Publications by authors named "Chris Hyde"

96 Publications

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

Lancet Digit Health 2022 07;4(7):e558-e565

Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

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.
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http://dx.doi.org/10.1016/S2589-7500(22)00088-7DOI Listing
July 2022

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

Eur J Cancer Care (Engl) 2022 May 15. Epub 2022 May 15.

NHS Digital, Leeds, UK.

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.
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http://dx.doi.org/10.1111/ecc.13606DOI Listing
May 2022

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

Value Health 2022 04 11;25(4):656-665. Epub 2021 Dec 11.

Exeter Test Group, University of Exeter Medical School, St Luke's Campus, Exeter, England, UK.

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.
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http://dx.doi.org/10.1016/j.jval.2021.11.1352DOI Listing
April 2022

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.

J Clin Epidemiol 2022 04 13;144:102-110. Epub 2021 Dec 13.

Exeter Test Group, College House, University of Exeter, Exeter EX1 2LU. UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jclinepi.2021.12.014DOI Listing
April 2022

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

Br J Cancer 2022 02 30;126(2):187-195. Epub 2021 Oct 30.

National Cancer Registration and Analysis Service, Public Health England, Wellington House, London, SE1 8U, UK.

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.
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http://dx.doi.org/10.1038/s41416-021-01573-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770501PMC
February 2022

Will better evidence on clinical utility bring about greater use of (genetic) tests?

Authors:
Chris Hyde

NPJ Genom Med 2021 Mar 4;6(1):22. Epub 2021 Mar 4.

Exeter Test Group, Institute of Health Research, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK.

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http://dx.doi.org/10.1038/s41525-021-00187-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933423PMC
March 2021

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.

Cochrane Database Syst Rev 2021 Feb 10;2:CD010945. Epub 2021 Feb 10.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

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.
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http://dx.doi.org/10.1002/14651858.CD010945.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078224PMC
February 2021

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

BMJ Open 2021 01 29;11(1):e037240. Epub 2021 Jan 29.

Institute of Cardiovascular Sciences, St. Boniface General Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada

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).
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http://dx.doi.org/10.1136/bmjopen-2020-037240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849881PMC
January 2021

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.

Diagn Progn Res 2020 Dec 2;4(1):20. Epub 2020 Dec 2.

Peninsula Technology Assessment Group (PenTAG), College of Medicine and Health, University of Exeter, St Luke's campus, Heavitree Road, Exeter, EX1 2LU, UK.

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.
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http://dx.doi.org/10.1186/s41512-020-00087-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709236PMC
December 2020

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.

BMC Med 2020 11 4;18(1):346. Epub 2020 Nov 4.

Centre for Medical Imaging, University College London, 2nd Floor, Charles Bell House, 43-45 Foley Street, London, W1W 7TS, UK.

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.
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http://dx.doi.org/10.1186/s12916-020-01810-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609379PMC
November 2020

The International Collaboration for Cancer Classification and Research.

Int J Cancer 2021 02 9;148(3):560-571. Epub 2020 Oct 9.

American Society of Clinical Oncology, Alexandria, Virginia, USA.

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 (IC 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 IC 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.
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http://dx.doi.org/10.1002/ijc.33260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756795PMC
February 2021

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

BMJ Open 2020 03 18;10(3):e034716. Epub 2020 Mar 18.

Exeter Test Group, University of Exeter Medical School, Exeter, Devon, UK.

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.
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http://dx.doi.org/10.1136/bmjopen-2019-034716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150598PMC
March 2020

Invited commentary-WHO Classification of Tumours: How should tumors be classified? Expert consensus, systematic reviews or both?

Int J Cancer 2020 06 2;146(12):3516-3521. Epub 2020 Apr 2.

World Health Organization, Classification of Tumours Group, International Agency for Research on Cancer, Lyon, France.

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http://dx.doi.org/10.1002/ijc.32975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818407PMC
June 2020

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

Diagn Progn Res 2019 28;3:23. Epub 2019 Nov 28.

1Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.

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; = 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.
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http://dx.doi.org/10.1186/s41512-019-0067-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933743PMC
November 2019

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

J Clin Epidemiol 2020 05 14;121:1-14. Epub 2019 Dec 14.

Test Evaluation Research Group, University of Birmingham, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK.

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.
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http://dx.doi.org/10.1016/j.jclinepi.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203546PMC
May 2020

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

J Clin Epidemiol 2020 01 24;117:29-35. Epub 2019 Sep 24.

Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team, Research Centre for Epidemiology and Biostatistics Sorbonne Paris Cité (CRESS), Paris Descartes University, Paris, France; Department of General Pediatrics and Pediatric Infectious Diseases, Necker - Enfants malades hospital, Assistance Publique - Hôpitaux de Paris, Paris Descartes University, Paris, France.

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.
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http://dx.doi.org/10.1016/j.jclinepi.2019.09.017DOI Listing
January 2020

Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting.

PLoS One 2019 30;14(8):e0221419. Epub 2019 Aug 30.

Exeter Test Group, University of Exeter Medical School, University of Exeter, Exeter, Devon, United Kingdom.

Background: Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer.

Methods: A decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used.

Results: Reflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over.

Conclusions: Testing for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221419PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716649PMC
March 2020

Diagnostic accuracy of contemporary and high-sensitivity cardiac troponin assays used in serial testing, versus single-sample testing as a comparator, to triage patients suspected of acute non-ST-segment elevation myocardial infarction: a systematic review protocol.

BMJ Open 2019 03 30;9(3):e026012. Epub 2019 Mar 30.

Exeter Test Group, University of Exeter Medical School, University of Exeter, Exeter, Devon, UK.

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-segment-elevation 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.

Prospero Registration Number: CRD42018106379.
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http://dx.doi.org/10.1136/bmjopen-2018-026012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475186PMC
March 2019

Three biomarker tests to help diagnose preterm labour: a systematic review and economic evaluation.

Health Technol Assess 2019 03;23(13):1-226

Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, University of Exeter, Exeter, UK.

Background: Preterm birth may result in short- and long-term health problems for the child. Accurate diagnoses of preterm births could prevent unnecessary (or ensure appropriate) admissions into hospitals or transfers to specialist units.

Objectives: The purpose of this report is to assess the test accuracy, clinical effectiveness and cost-effectiveness of the diagnostic tests PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim Partus (Medix Biochemica, Espoo, Finland) and the Rapid Fetal Fibronectin (fFN) 10Q Cassette Kit (Hologic, Inc., Marlborough, MA, USA) at thresholds ≠50 ng/ml [quantitative fFN (qfFN)] for women presenting with signs and symptoms of preterm labour relative to fFN at 50 ng/ml.

Methods: Systematic reviews of the published literature were conducted for diagnostic test accuracy (DTA) studies of PartoSure, Actim Partus and qfFN for predicting preterm birth, the clinical effectiveness following treatment decisions informed by test results and economic evaluations of the tests. A model-based economic evaluation was also conducted to extrapolate long-term outcomes from the results of the diagnostic tests. The model followed the structure of the model that informed the 2015 National Institute for Health and Care Excellence guidelines on preterm labour diagnosis and treatment, but with antenatal steroids use, as opposed to tocolysis, driving health outcomes.

Results: Twenty studies were identified evaluating DTA against the reference standard of delivery within 7 days and seven studies were identified evaluating DTA against the reference standard of delivery within 48 hours. Two studies assessed two of the index tests within the same population. One study demonstrated that depending on the threshold used, qfFN was more or less accurate than Actim Partus, whereas the other indicated little difference between PartoSure and Actim Partus. No study assessing qfFN and PartoSure in the same population was identified. The test accuracy results from the other included studies revealed a high level of uncertainty, primarily attributable to substantial methodological, clinical and statistical heterogeneity between studies. No study compared all three tests simultaneously. No clinical effectiveness studies evaluating any of the three biomarker tests were identified. One partial economic evaluation was identified for predicting preterm birth. It assessed the number needed to treat to prevent a respiratory distress syndrome case with a 'treat-all' strategy, relative to testing with qualitative fFN. Because of the lack of data, our de novo model involved the assumption that management of pregnant women fully adhered to the results of the tests. In the base-case analysis for a woman at 30 weeks' gestation, Actim Partus had lower health-care costs and fewer quality-adjusted life-years (QALYs) than qfFN at 50 ng/ml, reducing costs at a rate of £56,030 per QALY lost compared with qfFN at 50 ng/ml. PartoSure is less costly than Actim Partus while being equally effective, but this is based on diagnostic accuracy data from a small study. Treatment with qfFN at 200 ng/ml and 500 ng/ml resulted in lower cost savings per QALY lost relative to fFN at 50 ng/ml than treatment with Actim Partus. In contrast, qfFN at 10 ng/ml increased QALYs, by 0.002, and had a cost per QALY gained of £140,267 relative to fFN at 50 ng/ml. Similar qualitative results were obtained for women presenting at different gestational ages.

Conclusion: There is a high degree of uncertainty surrounding the test accuracy and cost-effectiveness results. We are aware of four ongoing UK trials, two of which plan to enrol > 1000 participants. The results of these trials may significantly alter the findings presented here.

Study Registration: The study is registered as PROSPERO CRD42017072696.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta23130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452238PMC
March 2019

Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation.

Health Technol Assess 2018 11;22(69):1-276

Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.

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

Objectives: To estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations.

Data Sources: Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library.

Methods: Clinical effectiveness - a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness - an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm.

Results: Clinical effectiveness - 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness - screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60-75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses.

Limitations: Clinical effectiveness - the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness - a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included.

Conclusions: LDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits.

Future Work: Clinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial].

Study Registration: This study is registered as PROSPERO CRD42016048530.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta22690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304730PMC
November 2018

18F-FDG PET for Prediction of Conversion to Alzheimer's Disease Dementia in People with Mild Cognitive Impairment: An Updated Systematic Review of Test Accuracy.

J Alzheimers Dis 2018 ;64(4):1175-1194

Cambridge Institute of Public Health, Forvie Site, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.

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.
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http://dx.doi.org/10.3233/JAD-171125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218118PMC
July 2019

Cost-effectiveness of diagnostic and therapeutic interventions for chronic hepatitis C: a systematic review of model-based analyses.

BMC Med Res Methodol 2018 06 13;18(1):53. Epub 2018 Jun 13.

University of Exeter Medical School, Evidence Synthesis & Modelling for Health Improvement, ESMI, Peninsula Technology Assessment Group, PenTAG, Exeter, UK.

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.
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http://dx.doi.org/10.1186/s12874-018-0515-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998601PMC
June 2018

A methodology review on the incremental prognostic value of computed tomography biomarkers in addition to Framingham risk score in predicting cardiovascular disease: the use of association, discrimination and reclassification.

BMC Cardiovasc Disord 2018 02 21;18(1):39. Epub 2018 Feb 21.

University of Exeter, South Cloisters, St Luke's Campus, Exeter, EX1 2LU, UK.

Background: Computed tomography (CT) biomarkers claim to improve cardiovascular risk stratification. This review focuses on significant differences in incremental measures between adequate and inadequate reporting practise.

Methods: Studies included were those that used Framingham Risk Score as a baseline and described the incremental value of adding calcium score or CT coronary angiogram in predicting cardiovascular risk. Searches of MEDLINE, EMBASE, Web of Science and Cochrane Central were performed with no language restriction.

Results: Thirty five studies consisting of 206,663 patients (men = 118,114, 55.1%) were included. The baseline Framingham Risk Score included the 1998, 2002 and 2008 iterations. Selective reporting, inconsistent reference groupings and thresholds were found. Twelve studies (34.3%) had major and 23 (65.7%) had minor alterations and the respective Δ AUC were significantly different (p = 0.015). When the baseline model performed well, the Δ AUC was relatively lower with the addition of a CT biomarker (Spearman coefficient = - 0.46, p < 0.0001; n = 33; 76 pairs of data). Other factors that influenced AUC performance included exploration of data analysis, calibration, validation, multivariable and AUC documentation (all p < 0.05). Most studies (68.7%) that reported categorical NRI (n = 16; 46 pairs of data) subjectively drew strong conclusions along with other poor reporting practices. However, no significant difference in values of NRI was found between adequate and inadequate reporting.

Conclusions: The widespread practice of poor reporting particularly association, discrimination, reclassification, calibration and validation undermines the claimed incremental value of CT biomarkers over the Framingham Risk Score alone. Inadequate reporting of discrimination inflates effect estimate, however, that is not necessarily the case for reclassification.
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http://dx.doi.org/10.1186/s12872-018-0777-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822603PMC
February 2018

A systematic review of test accuracy studies evaluating molecular micro-satellite instability testing for the detection of individuals with lynch syndrome.

BMC Cancer 2017 12 8;17(1):836. Epub 2017 Dec 8.

Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, South Cloisters, St Lukes Campus, Heavitree Road, Exeter, Devon, EX1 2LU, UK.

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).
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http://dx.doi.org/10.1186/s12885-017-3820-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723028PMC
December 2017

Micro-costing analysis of guideline-based treatment by direct-acting agents: the real-life case of hepatitis C management in Brazil.

BMC Gastroenterol 2017 Nov 23;17(1):119. Epub 2017 Nov 23.

Fundação Oswaldo Cruz, FIOCRUZ, Instituto Nacional de Infectologia Evandro Chagas, INI, Laboratório de Pesquisa Clínica em DST e AIDS, LAPCLIN-AIDS, Rio de Janeiro, Brazil.

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.
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http://dx.doi.org/10.1186/s12876-017-0676-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701370PMC
November 2017

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation.

Health Technol Assess 2017 09;21(51):1-238

Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK.

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. (MutL homologue 1) promoter methylation and 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 promoter methylation testing and 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, V600E and 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.
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http://dx.doi.org/10.3310/hta21510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611555PMC
September 2017

A content analysis of the representation of statins in the British newsprint media.

BMJ Open 2017 Aug 21;7(8):e012613. Epub 2017 Aug 21.

European Centre for Environment & Human Health, University of Exeter Medical School, Exeter, UK.

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.
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http://dx.doi.org/10.1136/bmjopen-2016-012613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724098PMC
August 2017

Age-standardized mortality rates related to viral hepatitis in Brazil.

BMC Infect Dis 2017 07 31;17(1):527. Epub 2017 Jul 31.

Fundação Oswaldo Cruz (FIOCRUZ), Instituto Nacional de Infectologia Evandro Chagas (INI), Laboratório de Pesquisa Clínica em DST e AIDS (LAPCLIN-AIDS), Rio de Janeiro, Brazil.

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.
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http://dx.doi.org/10.1186/s12879-017-2619-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537933PMC
July 2017

A directly comparative two-gate case-control diagnostic accuracy study of the pure tone screen and HearCheck screener tests for identifying hearing impairment in school children.

BMJ Open 2017 Jul 11;7(7):e017258. Epub 2017 Jul 11.

NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.

Objectives: This study directly compared the accuracy of two audiometry-based tests for screening school children for hearing impairment: the currently used test, pure tone screen and a device newly applied to children, HearCheck Screener.

Design: Two-gate case-control diagnostic test accuracy study.

Setting And Participants: Hearing impaired children ('intended cases') aged 4-6 years were recruited between February 2013 and August 2014 from collaborating audiology services. Children with no previously identified impairment ('intended controls') were recruited from Foundation and Year 1 of schools between February 2013 and June 2014 in central England. The reference standard was pure tone audiometry. Tests were administered at Nottingham Hearing Biomedical Research Unit or, for some intended cases only, in the participant's home.

Main Outcome Measures: Sensitivity and specificity of the pure tone screen and HearCheck tests based on pure tone audiometry result as reference standard.

Results: 315 children (630 ears) were recruited; 75 from audiology services and 240 from schools. Full test and reference standard data were obtained for 600 ears; 155 ears were classified as truly impaired and 445 as truly hearing based on the pure tone audiometry assessment. Sensitivity was estimated to be 94.2% (95% CI 89.0% to 97.0%) for pure tone screen and 89.0% (95% CI 82.9% to 93.1%) for HearCheck (difference=5.2% favouring pure tone screen; 95% CI 0.2% to 10.1%; p=0.02). Estimates for specificity were 82.2% (95% CI 77.7% to 86.0%) for pure tone screen and 86.5% (95% CI 82.5% to 89.8%) for HearCheck (difference=4.3% favouring HearCheck; 95% CI0.4% to 8.2%; p=0.02).

Conclusion: Pure tone screen was better than HearCheck with respect to sensitivity but inferior with respect to specificity. As avoiding missed cases is arguably of greater importance for school entry screening, pure tone screen is probably preferable in this context.

Study Registration Number: Current controlled trials: ISRCTN61668996.
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http://dx.doi.org/10.1136/bmjopen-2017-017258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541595PMC
July 2017
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