mean difference -25.42 (95 % CI -32.25, -18.57). Other members of the 'caine' family were also estimated to be more effective than no treatment as were Ametop®, EMLA® and Rapydan® patch. The meta-analysis compared the pain of anaesthetic application with the unattenuated pain of cannulation. This found that all applications of local anaesthetic were less painful than cannulation without local anaesthetic. In particular a 1 % lidocaine injection was estimated to be -12.97 (95 % CI -15.71, -10.24) points (100 mm VAS) less painful than unattenuated cannulation. CONCLUSIONS: the pain of peripheral venous cannulation in adults can be successfully treated. The pain of application of any local anaesthetic is less than that of unattenuated cannulation. Local anaesthetic prior to cannulation should become normal practice and a marker of high quality care. PROTOCOL REGISTRATION: the protocol for the larger study was registered with PROSPERO no. CRD42012002093.

BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: to systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES: Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS: Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p 

OBJECTIVE: Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS: We studied 808 patients (79.5% of the eligible population)

Objective to understand the meaning of having a false-positive screening mammogram. Design Qualitative interview study. Methods Twenty-one women, who had experienced false-positive screening mammograms, took part in semi-structured interviews that were analysed with Interpretive Phenomenological Analysis. This research took place in the United Kingdom. Results the analysis revealed a wide range of response to having a false-positive mammogram, from nonchalance to extreme fear. These reactions come from the potential for the belief that one is healthy to be challenged by being recalled, as the worst is frequently assumed. For most, the image of the lesion on the X-ray brought the reality of this challenge into sharp focus, as they might soon discover they had breast cancer. Waiting, whether for the appointment, at the clinic or for biopsy results was considered the worst aspect of being recalled. Generally, the uncertainty was quickly resolved with the pronouncement of the 'all-clear', which brought considerable relief and the restoration of belief in the healthy self. However, for some, lack of information, contradictory information, or poor interpersonal communication meant that uncertainty about their health status lingered at least until their next normal screening mammogram. Mammography screening related anxiety lasted for up to 12 years. Conclusion Breast cancer screening produces a 'crisis of visibility'. Accepting the screening invitation is taking a risk that you may experience unnecessary stress, uncertainty, fear, anxiety, and physical pain. Not accepting the invitation is taking a risk that malignant disease will remain invisible. Statement of contribution What is already known on this subject? More than 50,000 women a year in England have a false-positive mammogram (FPM). Having an FPM can cause anxiety compared with a normal mammogram. The anxiety can last up to 35 months. What does this study add? Refocuses attention from the average response found in quantitative studies to the wide range of individual response. Gives insight into the nature of the anxiety of having FPMs. Highlights the role of uncertainty in provoking distress from an FPM.

BACKGROUND: Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. METHODS: a decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. RESULTS: all strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh the health benefits of testing, resulting in overall QALY loss. CONCLUSIONS: Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is predicted to be a cost-effective use of limited financial resources in England and Wales. Research is recommended into the cost-effectiveness of reflex testing for Lynch syndrome in other associated cancers and into the impact of prophylactic H-BSO on HRQoL.

BACKGROUND: in breast cancer patients, sentinel lymph node biopsy is carried out at the same time as the removal of the primary tumour to postoperatively test with histopathology for regional metastases in the sentinel lymph node. Those patients with positive test results are then operated on 2-4 weeks after primary surgery to remove the lymph nodes from the axilla (axillary lymph node dissection, ALND). New molecular tests RD-100i [one-step nucleic acid amplification (OSNA); based on messenger RNA amplification to identify the cytokeratin-19 (CK19) gene marker] (Sysmex, Norderstedt, Germany) and Metasin (using the CK19 and mammaglobin gene markers) (Cellular Pathology, Princess Alexandra Hospital NHS Trust, Harlow, UK) are intended to provide an intraoperative diagnosis, thereby avoiding the need for postoperative histopathology and, in positive cases, a second operation for ALND. OBJECTIVE: to evaluate the clinical effectiveness and cost-effectiveness of using OSNA and Metasin in the NHS in England for the intraoperative diagnosis of sentinel lymph nodes metastases, compared with postoperative histopathology, the current standard. DATA SOURCES: Electronic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cochrane Library and the Health Economic Evaluations Database as well as clinical trial registries, grey literature and conference proceedings were searched up to July 2012. REVIEW METHODS: a systematic review of the evidence was carried out using standard methods. Single-gate studies were used to estimate the accuracy of OSNA with histopathology as the reference standard. The cost-effectiveness analysis adapted an existing simulation model of the long-term costs and health implications of early breast cancer diagnostic outcomes. The model accounted for the costs of an extended first operation with intraoperative testing, the loss of health-related quality of life (disutility) from waiting for postoperative test results, disutility and costs of a second operation, and long-term costs and disutility from lymphoedema related to ALND, adjuvant therapy, locoregional recurrence and metastatic recurrence. RESULTS: a total of 724 references were identified in the searches, of which 17 studies assessing test accuracy were included in the review, 15 on OSNA and two on Metasin. Both Metasin studies were unpublished. OSNA sensitivity of 84.5% [95% confidence interval (CI) 74.7% to 91.0%] and specificity of 91.8% (95% CI 87.8% to 94.6%) for patient nodal status were estimated in a meta-analysis of five studies [unadjusted for tissue allocation bias (TAB)]. At these values and a 20% node-positive rate, OSNA resulted in lifetime discounted cost-savings of £498 and a quality-adjusted life-year (QALY) loss of 0.048 relative to histopathology, that is, £4324 saved per QALY lost. The most favourable plausible scenario for OSNA in terms of the node-positive rate (range 10-40%), diagnostic accuracy values (91.3% sensitivity and 94.2% specificity, from three reports that adjusted for TAB), the costs of histopathology, OSNA and second surgery, and long-term costs and utilities resulted in a maximum saving per QALY lost of £10,500; OSNA sensitivity and specificity would need to be ≥ 95% for this figure to be ≥ £20,000. LIMITATIONS: There is limited evidence on the diagnostic test accuracy of intraoperative tests. The quality of information on costs of resource utilisation during the diagnostic pathway is low and no evidence exists on the disutility of waiting for a second surgery. No comparative studies exist that report clinical outcomes of intraoperative diagnostic tests. These knowledge gaps have more influence on the decision than current uncertainty in the performance of postoperative histopathology in standard practice. CONCLUSIONS: One-step nucleic acid amplification is not cost-effective for the intraoperative diagnosis of sentinel lymph node metastases. OSNA is less accurate than histopathology and the consequent loss of health benefits in this patient group is not compensated for by health gains elsewhere in the health system that may be obtained with the cost-savings made. The evidence on Metasin is insufficient to evaluate its cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002889. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

OBJECTIVE: Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7-15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes. DESIGN: Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C-peptide). DATA SOURCES: 14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide). ELIGIBILITY CRITERIA: Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin. RESULTS: 10,917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being

Chronic hepatitis C remains one of the main causes of chronic liver disease worldwide and presents a variable natural history ranging from minimal changes to advanced fibrosis and cirrhosis and its complications, such as development of hepatocellular carcinoma. Approximately, 1.45 million people are estimated to be infected by HCV in Brazil representing a major public health issue. The aim of this paper was to review the epidemiology and management of chronic hepatitis C from a Brazilian perspective. The management of chronic hepatitis C has been challenged by the use of noninvasive methods to stage liver fibrosis as an alternative to liver biopsy and the high cost of new interferon-free antiviral treatments. Moreover, the need of cost-effectiveness analysis in hepatitis C and the recent changes in treatment protocols were discussed.

OBJECTIVE: to obtain summary estimates of the accuracy of a single baseline measurement of the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) for the diagnosis of acute myocardial infarction in patients presenting to the emergency department. DESIGN: Systematic review and meta-analysis of diagnostic test accuracy studies. DATA SOURCES: Medline, Embase, and other relevant electronic databases were searched for papers published between January 2006 and December 2013. STUDY SELECTION: Studies were included if they evaluated the diagnostic accuracy of a single baseline measurement of Elecsys Troponin T high-sensitive assay for the diagnosis of acute myocardial infarction in patients presenting to the emergency department with suspected acute coronary syndrome. STUDY APPRAISAL AND DATA SYNTHESIS: the first author screened all titles and abstracts identified through the searches and selected all potentially relevant papers. The screening of the full texts, the data extraction, and the methodological quality assessment, using the adapted QUADAS-2 tool, were conducted independently by two reviewers with disagreements being resolved through discussion or arbitration. If appropriate, meta-analysis was conducted using the hierarchical bivariate model. RESULTS: Twenty three studies reported the performance of the evaluated assay at presentation. The results for 14 ng/L and 3-5 ng/L cut-off values were pooled separately. At 14 ng/L (20 papers), the summary sensitivity was 89.5% (95% confidence interval 86.3% to 92.1%) and the summary specificity was 77.1% (68.7% to 83.7%). At 3-5 ng/L (six papers), the summary sensitivity was 97.4% (94.9% to 98.7%) and the summary specificity was 42.4% (31.2% to 54.5%). This means that if 21 of 100 consecutive patients have the target condition (21%, the median prevalence across the studies), 2 (95% confidence interval 2 to 3) of 21 patients with acute myocardial infarction will be missed (false negatives) if 14 ng/L is used as a cut-off value and 18 (13 to 25) of 79 patients without acute myocardial infarction will test positive (false positives). If the 3-5 ng/L cut-off value is used,

Transient elastography (TE) based on liver stiffness measurement (LSM) is one of the most validated noninvasive methods for liver fibrosis staging in patients with chronic liver diseases. This method is painless, has no potential complications, is rapid (100 exams), in a 3-hour fasting status, and its results should be handled by specialist clinicians that are aware of the limitations of this method.

OBJECTIVE: to evaluate whether clinicians differ in how they evaluate and interpret diagnostic test information. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE and PsycINFO from inception to September 2013; bibliographies of retrieved studies, experts and citation search of key included studies. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Primary studies that provided information on the accuracy of any diagnostic test (eg, sensitivity, specificity, likelihood ratios) to health professionals and that reported outcomes relating to their understanding of information on or implications of test accuracy. RESULTS: We included 24 studies. 6 assessed ability to define accuracy metrics: health professionals were less likely to identify the correct definition of likelihood ratios than of sensitivity and specificity. -25 studies assessed Bayesian reasoning. Most assessed the influence of a positive test result on the probability of disease: they generally found health professionals' estimation of post-test probability to be poor, with a tendency to overestimation. 3 studies found that approaches based on likelihood ratios resulted in more accurate estimates of post-test probability than approaches based on estimates of sensitivity and specificity alone, while 3 found less accurate estimates. 5 studies found that presenting natural frequencies rather than probabilities improved post-test probability estimation and speed of calculations. CONCLUSIONS: Commonly used measures of test accuracy are poorly understood by health professionals. Reporting test accuracy using natural frequencies and visual aids may facilitate improved understanding and better estimation of the post-test probability of disease.

OBJECTIVES: to gain an understanding of the views of women with false-positive screening mammograms of screening recall services, their ideas for service improvements and how these compare with current UK guidelines. METHODS: Inductive qualitative content analysis of semistructured interviews of 21 women who had false-positive screening mammograms. These were then compared with UK National Health Service (NHS) guidelines. RESULTS: Participants' concerns about mammography screening recall services focused on issues of communication and choice. Many of the issues raised indicated that the 1998 NHS Breast Screening Programme guidelines on improving the quality of written information sent to women who are recalled, had not been fully implemented. This included being told a clear reason for recall, who may attend with them, the length of appointment, who they will see and what tests will be carried out. Additionally women voiced a need for: reassurance that a swift appointment did not imply they had cancer; choice about invasive assessment or watchful waiting; the offer of a follow-up mammogram for those uncertain about the validity of their all-clear and an extension of the role of the clinical nurse specialist, outlined in the 2012 NHS Breast Screening Programme (NHSBSP) guidelines, to include availability at the clinic after the all-clear for women with false-positive mammograms. CONCLUSIONS: it is time the NHSBSP 1998 recall information guidelines were fully implemented. Additionally, the further suggestions from this research, including extending the role of the clinical nurses from the 2012 NHSBSP guidelines, should be considered. These actions have the potential to reduce the anxiety of being recalled.

Rationale and Objectives: to compare image quality on computed tomographic colonography (CTC) acquired at standard dose (STD) and low dose (LD) using filtered-back projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction (MBIR) techniques. Materials and Methods: a total of 65 symptomatic patients were prospectively enrolled for the study and underwent STD and LD CTC with filtered-back projection, adaptive statistical iterative reconstruction, and MBIR to allow direct per-patient comparison. Objective image noise, subjective image analyses, and polyp detection were assessed. Results: Objective image noise analysis demonstrates significant noise reduction using MBIR technique (P.05). Doses: LD (dose-length product, 257.7), STD (dose-length product, 483.6). Conclusions: LD MBIR CTC objectively shows improved image noise using parameters in our study. Subjectively, image quality is maintained. Polyp detection shows no significant difference but because of small numbers needs further validation. Average dose reduction of 47% can be achieved. This study confirms feasibility of using MBIR in this context of CTC in symptomatic population.

Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies.

This is the protocol for a review and there is no abstract. The objectives are as follows: to investigate the accuracy of hearing screening tests, individually or in combination, used in children at or around school entry age (four to eight years old), excluding children with known hearing loss and those unable to perform the test due to significant developmental delay. A secondary objective is to assess the relative diagnostic accuracy of different hearing screening tests when directly compared (within the same study).

Background: Lateral elbow tendinopathy (LET) is a common complaint causing characteristic pain in the lateral elbow and upper forearm, and tenderness of the forearm extensor muscles. It is thought to be an overuse injury and can have a major impact on the patient's social and professional life. The condition is challenging to treat and prone to recurrent episodes. The average duration of a typical episode ranges from 6 to 24 months, with most (89%) reporting recovery by 1 year.Objectives: This systematic review aims to summarise the evidence concerning the clinical effectiveness and cost-effectiveness of conservative interventions for LET.Data sources: a comprehensive search was conducted from database inception to 2012 in a range of databases including MEDLINE, EMBASE and Cochrane Databases.Methods and outcomes: We conducted an overview of systematic reviews to summarise the current evidence concerning the clinical effectiveness and a systematic review for the cost-effectiveness of conservative interventions for LET. We identified additional randomised controlled trials (RCTs) that could contribute further evidence to existing systematic reviews. We searched MEDLINE, EMBASE, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library and other important databases from inception to January 2013.Results: a total of 29 systematic reviews published since 2003 matched our inclusion criteria. These were quality appraised using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist; five were considered high quality and evaluated using a Grading of Recommendations, Assessment, Development and Evaluation approach. A total of 36 RCTs were identified that were not included in a systematic review and 29 RCTs were identified that had only been evaluated in an included systematic review of intermediate/low quality. These were then mapped to existing systematic reviews where further evidence could provide updates. Two economic evaluations were identified.Limitations: the summary of findings from the review was based only on high-quality evidence (scoring of > 5 AMSTAR). Other limitations were that identified RCTs were not quality appraised and dichotomous outcomes were also not considered. Economic evaluations took effectiveness estimates from trials that had small sample sizes leading to uncertainty surrounding the effect sizes reported. This, in turn, led to uncertainty of the reported cost-effectiveness and, as such, no robust recommendations could be made in this respect. Conclusions: Clinical effectiveness evidence from the high-quality systematic reviews identified in this overview continues to suggest uncertainty as to the effectiveness of many conservative interventions for the treatment of LET. Although new RCT evidence has been identified with either placebo or active controls, there is uncertainty as to the size of effects reported within them because of the small sample size. Conclusions regarding cost-effectiveness are also unclear. We consider that, although updated or new systematic reviews may also be of value, the primary focus of future work should be on conducting large-scale, good-quality clinical trials using a core set of outcome measures (for defined time points) and appropriate follow-up. Subgroup analysis of existing RCT data may be beneficial to ascertain whether or not certain patient groups are more likely to respond to treatments. Study registration: This study is registered as PROSPERO CRD42013003593.

OBJECTIVES: Diagnostic test accuracy studies and meta-analyses may, in some cases, provide estimates that are highly improbable in practice; tailored meta-analysis provides a potential solution. To investigate the utility of tailored meta-analysis in synthesizing estimates of a test's accuracy compared with conventional meta-analysis for three case examples. STUDY DESIGN AND SETTING: MEDLINE, Embase, and CINAHL were searched for relevant studies, and routine data were collected on the test positive rate and disease prevalence from the case settings to define an applicable region for each setting. Three cases were evaluated: mammography in the NHS Breast Screening Programme, Patient Health Questionnaire-9 to screen for depression in general practice, and Centor's criteria used to diagnose group a β-hemolytic streptococcus in general practice. For conventional meta-analysis, studies were selected using standard systematic review methods; for tailored meta-analysis, this selection was refined to those with results compatible with the applicable region for the setting. RESULTS: in each example, studies were excluded as a result of incorporating an applicable region for the setting. Comparing tailored with conventional meta-analysis, the positive likelihood ratios (with 95% confidence intervals in brackets) were 36.5 (23.0, 57.9) and 19.8 (12.8, 30.9), respectively, for mammography and 4.89 (2.02, 11.8) and 2.35 (1.51, 3.67), respectively, for Centor's criteria. This had the effect of increasing the positive predictive value from 17% to 27% for mammography and 23% to 38% for Centor's criteria. CONCLUSION: Tailored meta-analysis has the potential to provide a plausible estimate for a test's accuracy, which is specific to the practice setting. When compared with conventional meta-analysis, the difference may, in some cases, be sufficient to lead to different decisions on patient management.

Objectives the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group developed an approach to assess the quality of evidence of diagnostic tests. Its use in Cochrane diagnostic test accuracy reviews is new. We applied this approach to three Cochrane reviews with the aim of better understanding the application of the GRADE criteria to such reviews. Study Design and Setting We selected reviews to achieve clinical and methodological diversities. At least three assessors independently assessed each review according to the GRADE criteria of risk of bias, indirectness, imprecision, inconsistency, and publication bias. Two teleconferences were held to share experiences. Results for the interpretation of the GRADE criteria, it made a difference whether assessors looked at the evidence from a patient-important outcome perspective or from a test accuracy standpoint. GRADE criteria such as inconsistency, imprecision, and publication bias were challenging to apply as was the assessment of comparative test accuracy reviews. Conclusion the perspective from which evidence is graded can influence judgments about quality. Guidance on application of GRADE to comparative test reviews and on the GRADE criteria of inconsistency, imprecision, and publication bias will facilitate the operationalization of GRADE for diagnostics. © 2014 the Authors. Published by Elsevier Inc. All rights reserved.

OBJECTIVES: to determine a plausible estimate for a test's performance in a specific setting using a new method for selecting studies. STUDY DESIGN AND SETTING: it is shown how routine data from practice may be used to define an "applicable region" for studies in receiver operating characteristic space. After qualitative appraisal, studies are selected based on the probability that their study accuracy estimates arose from parameters lying in this applicable region. Three methods for calculating these probabilities are developed and used to tailor the selection of studies for meta-analysis. The Pap test applied to the UK National Health Service (NHS) Cervical Screening Programme provides a case example. RESULTS: the meta-analysis for the Pap test included 68 studies, but at most 17 studies were considered applicable to the NHS. For conventional meta-analysis, the sensitivity and specificity (with 95% confidence intervals) were estimated to be 72.8% (65.8, 78.8) and 75.4% (68.1, 81.5) compared with 50.9% (35.8, 66.0) and 98.0% (95.4, 99.1) from tailored meta-analysis using a binomial method for selection. Thus, for a cervical intraepithelial neoplasia (CIN) 1 prevalence of 2.2%, the post-test probability for CIN 1 would increase from 6.2% to 36.6% between the two methods of meta-analysis. CONCLUSION: Tailored meta-analysis provides a method for augmenting study selection based on the study's applicability to a setting. As such, the summary estimate is more likely to be plausible for a setting and could improve diagnostic prediction in practice.

AIMS: Defining responders to glucose lowering therapy can be important for both clinical care and for the development of a stratified approach to diabetes management. Response is commonly defined by either HbA1c change after treatment or whether a target HbA1c is achieved. We aimed to determine the extent to which the individuals identified as responders and non-responders to glucose lowering therapy, and their characteristics, depend on the response definition chosen. METHODS: We prospectively studied 230 participants commencing GLP-1 agonist therapy. We assessed participant characteristics at baseline and repeated HbA1c after 3 months treatment. We defined responders (best quartile of response) based on HbA1c change or HbA1c achieved. We assessed the extent to which these methods identified the same individuals and how this affected the baseline characteristics associated with treatment response. RESULTS: Different definitions of response identified different participants. Only 39% of responders by one definition were also good responders by the other. Characteristics associated with good response depend on the response definition chosen: good response by HbA1c achieved was associated with low baseline HbA1c (p

OBJECTIVES: the objective of this study was to compare image quality (objective and subjective parameters) and confidence in lesion detection between 3 image reconstruction algorithms in computed tomographic (CT) examinations of the abdomen/pelvis. MATERIALS AND METHODS: This prospective institutional review board-approved study included 65 patients (mean [SD] age, 71.3 ± 9 years; mean [SD] body mass index, 24.4 [4.8] kg) who underwent routine CT examinations of the abdomen/pelvis followed immediately by 2 low-dose scans. Raw data sets were reconstructed by using filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and a model-based iterative reconstruction (MBIR). Measurements of objective noise and CT numbers were compared using repeated-measures analysis of variance. Six subjective image quality parameters were scored. Diagnostic confidence and accuracy in detection of various elementary lesions were performed. RESULTS: Objectively, mean image noise for MBIR was significantly superior at all dose levels (P < 0.001). Subjectively, standard-dose ASIR and low-dose MBIR scans were better than standard-dose FBP scan in all parameters assessed (P < 0.05). Low-dose MBIR scans were comparable with standard-dose ASIR scans in all parameters except at noise index of 70 (approximately 85% dose reduction), where, in this case, the detection of liver lesions less than 5 mm were rated inferior (P < 0.05) with diagnostic accuracy reducing to 77.4%. CONCLUSIONS: Low-dose MBIR scan shows superior objective noise reduction compared with standard-dose FBP and ASIR. Subjectively, low-dose MBIR scans at 76% dose reduction were also superior compared with standard-dose FBP and ASIR. However, at dose reductions of 85%, small liver lesions may be missed.

This is the protocol for a review and there is no abstract. The objectives are as follows: to determine the diagnostic accuracy of the plasma and CSF Abeta42 index tests for distinguishing Alzheimer's disease dementia from each of the other forms of dementia in people who meet the general criteria for a dementia syndrome. To investigate the heterogeneity of test accuracy in the included studies. We expect that heterogeneity will be likely and that it will be an important component of the review. The potential sources of heterogeneity, which will be used as a framework for the investigation of heterogeneity, include target population, index test, target disorder and study quality and are detailed in the analysis section.

Objective: to provide guidance on standards for reporting studies of diagnostic test accuracy for dementia disorders. Methods: an international consensus process on reporting standards in dementia and cognitive impairment (STARDdem) was established, focusing on studies presenting data from which sensitivity and specificity were reported or could be derived. A working group led the initiative through 4 rounds of consensus work, using a modified Delphi process and culminating in a face-to-face consensus meeting in October 2012. The aim of this process was to agree on how best to supplement the generic standards of the STARD statement to enhance their utility and encourage their use in dementia research. Results: More than 200 comments were received during the wider consultation rounds. The areas at most risk of inadequate reporting were identified and a set of dementia-specific recommendations to supplement the STARD guidance were developed, including better reporting of patient selection, the reference standard used, avoidance of circularity, and reporting of test-retest reliability. Conclusion: STARDdem is an implementation of the STARD statement in which the original checklist is elaborated and supplemented with guidance pertinent to studies of cognitive disorders. Its adoption is expected to increase transparency, enable more effective evaluation of diagnostic tests in Alzheimer disease and dementia, contribute to greater adherence to methodologic standards, and advance the development of Alzheimer biomarkers. © 2014 American Academy of Neurology.

BACKGROUND: Breast cancer is the most common cancer in the UK. GPs are encouraged to refer all women whose symptoms may represent cancer, rather than selecting those at highest risk. AIM: to identify and quantify features of breast cancer in primary care. DESIGN AND SETTING: a UK case-control study using the Clinical Practice Research Database (CPRD). METHOD: Possible features of breast cancer were identified in the year before diagnosis, and odds ratios calculated using conditional logistic regression. Positive predictive values (PPVs) were estimated for consulting women. RESULTS: a total of 3994 women aged ≥40 years with breast cancer between 2000 and 2009, and 16 873 age-, sex-, and practice-matched controls were studied. Median age at diagnosis was 63 years (interquartile range 55-74 years). Four features were significantly associated with breast cancer: breast lump (odds ratio [OR] 110; 95% confidence interval [CI] = I88 to 150), breast pain (OR = 4.2; 95% CI = 3.0 to 6.0), nipple retraction (OR = 26; 95% CI = 10 to 64), nipple discharge (OR = 19; 95% CI = 8.6 to 41): all P-values 70 years. PPVs were lower in women who also reported breast pain. CONCLUSION: Generally, the figures support current referral practice. However, the low likelihood of cancer for all the non-lump symptoms means that the current guidance recommends investigation for possible cancer at a more liberal risk threshold than for other cancers. Although supported by patients, this may not meet current NHS criteria for cost-benefit.

This is the protocol for a review and there is no abstract. The objectives are as follows: to determine the diagnostic accuracy of the PIB-PET index test at various thresholds for detecting participants with mild cognitive impairment at baseline who would clinically convert to Alzheimers disease dementia or other forms of dementia at follow-up. To investigate heterogeneity of test accuracy in the included studies.

BACKGROUND: Cochrane reviews are one of the best known and most trusted sources of evidence-based information in health care. While steps have been taken to make Cochrane intervention reviews accessible to a diverse readership, little is known about the accessibility of the newcomer to the Cochrane library: diagnostic test accuracy reviews (DTARs). The current qualitative study explored how healthcare decision makers, who varied in their knowledge and experience with test accuracy research and systematic reviews, read and made sense of DTARs. METHODS: a purposive sample of clinicians, researchers and policy makers (n = 21) took part in a series of think-aloud interviews, using as interview material the first three DTARs published in the Cochrane library. Thematic qualitative analysis of the transcripts was carried out to identify patterns in participants' 'reading' and interpretation of the reviews and the difficulties they encountered. RESULTS: Participants unfamiliar with the design and methodology of DTARs found the reviews largely inaccessible and experienced a range of difficulties stemming mainly from the mismatch between background knowledge and level of explanation provided in the text. Experience with systematic reviews of interventions did not guarantee better understanding and, in some cases, led to confusion and misinterpretation. These difficulties were further exacerbated by poor layout and presentation, which affected even those with relatively good knowledge of DTARs and had a negative impact not only on their understanding of the reviews but also on their motivation to engage with the text. Comparison between the readings of the three reviews showed that more accessible presentation, such as presenting the results as natural frequencies, significantly increased participants' understanding. CONCLUSIONS: the study demonstrates that authors and editors should pay more attention to the presentation as well as the content of Cochrane DTARs, especially if the reports are aimed at readers with various levels of background knowledge and experience. It also raises the question as to the anticipated target audience of the reports and suggests that different groups of healthcare decision-makers may require different modes of presentation.

Objective: to carry out a systematic review of recently published large-scale observational studies assessing the effects of red blood cell transfusion (RBCT) on mortality, with particular emphasis on the statistical methods used to adjust for confounding. Given the limited number of randomised trials of the efficacy of RBCT, clinicians often use evidence from observational studies. However, confounding factors, for example, individuals receiving blood generally being sicker than those who do not, make their interpretation challenging. Design: Systematic review. Information sources: We searched MEDLINE and EMBASE for studies published from 1 January 2006 to 31 December 2010. Eligibility criteria for included studies: We included prospective cohort, case-control studies or retrospective analyses of databases or disease registers where the effect of risk factors for mortality or survival was examined. Studies must have included more than 1000 participants receiving RBCT for any cause. We assessed the effects of RBCT versus no RBCT and different volumes and age of RBCT. Results: -32 studies were included in the review; 23 assessed the effects of RBCT versus no RBCT; 5 assessed different volumes and 4 older versus newer RBCT. There was a considerable variability in the patient populations, study designs and level of statistical adjustment. Overall, most studies showed a higher rate of mortality when comparing patients who received RBCT with those who did not, even when these rates were adjusted for confounding; the majority of these increases were statistically significant. The same pattern was observed in studies where protection from bias was likely to be greater, such as prospective studies. Conclusions: Recent observational studies do show a consistently adverse effect of RBCT on mortality. Whether this is a true effect remains uncertain as it is possible that even the best conducted adjustments cannot completely eliminate the impact of confounding.

OBJECTIVES: to estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service. METHODS: an "an area under the curve" cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources. RESULTS: Patients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan. Panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of £95,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at £187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at £88,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money. CONCLUSIONS: all three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries.

Objectives: to describe the development process for defining an appropriate model structure for the economic evaluation of test-treatment strategies for patients with monogenic diabetes (caused by mutations in the GCK, HNF1A or HNF4A genes). Design: Experts were consulted to identify and define realistic test-treatment strategies and care pathways. A systematic assessment of published diabetes models was undertaken to inform the model structure. Setting: National Health Service in England and Wales. Participants: Experts in monogenic diabetes whose collective expertise spans the length of the patient care pathway. Primary and secondary outcomes: a defined model structure, including the test-treatment strategies, and the selection of a published diabetes model appropriate for the economic evaluation of strategies to identify patients with monogenic diabetes. Results: Five monogenic diabetes test-treatment strategies were defined: no testing of any kind, referral for genetic testing based on clinical features as noted by clinicians, referral for genetic testing based on the results of a clinical prediction model, referral for genetic testing based on the results of biochemical and immunological tests, referral for genetic testing for all patients with a diagnosis of diabetes under the age of 30 years. The systematic assessment of diabetes models identified the IMS CORE Diabetes Model (IMS CDM) as a good candidate for modelling the long-term outcomes and costs of the test-treatment strategies for monogenic diabetes. The short-term test-treatment events will be modelled using a decision tree which will feed into the IMS CDM. Conclusions: Defining a model structure for any economic evaluation requires decisions to be made. Expert consultation and the explicit use of critical appraisal can inform these decisions. Although arbitrary choices have still been made, decision modelling allows investigation into such choices and the impact of assumptions that have to be made due to a lack of data.

This is the protocol for a review and there is no abstract. The objectives are as follows: This review has two primary objectives. Objective A: to estimate the accuracy of DAT imaging for the diagnosis of dementia with Lewy bodies (DLB) in patients with dementia in secondary care.Objective B: to assess the value of DAT imaging in clinical practice by estimating the accuracy of DAT imaging for the diagnosis of DLB in secondary care patients with a pre-existing suspicion of DLB on the basis of a clinical work-up. The secondary objective is to use subgroup analyses to investigate the following potential sources of heterogeneity. (a) Age of participants. (b) Severity of dementia. The performance of the index test itself may vary with dementia severity. For objective B, since the performance of the clinical criteria may also depend on the severity of dementia, the 'added value' to be obtained from the index test may vary significantly. (c) for objective B, diagnostic status at inclusion (possible or probable DLB, or both). (d) DAT imaging method (SPECT or PET, ligand).

OBJECTIVES: the aim of this study was to describe the evolution of a cost-utility model used to inform the UK National Institute for Health and Clinical Excellence's (NICE) most recent decisions on the cost-utility of drug treatments for Alzheimer's disease (AD), and to explore the impact of structural assumptions on the cost-utility results. METHODS: Changes informed by noted limitations of the decision model used in NICE's previous decisions (in 2006) were made cumulatively to the original decision model for donepezil compared with best supportive care (for patients with mild to moderate AD). Deterministic and probabilistic analyses were undertaken for each cumulative change of the model. The expected value of perfect information (EVPI) of parameter estimates and structural assumptions was also calculated. RESULTS: Cumulative changes to the decision model highlighted how the results of the original model (incremental cost-effectiveness ratio of £81,000 per quality-adjusted life-year gained) related to those of the new model (where donepezil was estimated to be cost-saving), mainly due to uncertainty in the incremental cost of donepezil treatment over best supportive care (ranging from -£600 to £3,000 per patient). The partial EVPI analysis reflected this finding where further information on treatment discontinuations and cost parameter estimates were shown to be valuable in terms of reducing decision uncertainty. CONCLUSIONS: Assessing the evolution of the cost-utility model helped to identify and explore structural differences between cohort-based models and is likely to be useful for decision models in other disease areas. This approach makes the structural uncertainty explicit, forcing decision makers to address structural uncertainty in addition to parameter uncertainty.

INTRODUCTION: in 2007 the National Institute of Health and Clinical Excellence (NICE) restricted the use of acetylcholinesterase inhibitors and memantine. METHODS: we conducted a health technology assessment (HTA) of the effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of AD to re-consider and up-date the evidence base used to inform the 2007 NICE decision. The systematic review of effectiveness targeted randomised controlled trials. A comprehensive search, including MEDLINE, Embase and the Cochrane Library, was conducted from January 2004 to March 2010. All key review steps were done by two reviewers. Random effects meta-analysis was conducted. The cost-effectiveness was assessed using a cohort-based model with three health states: pre-institutionalised, institutionalised and dead. The perspective was NHS and Personal Social Services and the cost year 2009. RESULTS: confidence about the size and statistical significance of the estimates of effect of galantamine, rivastigmine and memantine improved on function and global impact in particular. Cost-effectiveness also changed. For donepezil, galantamine and rivastigmine, the incremental cost per quality-adjusted life year (QALY) in 2004 was above £50,000; in 2010 the same drugs 'dominated' best supportive care (improved clinical outcome at reduced cost). This was primarily because of changes in the modelled costs of introducing the drugs. For memantine, the cost-effectiveness also improved from a range of £37-53,000 per QALY gained to a base-case of £32,000. CONCLUSION: there has been a change in the evidence base between 2004 and 2010 consistent with the change in NICE guidance. Further evolution in cost-effectiveness estimates is possible particularly if there are changes in drug prices.

BACKGROUND: Elicitation is a technique that can be used to obtain probability distribution from experts about unknown quantities. We conducted a methodology review of reports where probability distributions had been elicited from experts to be used in model-based health technology assessments. METHODS: Databases including MEDLINE, EMBASE and the CRD database were searched from inception to April 2013. Reference lists were checked and citation mapping was also used. Studies describing their approach to the elicitation of probability distributions were included. Data was abstracted on pre-defined aspects of the elicitation technique. Reports were critically appraised on their consideration of the validity, reliability and feasibility of the elicitation exercise. RESULTS: Fourteen articles were included. Across these studies, the most marked features were heterogeneity in elicitation approach and failure to report key aspects of the elicitation method. The most frequently used approaches to elicitation were the histogram technique and the bisection method. Only three papers explicitly considered the validity, reliability and feasibility of the elicitation exercises. CONCLUSION: Judged by the studies identified in the review, reports of expert elicitation are insufficient in detail and this impacts on the perceived usability of expert-elicited probability distributions. In this context, the wider credibility of elicitation will only be improved by better reporting and greater standardisation of approach. Until then, the advantage of eliciting probability distributions from experts may be lost.

This is the protocol for a review and there is no abstract. The objectives are as follows: to determine the cross-sectional diagnostic accuracy of [index test] at various thresholds for ADD and other dementias [target condition] in [target population].ORTo determine the accuracy of [index test] at various thresholds for diagnosing ADD and other dementias [target condition] in [target population] after a follow-up period (delayed-verification studies).To investigate the heterogeneity of test accuracy in the included studies.To highlight the quality and quantity of research evidence available on the effectiveness of the index test in the target population.To identify gaps in the evidence and determine where further research is required.

OBJECTIVES: to identify the psychological effects of false-positive screening mammograms in the UK. METHODS: Systematic review of all controlled studies and qualitative studies of women with a false-positive screening mammogram. The control group participants had normal mammograms. All psychological outcomes including returning for routine screening were permitted. All studies had a narrative synthesis. RESULTS: the searches returned seven includable studies (7/4423). Heterogeneity was such that meta-analysis was not possible. Studies using disease-specific measures found that, compared to normal results, there could be enduring psychological distress that lasted up to 3 years; the level of distress was related to the degree of invasiveness of the assessment. At 3 years the relative risks were, further mammography, 1.28 (95% CI 0.82 to 2.00), fine needle aspiration 1.80 (95% CI 1.17 to 2.77), biopsy 2.07 (95% CI 1.22 to 3.52) and early recall 1.82 (95% CI 1.22 to 2.72). Studies that used generic measures of anxiety and depression found no such impact up to 3 months after screening. Evidence suggests that women with false-positive mammograms have an increased likelihood of failing to reattend for routine screening, relative risk 0.97 (95% CI 0.96 to 0.98) compared with women with normal mammograms. CONCLUSIONS: Having a false-positive screening mammogram can cause breast cancer-specific distress for up to 3 years. The degree of distress is related to the invasiveness of the assessment. Women with false-positive mammograms are less likely to return for routine assessment than those with normal ones.

BACKGROUND: Uterine cancer is the fourth most common cancer in women in the UK, with approximately 7700 new diagnoses and 1700 deaths annually. AIM: to identify and quantify features of uterine cancer in primary care. DESIGN AND SETTING: Case-control study using electronic primary care records in primary care in the UK. METHOD: Putative features of uterine cancer were identified in the year before diagnosis, and odds ratios (ORs) calculated using conditional logistic regression. Positive predictive values (PPVs) were calculated for women who consulted. RESULTS: a total of 2732 women aged ≥40 years with uterine cancer between 2000 and 2009, and 9537 age-, sex- and practice-matched controls were selected from the General Practice Research Database. The median age at diagnosis was 67 years. Nine features were significantly associated with uterine cancer: postmenopausal bleeding (OR = 160; 95% confidence interval [CI] = 100 to 240), excessive vaginal bleeding (OR = 22; 95% CI = 12 to 42), irregular menstruation (OR = 42; 95% CI = 27 to -63), vaginal discharge (OR = 14; 95% CI = 10 to 21), haematuria (OR = 8.7; 95% CI = 5.0 to 15), abdominal pain (OR = 2.0; 95% CI = 1.4 to 2.8), low haemoglobin (OR = 2.1; 95% CI = 1.5 to 2.9), raised platelets (OR = 1.5; 95% CI = 1.0 to 2.3), and raised glucose (OR = 1.4; 95% CI = 1.1 to 1.8); all P

Background: Although recent diagnostic criteria for Alzheimer's disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta-analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies. Methods: a MEDLINE search was performed in August 2011 to identify all potentially relevant publications relating to the biomarkers β-amyloid, tau, positron emission tomography ( 18F-fluorodeoxyglucose or ligands for amyloid), or magnetic resonance imaging (MRI). The reporting and methodology were assessed using the Standards for Reporting of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies assessment tools, respectively. Because clinical progression to dementia is the most commonly used reference standard, this review focuses on participants with objective cognitive impairment but no dementia at baseline. Results: of the 19,104 published references identified by the search, 142 longitudinal studies relating to the biomarkers of interest were identified, which included subjects who had objective cognitive impairment but no dementia at baseline. The highest number of studies (n = 70) and of participants (n = 4722) related to structural MRI. MRI also yielded the highest number of studies with extractable data for meta-analysis (n = 32 [46% of all structural MRI studies]), followed by cerebrospinal fluid tau (n = 24 [73%]). There were few studies on positron emission tomography ligands for amyloid having suitable data for meta-analysis (n = 4). There was considerable variation across studies in reporting outcomes, methods of blinding and selection, means of accounting for indeterminate or missing values, the interval between the test and assessments, and the determination of test thresholds. Conclusions: the body of evidence for biomarkers is not large and is variable across the different types of biomarkers. Important information is missing from many study reports, highlighting the need for standardization of methodology and reporting to improve the rigor of biomarker validation. © 2013 the Alzheimer's Association. All rights reserved.

Background: in the UK, women aged 50-73 years are invited for screening by mammography every 3 years. In 2009-10, more than 2.24 million women in this age group in England were invited to take part in the programme, of whom 73% attended a screening clinic. of these, 64,104 women were recalled for assessment. of those recalled, 81% did not have breast cancer; these women are described as having a false-positive mammogram. Objective: the aim of this systematic review was to identify the psychological impact on women of false positive screening mammograms and any evidence for the effectiveness of interventions designed to reduce this impact. We were also looking for evidence of effects in subgroups of women. Data sources: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Health Management Information Consortium, Cochrane Central Register for Controlled Trials, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects, CRD Health Technology Assessment (HTA), Cochrane Methodology, Web of Science, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index-Science, Conference Proceeding Citation Index-Social Science and Humanities, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Sociological Abstracts, the International Bibliography of the Social Sciences, the British Library's Electronic Table of Contents and others. Initial searches were carried out between 8 October 2010 and 25 January 2011. Update searches were carried out on 26 October 2011 and 23 March 2012. Review methods: Based on the inclusion criteria, titles and abstracts were screened independently by two reviewers. Retrieved papers were reviewed and selected using the same independent process. Data were extracted by one reviewer and checked by another. Each included study was assessed for risk of bias. Results: Eleven studies were found from 4423 titles and abstracts. Studies that used disease-specific measures found a negative psychological impact lasting up to 3 years. Distress increased with the level of invasiveness of the assessment procedure. Studies using instruments designed to detect clinical levels of morbidity did not find this effect. Women with false-positive mammograms were less likely to return for the next round of screening [relative risk (RR) 0.97; 95% confidence interval (CI) 0.96 to 0.98] than those with normal mammograms, were more likely to have interval cancer [odds ratio (OR) 3.19 (95% CI 2.34 to 4.35)] and were more likely to have cancer detected at the next screening round [OR 2.15 (95% CI 1.55 to 2.98)]. Limitations: This study was limited to UK research and by the robustness of the included studies, which frequently failed to report quality indicators, for example failure to consider the risk of bias or confounding, or failure to report participants' demographic characteristics. Conclusions: We conclude that the experience of having a false-positive screening mammogram can cause breast cancer-specific psychological distress that may endure for up to 3 years, and reduce the likelihood that women will return for their next round of mammography screening. These results should be treated cautiously owing to inherent weakness of observational designs and weaknesses in reporting. Future research should include a qualitative interview study and observational studies that compare generic and disease-specific measures, collect demographic data and include women from different social and ethnic groups. © Queen's Printer and Controller of HMSO 2013.

This is the protocol for a review and there is no abstract. The objectives are as follows: to determine the diagnostic accuracy of the 18F-FDG-PET index test for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease or other forms of dementia at follow-up. To investigate heterogeneity of test accuracy in the included studies. We expect that heterogeneity will be likely and that it will be an important component of the review. The potential sources of heterogeneity, which will be used as a framework for the investigation of heterogeneity, include target population, index test, target disorder and study quality and are detailed in the analysis section.

BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab. OBJECTIVE: to investigate the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after first-line chemotherapy. DATA SOURCES: the assessment comprises a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted in a range of electronic databases, including MEDLINE, EMBASE and the Cochrane Library, from 2005 to November 2010. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after first-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). All steps in the review were performed by one reviewer and checked independently by a second. Synthesis was mainly narrative. An economic model was developed focusing on third-line and subsequent lines of treatment. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: the searches identified 7745 titles and abstracts. Two clinical trials (reported in 12 papers) were included. No data were available for bevacizumab in combination with non-oxaliplatin-based chemotherapy in previously treated patients. Neither of the included studies had KRAS status performed prospectively, but the studies did report retrospective analyses of the results for the KRAS WT subgroups. Third-line treatment with cetuximab plus best supportive care or panitumumab plus best supportive care appears to have statistically significant advantages over treatment with best supportive care alone in patients with KRAS WT status. For the economic evaluation, five studies met the inclusion criteria. The base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients for cetuximab compared with best supportive care is £98,000 per quality-adjusted life-year (QALY), for panitumumab compared with best supportive care is £150,000 per QALY and for cetuximab plus irinotecan compared with best supportive care is £88,000 per QALY. All ICERs are sensitive to treatment duration. LIMITATIONS: in the specific populations of interest, there is a lack of evidence on bevacizumab, cetuximab and cetuximab plus irinotecan used second line and on bevacizumab and cetuximab plus irinotecan used third line. For cetuximab plus irinotecan treatment for KRAS WT people, there is no direct evidence on progression-free survival, overall survival and duration of treatment. CONCLUSIONS: Although cetuximab and panitumumab appear to be clinically beneficial for KRAS WT patients compared with best supportive care, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT for patients with KRAS WT status receiving cetuximab plus irinotecan. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

BACKGROUND: the number of thyroid function tests (TFTs) performed in the UK and other countries has increased considerably in recent years. Inconsistent clinical practice associated with inappropriate requests for tests is thought to be an important cause for this increase. AIM: to study the extent of variability in requests for TFTs from general practices. METHODS: We analysed routine data on all TFTs on patients aged 16 years and over carried out by two hospitals in south-west England (Royal Cornwall Hospital and Royal Devon & Exeter Hospital) during 2010 at the request of 107 general practices. RESULTS: a total of 195 309 TFT requests were made for 148 412 patients (63% female). The total requests included 192 108 tests for thyroid-stimulating hormone (TSH), 43 069 for free thyroxine (FT4) and 1972 for free tri-iodothyronine (FT3). The number of TSH tests per 1000 list size varied widely across the practices, ranging from 84 to 482. Most of the variation was due to heterogeneity across practices and only 24% of this was accounted for by prevalence of hypothyroidism and socio-economic deprivation. CONCLUSIONS: There is wide variation in TFT requests from general practice and scope to reduce both unnecessary TFTs and the variability in the clinical practice. Further studies are required to understand the causes for the variability in testing thyroid function.

OBJECTIVE: to estimate the number of randomized controlled trials (RCTs) published annually that evaluate the impact of diagnostic tests on patient outcomes to gauge the extent of available randomized evidence assessing the effectiveness of diagnostic tests. STUDY DESIGN AND SETTING: Relevant RCTs published in 2004-2007 were identified from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL). Two search strategies were developed, one using diagnostic methodological terms and one using test names. Potentially relevant RCTs were identified by screening titles and abstracts. Final inclusion decisions were based on full-text review. A random 10% sample of all citations was independently screened by a second reviewer. Capture-recapture methodology was used to estimate the number of relevant RCTs missed by both searches. RESULTS: One hundred thirty-five relevant RCTs were identified from the 23,888 records retrieved. Interobserver agreement was substantial. Capture-recapture methodology estimated that 148 (95% confidence interval: 140, 160) relevant RCTs were published in the 4-year period, an average of only 37 publications per year. CONCLUSION: RCTs of diagnostic tests that evaluate patient outcomes are rare. Consequently recommendations on the use of diagnostic tests can rarely be made on the basis of randomized comparisons, lower grade evidence frequently being the best available.

Background: Evidence of variations in red blood cell transfusion practices have been reported in a wide range of clinical settings. Parallel studies in Canada and the United Kingdom were designed to explore transfusion behaviour in intensive care physicians. The aim of this paper is three-fold: first, to explore beliefs that influence Canadian intensive care physicians' transfusion behaviour; second, to systematically select relevant theories and models using the Theoretical Domains Framework (TDF) to inform a future predictive study; and third, to compare its results with the UK study.Methods: Ten intensive care unit (ICU) physicians throughout Canada were interviewed. Physicians' responses were coded into theoretical domains, and specific beliefs were generated for each response. Theoretical domains relevant to behaviour change were identified, and specific constructs from the relevant domains were used to select psychological theories. The results from Canada and the United Kingdom were compared.Results: Seven theoretical domains populated by 31 specific beliefs were identified as relevant to the target behaviour. The domains Beliefs about capabilities (confident to not transfuse if patients' clinical condition is stable), Beliefs about consequences (positive beliefs of reducing infection and saving resources and negative beliefs about risking patients' clinical outcome and potentially more work), Social influences (transfusion decision is influenced by team members and patients' relatives), and Behavioural regulation (wide range of approaches to encourage restrictive transfusion) that were identified in the UK study were also relevant in the Canadian context. Three additional domains, Knowledge (it requires more evidence to support restrictive transfusion), Social/professional role and identity (conflicting beliefs about not adhering to guidelines, referring to evidence, believing restrictive transfusion as professional standard, and believing that guideline is important for other professionals), and Motivation and goals (opposing beliefs about the importance of restrictive transfusion and compatibility with other goals), were also identified in this study. Similar to the UK study, the Theory of Planned Behaviour, Social Cognitive Theory, Operant Learning Theory, Action Planning, and Knowledge-Attitude-Behaviour model were identified as potentially relevant theories and models for further study. Personal project analysis was added to the Canadian study to explore the Motivation and goals domain in further detail.Conclusions: a wide range of beliefs was identified by the Canadian ICU physicians as likely to influence their transfusion behaviour. We were able to demonstrate similar though not identical results in a cross-country comparison. Designing targeted behaviour-change interventions based on unique beliefs identified by physicians from two countries are more likely to encourage restrictive transfusion in ICU physicians in respective countries. This needs to be tested in future prospective clinical trials. © 2012 Islam et al.; licensee BioMed Central Ltd.

INTRODUCTION: Management of a patient's diabetes is entirely dependent upon the type of diabetes they are deemed to have. Patients with Type 1 diabetes are insulin deficient so require multiple daily insulin injections, whereas patients with Type 2 diabetes still have some endogenous insulin production so insulin treatment is only required when diet and tablets do not establish good glycaemic control. Despite the importance of a correct diagnosis, classification of diabetes is based on aetiology and relies on clinical judgement. There are no clinical guidelines on how to determine whether a patient has Type 1 or Type 2 diabetes. We aim to systematically review the literature to derive evidence-based clinical criteria for the classification of the major subtypes of diabetes. METHODS AND ANALYSIS: We will perform a systematic review of diagnostic accuracy studies to establish clinical criteria that predict the subsequent development of absolute insulin deficiency seen in Type 1 diabetes. Insulin deficiency will be determined by reference standard C-peptide concentrations. Synthesis of criteria identified will be undertaken using hierarchical summary receiver operating characteristic curves. ETHICS AND DISSEMINATION: As this is a systematic review, there will be no ethical issues. We will disseminate results by writing up the final systematic review and synthesis for publication in a peer-reviewed journal and will present at national and international diabetes-related meetings.

PURPOSE OF REVIEW: Spontaneous preterm birth complicates 3-11% of pregnancies and is a major cause of neonatal mortality and morbidity worldwide. If accurate tests can be identified, a potentially effective screening strategy with an adjunct preventive therapy may be trialled to reduce the rate of spontaneous preterm birth or effective measures be deployed at an early stage of a suspected spontaneous preterm labour before the onset of cervical changes to ameliorate prematurity complications. RECENT FINDINGS: There are many tests predicting spontaneous preterm births, published in the literature individually or in a systematic review. The information has not been collated about all candidate tests simultaneously in a systematic review incorporating a framework on how these tests may be evaluated, modelled with an intervention to provide a number needed to treat and test to inform decision-making. SUMMARY: There were 319 studies evaluating 22 tests. There are many promising tests, for example, history of previous spontaneous preterm birth, cervicovaginal swabs for markers such as fibronectin or HCG, cervical ultrasound, serum CRP and amniotic fluid interleukins for predicting spontaneous preterm birth, but none have exceptional accuracy and the quality of studies was generally poor. Some tests were able to achieve high LR+, but at the expense of LR-, that is, tests good for ruling in disease were poor for ruling out disease and vice versa.

AIMS/HYPOTHESIS: Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual's probability of having MODY, as a crucial tool for rational genetic testing. METHODS: We developed prediction models using logistic regression on data from 1,191 patients with MODY (n = 594), type 1 diabetes (n = 278) and type 2 diabetes (n = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. RESULTS: the models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA(1c), parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA(1c), parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis

BACKGROUND: Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included the Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: the clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, the model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: the additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

OBJECTIVES: to review the published economic studies that have evaluated positron emission tomography/computed tomography (PET/CT) in the treatment of recurrent breast cancer, and to develop and carry out a model-based economic evaluation to investigate the relative cost-effectiveness of PET/CT to detect breast cancer recurrence compared with conventional work-up. DATA SOURCES: a systematic review of economic and diagnostic evidence for PET/CT in diagnosis of breast cancer recurrence. The original databases searched include MEDLINE (Ovid) (1950 to week 5 May 2009), EMBASE (Ovid) (1980 to 2009 week 22) and the NHS Economic Evaluation Database. An updated search was conducted for each database from May 2009 to week 4 April 2010. METHODS: a decision tree was developed in TREEAGE software (TreeAge Software Inc. Williamstown, MA, USA). The relevant data on accuracy, sensitivity and specificity of each diagnostic test were linked in the model, to costs and the primary outcome measure, cost per quality-adjusted life-year (QALY). The model estimated the mean cost associated with each diagnostic procedure and assumed that patients entering the model were aged 50-75 years. The results of the cost-effectiveness analysis are presented in terms of the incremental cost-effectiveness ratios (ICERs). RESULTS: the ICER for the strategy of PET compared with conventional work-up was estimated at £29,300 per QALY; the ICER for PET/CT compared with PET was £ 31,000 per QALY; and the ICER for PET/CT combined with conventional work-up versus PET/CT was £ 42,100. Clearly, for each additional diagnostic test that is added to PET, the more expensive the package becomes, but also the more effective it becomes in terms of QALYs gained. The probabilistic sensitivity analysis shows that at a willingness-to-pay threshold of £ 20,000 per QALY, conventional work-up is the preferred option. LIMITATIONS: Only data from indirect comparisons are available from the accuracy review, and there is some uncertainty about whether the data defining the accuracy of PET/CT present its use as a replacement or as an adjunct to conventional work-up. CONCLUSIONS: Based on the current model and given the limitations that are apparent in terms of limited availability of data, the result of the current analysis suggests that the use of PET/CT in the diagnosis of recurrent breast cancer in every woman suspected of having a recurrence is unlikely to be cost-effective given the current willingness-to-pay thresholds that are accepted in the UK by decision-making bodies such as the National Institute for Health and Clinical Excellence. Our modelling suggests that conventional work-up could be the most cost-effective diagnostic strategy given current data. Future studies need to secure robust cost data that can be verified from more than one source for the diagnostic tests involved in PET and PET/CT. Reliable and verifiable data on quality of life associated with this clinical condition are also crucial. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

The UK National Institute for Health and Clinical Excellence (NICE) has used its Single Technology Appraisal (STA) programme to assess several drugs for cancer. Typically, the evidence submitted by the manufacturer comes from one short-term randomized controlled trial (RCT) demonstrating improvement in overall survival and/or in delay of disease progression, and these are the pre-eminent drivers of cost effectiveness. We draw attention to key issues encountered in assessing the quality and rigour of the manufacturers' modelling of overall survival and disease progression. Our examples are two recent STAs: sorafenib (Nexavar®) for advanced hepatocellular carcinoma, and azacitidine (Vidaza®) for higher-risk myelodysplastic syndromes (MDS). The choice of parametric model had a large effect on the predicted treatment-dependent survival gain. Logarithmic models (log-Normal and log-logistic) delivered double the survival advantage that was derived from Weibull models. Both submissions selected the logarithmic fits for their base-case economic analyses and justified selection solely on Akaike Information Criterion (AIC) scores. AIC scores in the azacitidine submission failed to match the choice of the log-logistic over Weibull or exponential models, and the modelled survival in the intervention arm lacked face validity. AIC scores for sorafenib models favoured log-Normal fits; however, since there is no statistical method for comparing AIC scores, and differences may be trivial, it is generally advised that the plausibility of competing models should be tested against external data and explored in diagnostic plots. Function fitting to observed data should not be a mechanical process validated by a single crude indicator (AIC). Projective models should show clear plausibility for the patients concerned and should be consistent with other published information. Multiple rather than single parametric functions should be explored and tested with diagnostic plots. When trials have survival curves with long tails exhibiting few events then the robustness of extrapolations using information in such tails should be tested.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic lymphocytic leukaemia (CLL), based upon the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p < 0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression-free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer's estimates of effectiveness based on evidence from a single-arm, non-randomised study. An 'area-under-the-curve' or 'partitioned-survival' model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: 'alive pre-progression', 'alive post progression' and 'dead'. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were identified in the economic evaluation; for example, the BSC arm used data from patients in the Hx-CD20-406 study who did not respond to ofatumumab treatment - 'non-responders' - and the ofatumumab arm used data from all of those treated in the Hx-CD20-406 study. Further uncertainty arose regarding the choice of utilities, the omission of 17p and 11q chromosomal deletions as factors in the Cox proportional hazards models for PFS and OS, and the omission of the costs of drugs in progressive disease. It was felt that these factors biased cost-effectiveness in favour of ofatumumab. When revisions were made to the assumptions in the model based on the ERG's review of the published and submitted evidence, the revised base-case incremental cost-effectiveness ratio for ofatumumab increased to £ 81,500 per quality-adjusted life-year. The final appraisal determination was issued by NICE in September 2010 (www.nice.org.uk/nicemedia/live/12264/50758/50758.pdf).

No up-to-date overview of randomized controlled trials (RCTs) in red blood cell (RBC) transfusion exists. This systematic review examines the quantity and quality of the evidence for the clinical effects of RBC transfusion. One hundred forty-two eligible RCTs were identified through searches of the Cochrane Library (issue 4, 2009), MEDLINE (1950 to November 2009), EMBASE (1974 to November 2009), and other relevant sources. After data extraction and methodological quality assessment, trials were grouped by clinical specialty and type of RBC transfusion. Data analysis was predominantly descriptive. The 142 RCTs covered 11 specialties and 10 types of RBC transfusion. The number of included patients varied widely across the RCTs (median, 57; IQ range, 27-167). Most trials were single center comparing 2 parallel study arms. Overall, the reporting of methodological assessment was poor, although it improved markedly from 2001. Clinical areas with few trials are highlighted. Comparison with a study of RBC use in clinical practice highlighted a lack of correlation between the size of the evidence base for a given clinical specialty and the proportion of total RBC use by that clinical specialty. The gaps in the evidence base and the poor methodology of trials particularly in the past do not provide a strong evidence base for the use of RBC transfusions, but they indicate important targets for future research. © 2011.

Introduction: Worldwide, trauma is a leading cause of death and disability. Haemorrhage is responsible for up to 40% of trauma deaths. Recent strategies to improve mortality rates have focused on optimal methods of early hemorrhage control and correction of coagulopathy. We undertook a systematic review of randomized controlled trials (RCT) which evaluated trauma patients with hemorrhagic shock within the first 24 hours of injury and appraised how the interventions affected three outcomes: bleeding and/or transfusion requirements; correction of trauma induced coagulopathy and mortality.Methods: Comprehensive searches were performed of MEDLINE, EMBASE, CENTRAL (The Cochrane Library Issue 7, 2010), Current Controlled Trials, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the National Health Service Blood and Transplant Systematic Review Initiative (NHSBT SRI) RCT Handsearch Database.Results: a total of 35 RCTs were identified which evaluated a wide range of clinical interventions in trauma hemorrhage. Many of the included studies were of low methodological quality and participant numbers were small. Bleeding outcomes were reported in 32 studies; 7 reported significantly reduced transfusion use following a variety of clinical interventions, but this was not accompanied by improved survival. Minimal information was found on traumatic coagulopathy across the identified RCTs. Overall survival was improved in only three RCTs: two small studies and a large study evaluating the use of tranexamic acid.Conclusions: Despite 35 RCTs there has been little improvement in outcomes over the last few decades. No clear correlation has been demonstrated between transfusion requirements and mortality. The global trauma community should consider a coordinated and strategic approach to conduct well designed studies with pragmatic endpoints. © 2011 Curry et al.; licensee BioMed Central Ltd.

Systematic reviews are accepted as a robust and less biased means of appraising and synthesizing results from high-quality studies. This report collated and summarized all the systematic review evidence relating to the diagnosis and management of trauma-related coagulopathy and transfusion, thereby covering the widest possible body of literature. We defined 4 key clinical questions: (1) What are the best methods of predicting and diagnosing trauma-related coagulopathy? (2) Which methods of clinical management correct coagulopathy? (3) Which methods of clinical management correct bleeding? and (4) What are the outcomes of transfusion in trauma? Thirty-seven systematic reviews were identified through searches of MEDLINE (1950-July 2010), EMBASE (1980-July 2010), the Cochrane Library (Issue 7, 2010), National Guidelines Clearing House, National Library for Health Guidelines Finder, and UKBTS SRI Transfusion Evidence Library (www.transfusionevidencelibrary.com). The evidence from the systematic review literature was scanty with many gaps, and we were not able to conclusively answer any of our 4 questions. Much more needs to be understood about how coagulopathy and bleeding in trauma are altered by transfusion practices and, most importantly, whether this translates into improved survival. There is a need for randomized controlled trials to answer these questions. The approach described in this report provides a framework for incorporating new evidence. © 2011.

Background: the benefits and risks of off- label use of recombinant factor VIIa in patients without hemophilia are contested. We performed a systematic review to assess the effectiveness and safety of such use. Methods: We searched electronic databases including MEDLINE, EMBASE and CENTRAL for randomized controlled trials comparing recombinant factor VIIa with placebo in any patient population except those with hemophilia up to January 2010. Eligible articles were assessed for inclusion, data were extracted, and study quality was evaluated. Outcomes included mortality, blood loss, requirements for red blood cell transfusion, number of patients transfused and thromboembolic events. Results: We identified 26 trials: 14 on off-label prophylactic use of recombinant factor VIIa (n = 1137) and 12 on off-label therapeutic use (n = 2538). In the studies on prophylactic use, we found no significant difference in mortality or thromboembolic events between the treatment and placebo groups. We found modest benefits favouring recombinant factor VIIa in blood loss (weighted mean difference -276 mL, 95% confidence interval [CI] -411 to -141 mL), red blood cell transfusion (weighted mean difference -281 mL, 95% CI -433 to -129 mL) and number of patients transfused (relative risk 0.71, 95% CI 0.50 to 0.99). In the therapeutic trials, we found a nonsignificant decrease in mortality and a nonsignificant increase in thromboembolic events but no difference in control of bleeding or red blood cell transfusion. Interpretation: Clinically significant benefits of recombinant factor VIIa as a general hemostatic agent in patients without hemophilia remain unproven. Given its potential risks, such use cannot be recommended, and in most cases, it should be restricted to clinical trials. © 2011 Canadian Medical Association or its licensors.

BACKGROUND: Breast cancer (BC) accounts for one-third of all cases of cancer in women in the UK. Current strategies for the detection of BC recurrence include computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy. Positron emission tomography (PET) and, more recently, positron emission tomography/computed tomography (PET/CT) are technologies that have been shown to have increasing relevance in the detection and management of BC recurrence. OBJECTIVE: to review the accuracy of PET and PET/CT for the diagnosis of BC recurrence by assessing their value compared with current practice and compared with each other. DATA SOURCES: MEDLINE and EMBASE were searched from inception to May 2009. STUDY SELECTION: Studies were included if investigations used PET or PET/CT to diagnose BC recurrence in patients with a history of BC and if the reference standard used to define the true disease status was histological diagnosis and/or long-term clinical follow-up. Studies were excluded if a non-standard PET or PET/CT technology was used, investigations were conducted for screening or staging of primary breast cancer, there was an inadequate or undefined reference standard, or raw data for calculation of diagnostic accuracy were not available. STUDY APPRAISAL: Quality assessment and data extraction were performed independently by two reviewers. Direct and indirect comparisons were made between PET and PET/CT and between these technologies and methods of conventional imaging, and meta-analyses were carried out. Analysis was conducted separately on patient- and lesion-based data. Subgroup analysis was conducted to investigate variation in the accuracy of PET in certain populations or contexts and sensitivity analysis was conducted to examine the reliability of the primary outcome measures. RESULTS: of the 28 studies included in the review, 25 presented patient-based data and 7 presented lesion-based data for PET and 5 presented patient-based data and 1 presented patient- and lesion-based data for PET/CT; 16 studies conducted direct comparisons with 12 comparing the accuracy of PET or PET/CT with conventional diagnostic tests and 4 with MRI. For patient-based data (direct comparison) PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] and significantly higher specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 67% to 92%, relative specificity 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with conventional imaging tests (CITs)--test performance did not appear to vary according to the type of CIT tested. For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, p = 0.015), but the increase in specificity was not significant (89%, 95% CI 69% to 97% vs 77%, 95% CI 50% to 92%, relative specificity 1.15, 95% CI 0.95 to 1.41, p = 0.157). For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with PET (96%, 95% CI 90% to 98% vs 85%, 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 to 1.18, p = 0.006), but the increase in specificity was not significant (89%, 95% CI 74% to 96% vs 82%, 95% CI 64% to 92%, relative specificity 1.08, 95% CI 0.94 to 1.20, p = 0.267). For patient-based data there were no significant differences in the sensitivity or specificity of PET when compared with MRI, and, in the one lesion based study, there was no significant differences in the sensitivity or specificity of PET/CT when compared with MRI. LIMITATIONS: Studies reviewed were generally small and retrospective and this may have limited the generalisability of findings. Subgroup analysis was conducted on the whole set of studies investigating PET and was not restricted to comparative studies. Conventional imaging studies that were not compared with PET or PET/CT were excluded from the review. CONCLUSIONS: Available evidence suggests that for the detection of BC recurrence PET, in addition to conventional imaging techniques, may generally offer improved diagnostic accuracy compared with current standard practice. However, uncertainty remains around its use as a replacement for, rather than an add-on to, existing imaging technologies. In addition, PET/CT appeared to show clear advantage over CT and PET alone for the diagnosis of BC recurrence. FUTURE WORK: Future research should include: prospective studies with patient populations clearly defined with regard to their clinical presentation; a study of diagnostic accuracy of PET/CT compared with conventional imaging techniques; a study of PET/CT compared with whole-body MRI; studies investigating the possibility of using PET/CT as a replacement for rather than an addition to CITs; and using modelling of the impact of PET/CT on patient outcomes to inform the possibility of conducting large-scale intervention trials.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of azacitidine (aza) compared with conventional care regimes (CCR) for higher risk patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML), based on the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The patient outcomes governing relative effectiveness and cost-effectiveness were defined as overall survival, time to progression (TTP) to AML, adverse events and health-related quality of life (HRQoL). The clinical evidence was derived from an open-label randomised controlled trial referred to as study AZA-001. It compared aza with CCR in 358 patients with higher risk MDS, CMML and AML 20-30% blasts. The outcomes reported in AZA-001 included overall survival, TTP to AML and adverse events. No HRQoL results were reported; however, outcomes likely to impact on HRQoL were provided. The results showed that: the median overall survival was 24.5 months on aza, compared with 15.0 months in the CCR group (p = 0.0001); the response rates were low (complete remission 17% aza versus 8% CCR); the median time to transformation to AML was greater in the aza group (17.8 versus 11.5 months; p < 0.0001); and of patients who were red blood cell (RBC) transfusion-dependent at baseline, 45% of those on aza became RBC transfusion-independent during the treatment period, compared with 11.8% in the CCR group (p < 0.0001). The ERG reran the submission's search strategies after some modifications incorporating minor improvements. The ERG analysed the submitted economic model (model 1) and identified a number of inconsistencies and errors within the model. The manufacturer submitted a revised model for analysis by the ERG. Using the issues identified in the earlier analysis, the ERG conducted those repairs to the revised model that were feasible within time constraints. The ERG ran this version in probabilistic sensitivity analyses to generate cost-effectiveness acceptability frontiers. The results of these exploratory analyses indicated that: for standard-dose chemotherapy (SDC)-treated patients, of six treatment options available, best supportive care (BSC) was likely the most cost-effective option up to a threshold of 51,000 pounds/quality-adjusted life-year (QALY) [beyond 51,000 pounds/QALY, aza + low-dose chemotherapy (LDC) became cost-effective]; for LDC-treated patients, of four options available, BSC was again the most cost-effective option up to a willingness-to-pay threshold of 51,000 pounds/QALY (aza + LDC became cost-effective after 51,000 pounds/QALY); for BSC-treated patients, aza + BSC became cost-effective relative to BSC at a threshold of about 52,000 pounds/QALY. The ERG considers these results exploratory and considers that they should be viewed with caution. The AZA-001 study showed that, compared with CCR, those MDS patients receiving aza had prolonged median survival, had delayed progression to AML, had reduced dependence on transfusions and had a small improvement in response rate. Given the general paucity of economic modelling work in MDS and the limitations of the submitted industry model there is an evident need for an independent cost-effectiveness analysis of aza in MDS. At the time of writing, the guidance appraisal consultation document issued by NICE on 4 March 2010 states that azacitidine is not recommended as a treatment option for people not eligible for haemopoietic stem cell transplantation with the the following conditions: intermediate-2 and high-risk MDS according to the International Prognostic Scoring System, CMML with 10-29% marrow blasts without myeloproliferative disorder, or with AML with 20-30% blasts and multilineage dysplasia, according to World Health Organization classification.

BACKGROUND: Acute leukaemia is a group of rapidly progressing cancers of bone marrow and blood classified as either acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL). Haemopoietic stem cell transplantation (SCT) has developed as an adjunct to or replacement for conventional chemotherapy with the aim of improving survival and quality of life. OBJECTIVES: a systematic overview of the best available evidence on the clinical effectiveness and cost-effectiveness of SCT in the treatment of acute leukaemia. DATA SOURCES: Clinical effectiveness: electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched from inception to December 2008 to identify published systematic reviews and meta-analyses. Cochrane CENTRAL, MEDLINE, EMBASE and Science Citation Index (SCI) were searched from 1997 to March 2009 to identify primary studies. Cost-effectiveness: MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (NHS EED) were searched from inception to January 2009. STUDY SELECTION: Potentially relevant papers were retrieved and independently checked against predefined criteria by two reviewers (one in the case of the cost-effectiveness review). STUDY APPRAISAL: Included reviews and meta-analyses were critically appraised and data extracted and narratively presented. Included randomised controlled trials (RCTs) and donor versus no donor (DvND) studies were mapped to the evidence covered in existing systematic reviews and meta-analyses according to a framework of 12 decision problems (DPs): DP1 related to SCT in adults with AML in first complete remission (CR1); DP2 to adults with AML in second or subsequent remission or with refractory disease (CR2+); DP3 to children with AML in CR1; DP4 to children with AML in CR2+; DP5 to adults with ALL in CR1; DP6 to adults with ALL in CR2+; DP7 to children with ALL in CR1; DP8 to children with ALL in CR2+; DP9 to comparison of different sources of stem cells in transplantation; DP10 to different conditioning regimens; DP11 to the use of purging in autologous SCT; and DP12 to the use of T-cell depletion in allogeneic SCT. RESULTS: Fifteen systematic reviews/meta-analyses met the inclusion criteria for the review of clinical effectiveness, thirteen of which were published from 2004 onwards. Taking into account the timing of their publications, most reviews appeared to have omitted an appreciable proportion of potentially available evidence. The best available evidence for effectiveness of allogeneic SCT using stem cells from matched sibling donors came from DvND studies: there was sufficient evidence to support the use of allogeneic SCT in DP1 (except in good-risk patients), DP3 (role of risk stratification unclear) and DP5 (role of risk stratification unclear). There was conflicting evidence in DP7 and a paucity of evidence from DvND studies for all decision problems concerning patient groups in CR2+. The best available evidence for effectiveness of autologous SCT came from RCTs: overall, evidence suggested that autologous SCT was either similar to or less effective than chemotherapy. There was a paucity of evidence from published reviews of RCTs for DPs 9-12. Nineteen studies met the inclusion criteria in the cost-effectiveness review, most reporting only cost information and only one incorporating an economic model. Although there is a wealth of information on costs and some information on cost-effectiveness of allogeneic SCT in adults with AML (DPs 1 and 2), there is very limited evidence on relative costs and cost-effectiveness for other DPs. LIMITATIONS: Time and resources did not permit critical appraisal of the primary studies on which the reviews/meta-analyses reviewed were based; there were substantial differences in methodologies, and consequently quantitative synthesis of data was neither planned in the protocol nor carried out; some of the studies were quite old and might not reflect current practice; and a number of the studies might not be applicable to the UK. CONCLUSIONS: Bearing in mind the limitations, existing evidence suggests that sibling donor allogeneic SCT may be more effective than chemotherapy in adult AML (except in good-risk patients) in CR1, childhood AML in CR1 and adult ALL in CR1, and that autologous SCT is equal to or less effective than chemotherapy. No firm conclusions could be drawn regarding the cost-effectiveness of SCT in the UK NHS owing to the limitations given above. Future research should include the impact of the treatments on patients' quality of life as well as information on health service use and costs associated with SCT from the perspective of the UK NHS.

In this systematic review, the authors aimed to assess the effectiveness of community programs for prevention of cardiovascular disease (CVD). They searched numerous electronic databases (CDSR, DARE, HTA, EED, and CENTRAL via the Cochrane Library, MEDLINE, MEDLINE in Process, EMBASE, CINAHL, PsycINFO, HMIC, and ASSIA) and relevant Web sites from January 1970 to mid-July 2008. Controlled studies of community programs for the primary prevention of CVD were included. Net changes in CVD risk factors were used to generate an overall index for net change in 10-year CVD risk. The authors identified 36 relevant community programs that took place between 1970 and 2008. These programs were multifaceted interventions employing combinations of media, screening, and counseling activities and environmental changes and were primarily evaluated using controlled before-after studies. In 7 studies, investigators reported changes in CVD/total mortality rates, and in 5 they reported net changes. In all cases, these net changes were positive but were largely nonsignificant. In 22 studies, investigators reported changes in physiologic CVD risk factors, and there was a positive trend in the calculated CVD risk score. The average net reduction in 10-year CVD risk was 0.65%. Community programs for CVD prevention appear to have generally achieved favorable changes in overall CVD risk and, with adaptation to current circumstances, deserve continued consideration as possible approaches to preventing CVD.

This paper represents a summary of the evidence review group (ERG) report into the clinical efficacy, safety and cost-effectiveness of everolimus plus best supportive care (BSC) for the treatment of advanced renal cell carcinoma (RCC) which has progressed following or on vascular endothelial growth factor-targeted therapy (sunitinib, sorafenib, bevacizumab), compared to BSC alone. The submitting manufacturer's case for clinical effectiveness and cost-effectiveness was mainly based on a well-conducted randomised controlled trial (RCT), Renal Cell Cancer Treatment with Oral RAD001 Given Daily-1 (RECORD-1), comparing BSC plus everolimus with BSC plus placebo and a de novo economic model. The RCT indicated a marked statistically significant effect on progression-free survival. The base-case incremental cost-effectiveness ratio (ICER) estimate was 52,000 pounds per quality-adjusted life-year (this included a reduction in drug cost associated with an approved patient access scheme). The ERG undertook a critical appraisal of the submission. The ERG was generally in agreement with the submitting manufacturer concerning its estimates of effectiveness; however, there was greater concern surrounding the estimates of cost-effectiveness. The ERG judged that if potential errors in the model were corrected, the ICERs offered by the submitting manufacturer would overstate the cost-effectiveness of everolimus for the second-line treatment of metastatic RCC (that this ICER would be a higher value). Concerning the estimates of cost-effectiveness in RCC, the observations in the ERG report provide strong further support for research collecting rigorous estimates of utilities associated with the main health states likely to be experienced by patients with renal cell cancer. At the time of writing, NICE was yet to issue the Appraisal Consultation Document for this appraisal.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of infliximab for the treatment of acute exacerbations of ulcerative colitis, in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included four randomised controlled trials (RCTs), two comparing infliximab with placebo in patients not responsive to initial treatment with intravenous corticosteroids and one comparing ciclosporin with placebo. A fourth RCT compared ciclosporin with intravenous corticosteroids as the initial treatment after hospitalisation. The manufacturer's submission concluded that infliximab provides clinical benefit to patients with acute severe, steroid-refractory ulcerative colitis and is well tolerated; it also provides additional clinical benefits over ciclosporin, particularly avoidance of colectomy. A decision tree model was built to compare infliximab with strategies involving ciclosporin, standard care and surgery. After correcting a small number of errors in the model, the revised base-case incremental cost-effectiveness ratio (ICER) for infliximab compared with standard care was 20,000 pounds. However, sensitivity analyses revealed considerable uncertainty emanating from the weight of the patient, the timeframe considered and, most importantly, the colectomy rates used. When a more appropriate mix of trials were included in the estimation of colectomy rates, the ICER for infliximab rose to 48,000 pounds. The guidance issued by NICE on 31 October 2008 states that infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient; for people who do not meet this criterion, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials.

Transfusion medicine has become a large and complex specialty. Although there are now systematic reviews covering many aspects of transfusion, these span a large number of clinical areas and are published across more than a hundred different medical journals, making it difficult for transfusion medicine practitioners and researchers to keep abreast of the current high-level evidence. In response to this problem, NHS Blood and Transplant's Systematic Review Initiative (SRI) has produced a comprehensive overview of systematic reviews in transfusion medicine. A systematic search (to December 2009) and screening procedure were followed by the appraisal of systematic reviews according to predefined inclusion criteria. The 340 eligible systematic reviews were mapped to 10 transfusion intervention groups and 14 topic groups within clinical medicine. Trends in the systematic review literature were examined and gaps in the literature described. The spread of systematic reviews across clinical areas was found to be very uneven, with some areas underreviewed and others with multiple systematic reviews on the same topic, making the identification of the best evidence for current transfusion practice a continuing challenge. References and links to all systematic reviews included in this overview can be freely accessed via the SRI's new online database, the Transfusion Evidence Library (www.transfusionguidelines.org). © 2010.

OBJECTIVE: to investigate the potential cost-effectiveness of alternative 'test-and-treat' strategies in the prevention of spontaneous pre-term birth before 34 and 37 weeks' gestation. DESIGN: Model-based economic evaluation. Setting. Clinics, general practices, health centers or any setting delivering antenatal care. POPULATION: Asymptomatic women in early pregnancy and symptomatic women with threatened pre-term labor in later pregnancy. METHODS: Data from systematic reviews of effectiveness and accuracy were combined into strategies and analyzed using a decision-tree model. Full deterministic and probabilistic sensitivity analyses were carried out. MAIN OUTCOME MEASURES: Spontaneous pre-term labor avoided for asymptomatic women and spontaneous pre-term birth avoided for symptomatic women. RESULTS: the systematic reviews identified evidence on the accuracy of 22 types of tests and on the effectiveness of 40 possible interventions. Cost data were based on secondary evidence, supplemented with primary data from local sources. Testing prior to intervention was not shown to be the most cost-effective strategy in the main analyses for 34 and 37 weeks. Prophylactic fish oil in asymptomatic women, without prior testing, was highlighted as potentially cost-effective in preventing threatened pre-term labor before 34 weeks. In symptomatic women with a viable pregnancy, indomethacin without prior testing was a potentially cost-effective strategy to prevent pre-term birth occurring before 37 weeks. CONCLUSION: an effective, affordable and safe intervention applied to all mothers without prior testing is likely to be the most cost-effective strategy in the prevention of spontaneous pre-term labor and birth. The results reported in this paper are important for prioritizing future research, world-wide.

The aim of this article is to review the accuracy of tests purported to be predictive of pre-eclampsia, a major cause of maternal and perinatal mortality and morbidity worldwide. A review of systematic reviews was done. A total of 219 studies were evaluated for the accuracy of 27 tests for predicting pre-eclampsia. Study quality assessment and data abstraction were performed using piloted proformas. Bivariate meta-analyses were used to synthesize data. Levels of sensitivity and specificity were measured. There were deficiencies in many areas of methodology including blinding, test description, and reference standard adequacy. No test had a high level of both sensitivity and specificity of greater than 90%. Where multiple studies were available, only BMI > 34, alpha-fetoprotein, fibronectin (cellular and total), and uterine artery Doppler (bilateral notching) measurements reached specificity above 90%. Only Doppler (any/unilateral notching, resistance index, and combinations) measurements were over 60% sensitive. Studies were of variable quality and most tests performed poorly. Further research should focus on tests which offer much higher levels of sensitivity than tests currently available. High sensitivity is a more useful attribute in early detection of pre-eclampsia than specificity because consideration of benefits, harms and costs indicates a much greater preference for minimizing false negatives than false positives, although the ideal would be to avoid both.

BACKGROUND: Haemopoietic stem cells can be collected from a donor either as a bone marrow harvest or by peripheral blood collection. Both techniques have risks for the donor. OBJECTIVES: the aim of this review was to identify the adverse effects of haemopoietic stem cell donation and to compare the tolerability and safety of the two methods. SEARCH STRATEGY: We searched bibliographic databases including the Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library 2008, issue 2), MEDLINE and EMBASE up to May 2008. We also searched reference lists of articles and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials enrolling haemopoietic stem cell donors and evaluating the different methods of donating haemopoietic stem cells were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for inclusion. We extracted data and evaluated methodological quality. Quantitative analysis was not possible for most outcomes, but where used we preferred random-effects models due to the variability between the included studies. MAIN RESULTS: Six trials (807 donors) were eligible: all were substudies, or constituent parts of, larger randomised controlled trials of bone marrow and peripheral blood stem cell allogeneic transplantation. No included trial was designed solely to measure and assess the experience of stem cell donors. The donors in all studies were related to the stem cell recipient. Overall, both types of donors experienced pain subsequent to donation, and psychological morbidity. The trend was for bone marrow donors to experience more pain at the donation site, more overall adverse events, and more days of restricted activity. They were also more likely to require hospitalisation than peripheral blood stem cell donors. In contrast, peripheral blood stem cell donors experienced more pain prior to donation, which may be related to the pre-donation administration of granulocyte colony stimulating factor (G-CSF). The methodological quality of the studies was poor and indicated limitations due to the risk of selection and attrition bias. The proportion of donors from the parent trial not included in the donor substudies was also inadequately explained. AUTHORS' CONCLUSIONS: the different short-term morbidities associated with each type of haemopoietic stem cell donation were clear, with bone marrow donors experiencing more pain and more restriction post-donation than peripheral blood donors. However, the studies were limited by their methodological quality, failure to provide long-term follow up (for which larger numbers of donors would be required) and a failure to apply consistent measures of quality of life in a way which allows more meaningful evaluation across studies.

OBJECTIVE(S): to investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications. DATA SOURCES: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies. REVIEW METHODS: the systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out. RESULTS: in total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results. CONCLUSION(S): all five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

BACKGROUND: Many theories of behaviour are potentially relevant to predictive and intervention studies but most studies investigate a narrow range of theories. Michie et al. (2005) agreed 12 'theoretical domains' from 33 theories that explain behaviour change. They developed a 'Theoretical Domains Interview' (TDI) for identifying relevant domains for specific clinical behaviours, but the framework has not been used for selecting theories for predictive studies. It was used here to investigate clinicians' transfusion behaviour in intensive care units (ICU). Evidence suggests that red blood cells transfusion could be reduced for some patients without reducing quality of care. OBJECTIVES: (1) to identify the domains relevant to transfusion practice in ICUs and neonatal intensive care units (NICUs), using the TDI. (2) to use the identified domains to select appropriate theories for a study predicting transfusion behaviour. METHODS: an adapted TDI about managing a patient with borderline haemoglobin by watching and waiting instead of transfusing red blood cells was used to conduct semi-structured, one-to-one interviews with 18 intensive care consultants and neonatologists across the UK. RESULTS: Relevant theoretical domains were: knowledge, beliefs about capabilities, beliefs about consequences, social influences, behavioural regulation. Further analysis at the construct level resulted in selection of seven theoretical approaches relevant to this context: Knowledge-Attitude-Behaviour Model, Theory of Planned Behaviour, Social Cognitive Theory, Operant Learning Theory, Control Theory, Normative Model of Work Team Effectiveness and Action Planning Approaches. CONCLUSIONS: This study illustrated, the use of the TDI to identify relevant domains in a complex area of inpatient care. This approach is potentially valuable for selecting theories relevant to predictive studies and resulted in greater breadth of potential explanations than would be achieved if a single theoretical model had been adopted.

Clarifying the existing evidence base is crucial to improve the effectiveness of transfusion practice. The UK Systematic Review Initiative has been pursuing this objective primarily through writing systematic reviews on important topics in transfusion medicine. Here, we describe our progress for the past 5 years. We are the only research group that identifies transfusion medicine randomized controlled trials (RCTs) for the Cochrane Central Register of Controlled Trials, and to date, we have contributed 3002 RCT citations. The article considers future challenges including the need for wider involvement from the transfusion medicine community in the process of maintaining and updating systematic reviews and the identification and prioritization of topics for further clinical research including clinical trials. Collaboration between international and local research groups is important if these challenges are to be met.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of infliximab for moderately to severely active ulcerative colitis (UC) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellent (NICE) as part of the single technology appraisal (STA) process. The submission indicated that the efficacy of infliximab (5 mg/kg) had been demonstrated in terms of higher response rates and a sustained response in health-related quality of life. For the cost-effectiveness analysis, the manufacturer built a Markov model to compare infliximab with standard care. It estimated the incremental cost per quality-adjusted life-year (QALY) gained was between 25,044 pounds and 33,866 pounds depending on the strategy used. The ERG report generally agreed with the evidence on effectiveness of infliximab for subacute exacerbations of UC. However, there were several areas of uncertainty, of which the interpretation of the importance of the quality of life changes in the subacute situation and the assessment of the adequacy of the evidence of effectiveness of infliximab in the acute hospital-based situation were considered pre-eminent by the ERG. This challenged the estimates of cost-effectiveness offered and suggested that there should be a separate assessment of infliximab for acute exacerbations of moderately to severely active UC. The summary of the NICE guidance issued in April 2008 as a result of the STA states that: infliximab is not recommended for the treatment of subacute manifestations of moderately to severely active UC.

The primary antibody deficiency syndromes are a rare group of immunodeficiencies where diagnostic delay remains common due to limited awareness of the existence and heterogeneity of their presenting features. Referral for specialist assessment leads to earlier diagnosis and appropriate therapy to prevent or limit structural organ and tissue damage. Greater education of healthcare professionals is required to ensure prompt recognition and referral to specialists with expertise in the care of primary immunodeficiencies, especially since study of these rare conditions is a minor part of undergraduate and general postgraduate training. Greater awareness would lead to reduced morbidity, improved quality of life and survival outcomes in this patient group.

BACKGROUND: Impaction grafting is a technique to restore bone loss both in the femur and the acetabulum during revision hip arthroplasty surgery. Initially impaction grafting was undertaken using fresh frozen femoral head allografts that were milled to create morselized bone pieces that could be impacted to create a neo-cancellous bone bed prior to cementation of the new implant. Results of medium and long term outcome studies have shown variable results using this technique. Currently both processed and non-processed allograft bone are used and the purpose of this review was to analyse the evidence for both. OBJECTIVES: to determine the clinical effectiveness of processed (freeze dried or irradiated) bone in comparison to fresh frozen (unprocessed) bone. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1985 to 2008), EMBASE (1985 to 2008), CINAHL(1985 to 2008) and the National Research Register. Additional sources were also searched. Handsearching of relevant journals and conference abstracts was also undertaken. Searches were complete to 31 August 2008. SELECTION CRITERIA: Randomised controlled trials that compared different types of bone for impaction grafting. DATA COLLECTION AND ANALYSIS: Three hundred and sixty references were identified from the searches. Following detailed eligibility screening, three hundred and fifty nine references did not meet the eligibility criteria. Further details are required about one trial in order to determine it's eligibility. MAIN RESULTS: No trials were identified that met the criteria for inclusion in the review. AUTHORS' CONCLUSIONS: Good quality randomised controlled trials are required in this area so that a surgeon's choice of bone graft can be informed by evidence rather than personal preference.

BACKGROUND: Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year and has a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is not known. OBJECTIVES: to assess the effects of red blood cell transfusion in adults with upper gastrointestinal haemorrhage. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials, haematology and gastroenterology conference proceedings, and reference lists of articles. We also searched databases of ongoing clinical trials. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing red blood cell transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three trials involving 126 patients were included in the review, with complete data available for 93 patients. The participants were heterogeneous and none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to red blood cell transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study less than half the participants were included in the final analysis.One randomised controlled trial of restrictive versus liberal red blood cell transfusion, which aims to recruit 860 patients, has yet to be completed. AUTHORS' CONCLUSIONS: There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed randomised controlled trials of sufficient power are urgently needed.

AIMS: Previous evaluation of autologous bone-marrow stem-cell (BMSC) therapy following acute myocardial infarction (AMI) suggests that cell dose and timing of stem-cell administration post-MI are important factors in the efficacy of cellular therapy. This study aimed to assess whether route of delivery and baseline left ventricular ejection fraction (LVEF) of the participants may also affect the outcome of BMSC treatment in patients with AMI and ischaemic heart disease (IHD). METHODS AND RESULTS: Randomized controlled trials of BMSCs as treatment for AMI and IHD were identified by searching MEDLINE, EMBASE, the Cochrane Library, and the Current Controlled Trials Register through to November 2008. Twenty-one trials (25 comparisons) with a total of 1091 participants were eligible. Data were analysed using a random-effects model. Improvement in LVEF in favour of the control was observed when BMSC were administered by intracoronary infusion [-0.19% (95% CI, -0.24 to -0.14; P < 0.00001)] in IHD patients. However, the effect on LVEF was statistically significant and in favour of BMSC when cells were delivered by intra-myocardial injection [5.85% (95% CI, 2.50-9.19; P = 0.0006)]. The significant improvement in LVEF observed in AMI patients was independent from the baseline LVEF of the participants. However, in patients suffering from chronic IHD, increase in LVEF was significant only in the group with lower LVEF at baseline [4.42% (CI, 1.87-6.96; P = 0.0007)]. CONCLUSION: Clinical evidence suggests that route of delivery and baseline LVEF influence the effect of BMSC therapy in treating AMI and chronic IHD.

OBJECTIVES: to identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. DATA SOURCES: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. REVIEW METHODS: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. RESULTS: of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance. CONCLUSIONS: for primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

Haematopoietic stem cell transplantation (HSCT) is widely used to treat patients with a range of haematological and non-haematological disorders. Both bone marrow and peripheral blood stem cell collection are associated with morbidity and, very rarely, mortality. We investigated the information that exists to adequately inform donors about the relative merits of each procedure. We carried out a systematic review analysing data from six prospective randomised controlled trials of related donors and discuss here the merits and drawbacks of this approach. Registry data mostly describes patient outcome but stem cell donor registries collect and report information on unrelated donors which could easily be extended to related donors. Further well-designed, randomised studies are required.

BACKGROUND: Conduct problems are common, disabling and costly. The prognosis for children with conduct problems is poor, with outcomes in adulthood including criminal behaviour, alcoholism, drug abuse, domestic violence, child abuse and a range of psychiatric disorders. There has been a rapid expansion of group based parent-training programmes for the treatment of children with conduct problems in a number of countries over the past 10 years. Existing reviews of parent training have methodological limitations such as inclusion of non-randomised studies, the absence of investigation for heterogeneity prior to meta-analysis or failure to report confidence intervals. The objective of the current study was to systematically review randomised controlled trials of parenting programmes for the treatment of children with conduct problems. METHODS: Standard systematic review methods were followed including duplicate inclusion decisions, data extraction and quality assessment. Twenty electronic databases from the fields of medicine, psychology, social science and education were comprehensively searched for RCTs and systematic reviews to February 2006. Inclusion criteria were: randomised controlled trial; of structured, repeatable parenting programmes; for parents/carers of children up to the age of 18 with a conduct problem; and at least one measure of child behaviour. Meta-analysis and qualitative synthesis were used to summarise included studies. RESULTS: 57 RCTs were included. Studies were small with an average group size of 21. Meta-analyses using both parent (SMD -0.67; 95% CI: -0.91, -0.42) and independent (SMD -0.44; 95% CI: -0.66, -0.23) reports of outcome showed significant differences favouring the intervention group. There was insufficient evidence to determine the relative effectiveness of different approaches to delivering parenting programmes. CONCLUSION: Parenting programmes are an effective treatment for children with conduct problems. The relative effectiveness of different parenting programmes requires further research.

BACKGROUND: Blood transfusion is an essential part of healthcare and can improve patient outcomes. However, like most therapies, it is also associated with significant clinical risks. In addition, there is some evidence of overuse. Understanding the potential barriers and enablers to reduced prescribing of blood products will facilitate the selection of intervention components likely to be effective, thereby reducing the number of costly trials evaluating different implementation strategies. Using a theoretical basis to understand behaviours targeted for change will contribute to a 'basic science' relating to determinants of professional behaviour and how these inform the selection of techniques for changing behaviour. However, it is not clear which theories of behaviour are relevant to clinicians' transfusing behaviour. The aim of this study is to use a theoretical domains framework to identify relevant theories, and to use these theories to identify factors that predict the decision to transfuse. METHODS: the study involves two steps: interview study and questionnaire study. Using a previously identified framework, we will conduct semi-structured interviews with clinicians to elicit their views about which factors are associated with waiting and further monitoring the patient rather than transfusing red blood cells. Interviews will cover the following theoretical domains: knowledge; skills; social/professional role and identity; beliefs about capabilities; beliefs about consequences; motivation and goals; memory, attention, and decision processes; environmental context and resources; social influences; emotion; behavioural regulation; nature of the behaviour. The interviews will take place independently in Canada and the UK and involve two groups of physicians in each country (UK: adult and neonatal intensive care physicians; Canada: intensive care physicians and orthopaedic surgeons). We will: analyse interview transcript content to select relevant theoretical domains; use consensus processes to map these domains on to theories of behaviour; develop questionnaires based on these theories; and mail them to each group of physicians in the two countries. From our previous work, it is likely that the theories will include: theory of planned behaviour, social cognitive theory and the evidence-based strategy, implementation intention. The questionnaire data will measure predictor variables (theoretical constructs) and outcome variables (intention and clinical decision), and will be analysed using multiple regression analysis. We aim to achieve 150 respondents in each of the four groups for each postal survey.

BACKGROUND: Allergies cause a considerable burden to both sufferers and the National Health Service. There is growing interest in acupuncture as a treatment for a range of conditions. Since acupuncture may modulate the immune system it could be a useful treatment for allergic rhinitis (AR) sufferers. We therefore assessed the evidence for the clinical effectiveness of acupuncture in patients with AR by performing a systematic review of the literature. METHODS: Searches (to 2007) were conducted in all major databases for randomised controlled trials (RCTs) evaluating the clinical effectiveness of acupuncture in the treatment of AR. No limits were placed on language. Studies were included if they compared acupuncture to a sham or inactive acupuncture treatment (placebo) with or without standard care. Meta-analysis was performed where feasible. RESULTS: Seven relevant RCTs were included after screening and application of inclusion and exclusion criteria. The trials were generally of poor quality as assessed by a modified Jadad scale, with the exception of two studies which scored highly. A wide variety of outcomes was measured but most assessed symptom severity on a visual analogue scale. A meta-analysis failed to show any summary benefits of acupuncture treatment for symptom severity scores or serum IgE measures which could not have been accounted for by chance alone. Acupuncture was not associated with any additional adverse events in the trials. CONCLUSION: There is currently insufficient evidence to support or refute the use of acupuncture in patients with AR. A large well conducted RCT, which overcomes identified methodological problems in the existing RCTs, would be required to resolve this question.

AIMS: to provide systematic assessment of the safety and efficacy of autologous bone marrow-derived stem cell (BMSC) transplantation in acute myocardial infarction (AMI) based on clinical evidence. METHODS AND RESULTS: the search strategy included MEDLINE, EMBASE, the Cochrane Library, and Current Controlled Trials Register through to August 2007 for randomized controlled trials of BMSC treatment for AMI. Thirteen trials (14 comparisons) with a total of 811 participants were included. Data were analysed using a random effects model. Overall, stem cell therapy improved left ventricular ejection fraction (LVEF) by 2.99% [95% confidence interval (CI), 1.26-4.72%, P = 0.0007], significantly reduced left ventricular end-systolic volume (LVESV) by 4.74 mL (95% CI, -7.84 to -1.64 mL, P = 0.003), and myocardial lesion area by 3.51% (95% CI, -5.91 to -1.11%, P = 0.004) compared with controls. Subgroup analysis revealed that there was statistical significant difference in LEVF in favour of BMSCs when cells were infused within 7 days following AMI and when the BMSC dose administered was higher than 10(8) BMSCs. In addition, there were trends in favour of benefit for most clinical outcomes examined, although it should be acknowledged that the 95%CI included no significant difference. CONCLUSION: Stem cell treatment for AMI still holds promise. Clinically, these data suggest that improvement over conventional therapy can be achieved. Further, adequately powered trials using optimal dosing, longer term outcome assessments, more reliable, and more patient-centred outcomes are required.

Use of recombinant Factor VIIa (rFVIIa) has extended to nonhemophiliac patients anticipated to be at risk of major bleeding (prophylactic) or who have uncontrolled bleeding (therapeutic). The aim of this review was to systematically appraise randomized controlled trial (RCT) evidence for effectiveness of rFVIIa, by updating and extending the earlier Cochrane Systematic Review. Up to January 2007, 17 RCTs were identified in which rFVIIa was used to try to reduce bleeding in patients undergoing planned high blood loss surgery or in acute situations such as trauma, gastrointestinal bleeding, and intracerebral hemorrhage (ICH). Overall, there was little evidence of rFVIIa benefit during planned surgical procedures. Although use in ICH was impressive as both bleed progression and mortality were reduced, preliminary results from a subsequent phase III trial have found no outcome benefit. Selected subgroup analysis or secondary outcome results for other therapeutic trials appeared promising but were usually associated with methodological limitations. The thromboembolic adverse event incidence in subjects who received rFVIIa is of concern and occurred despite a common trial exclusion criterion of patients with a history of previous thromboembolic or vasoocclusive disease. The reasons for increasing use of this drug off license remain unclear, and the results of further trials are required to establish effectiveness.

To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia.

BACKGROUND: Needle biopsy of a suspicious liver lesion could guide management in the setting of equivocal imaging and serology, although it is not recommended generally because there is the possibility of tumour dissemination outside the liver. The incidence of needle track seeding following biopsy of a suspicious liver lesion is ill-defined, however. METHODS: a systematic review and meta-analysis of observational studies published before March 2007 was performed. Studies that reported on needle tract seeding following biopsy of suspicious liver lesions were identified. Lesions suspected of being hepatocelleular cancer (HCC) were considered. Data on the type of needle biopsy, diagnosis, incidence of needle track seeding duration to seeding, follow-up and impact on outcome were tabulated. RESULTS: Eight studies identified by systematic review on biopsy of HCC were included in a meta-analysis. The pooled estimate of a patient with seeding per 100 patients with HCC was 0.027 (95% confidence interval (CI) 0.018 to 0.040). There was no difference whether a fixed or random effects model was used. Q was 4.802 with 7 degrees of freedom, p = 0.684; thus the observed heterogeneity was compatible with variation by chance alone. The pooled estimate of a patient with seeding per 100 patients per year was 0.009 (95% CI 0.006 to 0.013), p = 0.686. CONCLUSIONS: in this systematic review we have shown that the incidence of needle tract tumour seeding following biopsy of a HCC is 2.7% overall, or 0.9% per year.

BACKGROUND: Stem cell therapy offers a promising approach to the regeneration of damaged vascular and cardiac tissue after myocardial infarction (MI). This has resulted in multiple randomised controlled trials (RCTs) worldwide. OBJECTIVES: to critically evaluate evidence from RCTs on the effectiveness of adult bone marrow-derived stem cells (BMSC) to treat acute MI. SEARCH STRATEGY: MEDLINE (1950 to August 2007), EMBASE (1974 to August 2007), the Cochrane Library (Issue 3 2007), and CINAHL (1982 to August 2007) were searched. In addition LILACS, KOREAMED, INMED, Current Controlled Trials Register, the UK National Research Register and other handsearching was undertaken to August 2007. SELECTION CRITERIA: RCTs comparing autologous stem/progenitor cells with no autologous stem/progenitor cells in patients diagnosed with acute myocardial infarction (AMI) were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened all references, assessed trial quality and extracted data. Meta-analyses using a random-effects model were conducted and heterogeneity was explored using sub-group analyses. MAIN RESULTS: Thirteen RCTs (811 participants) were included. There were insufficient events on clinical outcomes like mortality to draw clear conclusions. Stem/progenitor cell treatment does not appear to be associated with an increase in adverse events but again the data do not allow clear conclusions. Left ventricular ejection fraction (LVEF) was the outcome with most results and there was marked heterogeneity between trials. There was however a consistent pattern indicating that BMSC treatment generally improves short-term LVEF, with similar trends for left ventricular end systolic and end diastolic volumes (LVESV and LVEDV), infarct size or cardiac wall motion. There was a positive correlation between cell dose infused and the effect on LVEF measured by magnetic resonance imaging. AUTHORS' CONCLUSIONS: the results of this systematic review suggest that there is little evidence to assess the clinical effects of this treatment. Larger trials using optimal dosing and more reliable, patient-centred outcomes are required. Several trials are ongoing but is unclear whether these will overcome the limitations of the current evidence base.

OBJECTIVES: to assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment. DATA SOURCES: Electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004. REVIEW METHODS: Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model). RESULTS: in total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound 10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound 13,000 to pound 28,000, but generated estimates from pound 84,000 to pound 159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound 150,000, falling to pound 40,000 when the lower, more favourable, confidence interval for survival was used. CONCLUSIONS: Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.

The primary purpose of this systematic review was to produce an evidence-based review of the literature as a means of informing current clinical practice in the recognition, diagnosis and management of patients with suspected primary antibody deficiency. Randomized controlled trials (RCTs) were identified from a search of MEDLINE, EMBASE, the Cochrane Library, DARE (CRD website) and CINAHL by combining the search strategies with the Cochrane Collaboration's validated RCT filter. In addition, other types of studies were identified in a separate search of MEDLINE and EMBASE. Patients at any age with recurrent infections, especially in the upper and lower respiratory tracts, should be investigated for possible antibody deficiency. Replacement therapy with immunoglobulin in primary antibody deficiencies increases life expectancy and reduces infection frequency and severity. Higher doses of immunoglobulin are associated with reduced infection frequency. Late diagnosis and delayed institution of immunoglobulin replacement therapy results in increased morbidity and mortality. A wide variety of organ-specific complications can occur in primary antibody deficiency syndromes, including respiratory, gastroenterological, hepatic, haematological, neurological, rheumatological and cutaneous. There is an increased risk of malignancy. Some of these complications appear to be related to diagnostic delay and inadequate therapy. High-quality controlled trial data on the therapy of these complications is generally lacking. The present study has identified a number of key areas for further research, but RCT data, while desirable, is not always obtained easily for rare conditions. Few data from registries or large case-series have been published in the past 5 years and a greater focus on international collaboration and pooling of data is needed.

BACKGROUND: Recombinant factor VIIa (rFVIIa) is licensed for use in patients with haemophilia and inhibitory allo-antibodies. It is also increasingly being used for off-license indications to prevent bleeding in operations where blood loss is likely to be high, and/or to stop bleeding that is proving difficult to control by other means. OBJECTIVES: to assess the effectiveness of rFVIIa when used therapeutically to control active bleeding, or prophylactically to prevent (excessive) bleeding in patients without haemophilia. SEARCH STRATEGY: We searched the Cochrane Injuries Group's Specialised Register, CENTRAL, MEDLINE, EMBASE and other specialised databases up to March 2006. We also searched reference lists of articles and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population with the exception of those with haemophilia. There was no restriction by outcomes examined, but this review focuses on mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thromboembolic adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently assessed potentially relevant studies for inclusion. Data were extracted and methodological quality was examined. Studies using rFVIIa prophylactically and those using rFVIIa therapeutically have been considered separately. Data were pooled using fixed and random effects models, but random effects models were preferred because of the variability in clinical features of the included studies. MAIN RESULTS: Thirteen trials met the inclusion criteria; all were placebo-controlled double-blind RCTs. Six trials involving 724 participants examined the prophylactic use of rFVIIa; 379 received rFVIIa. There were no outcomes by which any observed advantage, or disadvantage, of rFVIIa over placebo could not have been observed by chance alone. There were trends in favour of rFVIIa for a number of outcomes, particularly the number of participants transfused, pooled RR 0.85 (95% CI 0.72 to 1.01) but this was balanced by a trend against rFVIIa with respect to thromboembolic adverse events, pooled RR 1.25 (95% CI 0.76 to 2.07). Seven trials involving 1214 participants examined the therapeutic use of rFVIIa; 687 received rFVIIa. There were no outcomes where any observed advantage, or disadvantage, of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality, RR 0.82 (95% CI 0.64 to 1.04), although no other clear trends in favour of rFVIIa were noted for other desired outcomes. Interpretation of these results must take into account one study which could not be included in the quantitative summary but which showed results strongly in favour of rFVIIa for the treatment of intra-cerebral haemorrhage. There was a trend against rFVIIa with respect to thromboembolic adverse events; the RR 1.50 (95% CI 0.86 to 2.62). AUTHORS' CONCLUSIONS: Although rFVIIa has a role in the management of patients with haemophilia, its effectiveness as a more general haemostatic drug, either prophylactically or therapeutically, remains uncertain. Its effectiveness as a therapeutic agent, particularly for intra-cerebral haemorrhage, looks more encouraging than prophylactic use. The use of rFVIIa outside its current licensed indications should be very limited and its wider use await the results of ongoing and possibly newly commissioned RCTs. In the interim, rFVIIa use should be restricted to clinical trials.

Randomised, controlled trials of good quality are a recognised means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomised trials involving fresh frozen plasma (FFP) indicates that most clinical indications for FFP, as currently recommended by practice guidelines, are not supported by evidence from randomised trials. This chapter will largely consider the implications of some of the findings from this systematic review. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias; no studies had taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. In addition, there is little evidence for the effectiveness of the prophylactic use of FFP. There is a pressing need to consider how best to develop new trials to determine the effectiveness of FFP. How this can be achieved can be illustrated by reference to studies of albumin in critical care. A recent, large and well-designed randomised trial (Saline versus Albumin Fluid Evaluation study; SAFE) in critical care found no evidence of an increase in mortality with the use of albumin compared to saline, which had been hypothesised in an earlier systematic review. How the study findings will actually now influence the clinical use of albumin remains to be seen. Although the SAFE trial showed no increase in mortality with albumin compared with saline, it is difficult to justify its use in critical care given its considerably greater cost.

BACKGROUND: in 2003 the National Institute of Clinical Excellence published guidelines recommending the use of brain natriuretic peptide (BNP) and the electrocardiogram (ECG) as part of the diagnostic work up of individuals with heart failure. However, the guideline did not address whether one test was superior to the other or whether performing both tests was superior to performing single tests. AIM: to investigate the relative test accuracy of the ECG, BNP, N terminal-pro brain natriuretic peptide (NT-proBNP) and combinations of two or more tests in the diagnosis of left ventricular systolic dysfunction (LVSD) in the primary care setting. DESIGN OF STUDY: Cohort studies making within-subject comparisons of intervention diagnostic test(s) with reference standard results. METHOD: Standard systematic review methodology was followed. RESULTS: Thirty-two primary studies met the review inclusion criteria. Studies were of variable quality and highly clinically heterogeneous, therefore restricting the use of meta-analysis. Within these limitations BNP, NT-proBNP and the ECG all had similar test sensitivity (>80% in the majority of studies). Specificity of the three tests was not as good. Three studies directly comparing BNP and the ECG found no difference in sensitivity and limited support for improved specificity of BNP. Two studies found no difference in sensitivity and limited evidence for an improvement in specificity for the combination of the ECG and BNP compared to single tests. CONCLUSION: on the basis of existing evidence, the ECG, BNP and NT-proBNP are useful in excluding a diagnosis of LVSD (good sensitivity). However, use of abnormal test results to select individuals for echocardiography may overwhelm services. There is currently no evidence to justify the use of one test over another or the use of tests in combination. The additional cost of BNP is not self-evidently justified by improved test accuracy. Further research is needed to directly compare the diagnostic performance of these tests in homogeneous, representative primary care populations.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: the aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e. epoetin) and darbepoetin alfa (i.e. darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

OBJECTIVES: to assess the effectiveness and cost-effectiveness of adding automated image analysis to cervical screening programmes. DATA SOURCES: Searching of all major electronic databases to the end of 2000 was supplemented by a detailed survey for unpublished UK literature. METHOD: Four systematic reviews were conducted according to recognised guidance. The review of 'clinical effectiveness' included studies assessing reproducibility and impact on health outcomes and processes in addition to evaluations of test accuracy. A discrete event simulation model was developed, although the economic evaluation ultimately relied on a cost-minimisation analysis. RESULTS: the predominant finding from the systematic reviews was the very limited amount of rigorous primary research. None of the included studies refers to the only commercially available automated image analysis device in 2002, the AutoPap Guided Screening (GS) System. The results of the included studies were debatably most compatible with automated image analysis being equivalent in test performance to manual screening. Concerning process, there was evidence that automation does lead to reductions in average slide processing times. In the PRISMATIC trial this was reduced from 10.4 to 3.9 minutes, a statistically significant and practically important difference. The economic evaluation tentatively suggested that the AutoPap GS System may be efficient. The key proviso is that credible data become available to support that the AutoPap GS System has test performance and processing times equivalent to those obtained for PAPNET. CONCLUSIONS: the available evidence is still insufficie