Do we know enough about the effect of low-dose computed tomography screening for lung cancer on mortality to act? An updated systematic review, meta-analysis and network meta-analysis of randomised controlled trials 2017 to 2021.

BACKGROUND: For people at high risk of lung cancer, low-dose computed tomography (LDCT) is proposed as a method to reduce mortality. 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) 0.86, 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 updating 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.

Real-world post-deployment performance of a novel machine learning-based digital health technology for skin lesion assessment and suggestions for post-market surveillance.

Introduction: Deep Ensemble for Recognition of Malignancy (DERM) is an artificial intelligence as a medical device (AIaMD) tool for skin lesion assessment. Methods: We report prospective real-world performance from its deployment within skin cancer pathways at two National Health Service hospitals (UK) between July 2021 and October 2022. Results: A total of 14,500 cases were seen, including patients 18-100 years old with Fitzpatrick skin types I-VI represented. Based on 8,571 lesions assessed by DERM with confirmed outcomes, versions A and B demonstrated very high sensitivity for detecting melanoma (95.0-100.0%) or malignancy (96.0-100.0%). Benign lesion specificity was 40.7-49.4% (DERM-vA) and 70.1-73.4% (DERM-vB). DERM identified 15.0-31.0% of cases as eligible for discharge. Discussion: We show DERM performance in-line with sensitivity targets and pre-marketing authorisation research, and it reduced the caseload for hospital specialists in two pathways. Based on our experience we offer suggestions on key elements of post-market surveillance for AIaMDs.

Health technology assessment of diagnostic tests: a state of the art review of methods guidance from international organizations.

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.

Serial high-sensitivity cardiac troponin testing for the diagnosis of myocardial infarction: a scoping review.

OBJECTIVES: We 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). METHODS: We 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. RESULTS: We 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. CONCLUSION: Evidence 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 NUMBER: CRD42018106379.

UK National Screening Committee's approach to reviewing evidence on artificial intelligence in breast cancer screening.

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.

A prospective evaluation of the fourth national Be Clear on Cancer 'Blood in Pee' campaign in England.

OBJECTIVE: To assess the impact of the fourth Be Clear on Cancer (BCoC) 'Blood in Pee' (BiP) campaign (July to September 2018) on bladder and kidney cancer symptom awareness and outcomes in England. METHODS: In this uncontrolled before and after study, symptom awareness and reported barriers to GP attendance were assessed using panel and one-to-one interviews. The Health Improvement Network (THIN), National Cancer Registration and Analysis Service (NCRAS) and NHS Cancer Waiting Times (CWT) data were analysed to assess the impact on GP attendances, urgent cancer referrals, cancer diagnoses and 1-year survival. Analyses used Poisson, negative binomial and Cox regression. RESULTS: Symptom awareness and intention to consult a GP after one episode of haematuria increased following the campaign. GP attendance with haematuria (rate ratio (RR) 1.17, 95% confidence interval (CI): 1.07-1.28) and urgent cancer referrals (RR 1.18 95% CI: 1.08-1.28) increased following the campaign. Early-stage diagnoses increased for bladder cancer (difference in percentage 2.8%, 95% CI: -0.2%-5.8%), but not for kidney cancer (difference -0.6%, 95% CI: -3.2%-2.1%). CONCLUSIONS: The fourth BCoC BiP campaign appears to have been effective in increasing bladder cancer symptom awareness and GP attendances, although long-term impacts are unclear.

Variation in Model-Based Economic Evaluations of Low-Dose Computed Tomography Screening for Lung Cancer: A Methodological Review.

OBJECTIVES: There is significant heterogeneity in the results of published model-based economic evaluations of low-dose computed tomography (LDCT) screening for lung cancer. We sought to understand and demonstrate how these models differ. METHODS: An expansion and update of a previous systematic review (N = 19). Databases (including MEDLINE and Embase) were searched. Studies were included if strategies involving (single or multiple) LDCT screening were compared with no screening or other imaging modalities, in a population at risk of lung cancer. More detailed data extraction of studies from the previous review was conducted. Studies were critically appraised using the Consensus Health Economic Criteria list. RESULTS: A total of 16 new studies met the inclusion criteria, giving a total of 35 studies. There are geographic and temporal differences and differences in screening intervals and eligible populations. Studies varied in the types of models used, for example, decision tree, Markov, and microsimulation models. Most conducted a cost-effectiveness analysis (using life-years gained) or cost-utility analysis. The potential for overdiagnosis was considered in many models, unlike with other potential consequences of screening. Some studies report considering lead-time bias, but fewer mention length bias. Generally, the more recent studies, involving more complex modeling, tended to meet more of the critical appraisal criteria, with notable exceptions. CONCLUSIONS: There are many differences across the economic evaluations contributing to variation in estimates of the cost-effectiveness of LDCT screening for lung cancer. Several methodological factors and evidence needs have been highlighted that will require consideration in future economic evaluations to achieve better agreement.

It was not easy to identify the study design from the title and abstract of articles indexed as diagnostic (test) accuracy studies in EMBASE in 2012 and 2019.

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.

An evaluation of a national mass media campaign to raise public awareness of possible lung cancer symptoms in England in 2016 and 2017.

BACKGROUND: A two-phase 'respiratory symptoms' mass media campaign was conducted in 2016 and 2017 in England raising awareness of cough and worsening shortness of breath as symptoms warranting a general practitioner (GP) visit. METHOD: A prospectively planned pre-post evaluation was done using routinely collected data on 15 metrics, including GP attendance, GP referral, emergency presentations, cancers diagnosed (five metrics), cancer stage, investigations (two metrics), outpatient attendances, inpatient admissions, major lung resections and 1-year survival. The primary analysis compared 2015 with 2017. Trends in metrics over the whole period were also considered. The effects of the campaign on awareness of lung cancer symptoms were evaluated using bespoke surveys. RESULTS: There were small favourable statistically significant and clinically important changes over 2 years in 11 of the 15 metrics measured, including a 2.11% (95% confidence interval 1.02-3.20, p < 0.001) improvement in the percentage of lung cancers diagnosed at an early stage. However, these changes were not accompanied by increases in GP attendances. Furthermore, the time trends showed a gradual change in the metrics rather than steep changes occurring during or after the campaigns. CONCLUSION: There were small positive changes in most metrics relating to lung cancer diagnosis after this campaign. However, the pattern over time challenges whether the improvements are wholly attributable to the campaign. Given the importance of education on cancer in its own right, raising awareness of symptoms should remain important. However further research is needed to maximise the effect on health outcomes.

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

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.

Randomised controlled trial protocol for the PROTECT-CS Study: PROTein to Enhance outComes of (pre)frail paTients undergoing Cardiac Surgery.

INTRODUCTION: In the past 20 years, the increasing burden of heart disease in an ageing population has resulted in cardiac surgery (CS) being offered to more frail and older patients with multiple comorbidities. Frailty and malnutrition are key geriatric syndromes that impact postoperative outcomes, including morbidity, mortality and prolonged hospital length of stay. Enhanced recovery protocols (ERPs), such as prehabilitation, have been associated with a reduction in complications after CS in vulnerable patients. The use of nutritional ERPs may enhance short-term and long-term recovery and mitigate frailty progression while improving patient-reported outcomes. METHODS AND ANALYSIS: This trial is a two-centre, double-blinded, placebo, randomised controlled trial with blinded endpoint assessment and intention-to-treat analysis. One-hundred and fifty CS patients will be randomised to receive either a leucine-rich protein supplement or a placebo with no supplemented protein. Patients will consume their assigned supplement two times per day for approximately 2 weeks pre-procedure, during in-hospital postoperative recovery and for 8 weeks following discharge. The primary outcome will be the Short Physical Performance Battery score. Data collection will occur at four time points including baseline, in-hospital (pre-discharge), 2-month and 6-month time points post-surgery. ETHICS AND DISSEMINATION: The University of Manitoba Biomedical Research Ethics Board (20 March 2018) and the St Boniface Hospital Research Review Committee (28 June 2019) approved the trial protocol for the primary site in Winnipeg, Manitoba, Canada. The second site's (Montreal, Quebec) ethics has been submitted and pending approval from the Research Ethics and New Technology Development Committee for the Montreal Heart Institute (December 2020). Recruitment for the primary site started February 2020 and the second site will begin January 2021. Data gathered from the PROTein to Enhance outComes of (pre)frail paTients undergoing Cardiac Surgery Study will be published in peer-reviewed journals and presented at national and international conferences. Knowledge translation strategies will be created to share findings with stakeholders who are positioned to implement evidence-informed change. POTENTIAL STUDY IMPACT: Malnutrition and frailty play a crucial role in post-CS recovery. Nutritional ERPs are increasingly being recognised as a clinically relevant aspect of perioperative care. As such, this trial is to determine if leucine-rich protein supplementation at key intervals can mitigate frailty progression and facilitate enhanced postoperative recovery. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04038294).

The International Collaboration for Cancer Classification and Research.

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.

Lung cancer screening by low-dose computed tomography: a cost-effectiveness analysis of alternative programmes in the UK using a newly developed natural history-based economic model.

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.

At what times during infection is SARS-CoV-2 detectable and no longer detectable using RT-PCR-based tests? A systematic review of individual participant data.

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.

Strategies to identify individuals with monogenic diabetes: results of an economic evaluation.

OBJECTIVES: To evaluate and compare the lifetime costs associated with strategies to identify individuals with monogenic diabetes and change their treatment to more appropriate therapy. DESIGN: A decision analytical model from the perspective of the National Health Service (NHS) in England and Wales was developed and analysed. The model was informed by the literature, routinely collected data and a clinical study conducted in parallel with the modelling. SETTING: Secondary care in the UK. PARTICIPANTS: Simulations based on characteristics of patients diagnosed with diabetes <30 years old. INTERVENTIONS: Four test-treatment strategies to identify individuals with monogenic diabetes in a prevalent cohort of diabetics diagnosed under the age of 30 years were modelled: clinician-based genetic test referral, targeted genetic testing based on clinical prediction models, targeted genetic testing based on biomarkers, and blanket genetic testing. The results of the test-treatment strategies were compared with a strategy of no genetic testing. PRIMARY AND SECONDARY OUTCOME MEASURES: Discounted lifetime costs, proportion of cases of monogenic diabetes identified. RESULTS: Based on current evidence, strategies using clinical characteristics or biomarkers were estimated to save approximately £100-£200 per person with diabetes over a lifetime compared with no testing. Sensitivity analyses indicated that the prevalence of monogenic diabetes, the uptake of testing, and the frequency of home blood glucose monitoring had the largest impact on the results (ranging from savings of £400-£50 per person), but did not change the overall findings. The model is limited by many model inputs being based on very few individuals, and some long-term data informed by clinical opinion. CONCLUSIONS: Costs to the NHS could be saved with targeted genetic testing based on clinical characteristics or biomarkers. More research should focus on the economic case for the use of such strategies closer to the time of diabetes diagnosis. TRIAL REGISTRATION NUMBER: NCT01238380.

An analysis reveals differences between pragmatic and explanatory diagnostic accuracy studies.

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.

Methods and reporting of systematic reviews of comparative accuracy were deficient: a methodological survey and proposed guidance.

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.