Improving reporting standards for polygenic scores in risk prediction studies.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.

Polygenic risk scores for the prediction of cardiometabolic disease.

Cardiometabolic diseases contribute more to global morbidity and mortality than any other group of disorders. Polygenic risk scores (PRSs), the weighted summation of individually small-effect genetic variants, represent an advance in our ability to predict the development and complications of cardiometabolic diseases. This article reviews the evidence supporting the use of PRS in seven common cardiometabolic diseases: coronary artery disease (CAD), stroke, hypertension, heart failure and cardiomyopathies, obesity, atrial fibrillation (AF), and type 2 diabetes mellitus (T2DM). Data suggest that PRS for CAD, AF, and T2DM consistently improves prediction when incorporated into existing clinical risk tools. In other areas such as ischaemic stroke and hypertension, clinical application appears premature but emerging evidence suggests that the study of larger and more diverse populations coupled with more granular phenotyping will propel the translation of PRS into practical clinical prediction tools.

Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation' which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.

Practice variation in the use of tests in UK primary care: a retrospective analysis of 16 million tests performed over 3.3 million patient years in 2015/16.

BACKGROUND: The UK's National Health Service (NHS) is currently subject to unprecedented financial strain. The identification of unnecessary healthcare resource use has been suggested to reduce spending. However, there is little very research quantifying wasteful test use, despite the £3 billion annual expenditure. Geographical variation has been suggested as one metric in which to quantify inappropriate use. We set out to identify tests ordered from UK primary care that are subject to the greatest between-practice variation in their use. METHODS: We used data from 444 general practices within the Clinical Practice Research Datalink to calculate a coefficient of variation (CoV) for the ordering of 44 specific tests from UK general practices. The coefficient of variation was calculated after adjusting for differences between practice populations. We also determined the tests that had both a higher-than-average CoV and a higher-than-average rate of use. RESULTS: In total, 16,496,218 tests were ordered for 4,078,091 patients over 3,311,050 person-years from April 1, 2015, to March 31, 2016. The tests subject to the greatest variation were drug monitoring 158% (95%CI 153 to 163%), urine microalbumin (52% (95%CI 49.9 to 53.2%)), pelvic CT (51% (95%CI 50 to 53%)) and Pap smear (49% (95%CI 48 to 51%). Seven tests were classified as high variability and high rate (clotting, vitamin D, urine albumin, prostate-specific antigen (PSA), bone profile, urine MCS and C-reactive protein (CRP)). CONCLUSIONS: There are wide variations in the use of common tests, which is unlikely to be explained by clinical indications. Since £3 billion annually are spent on tests, this represents considerable variation in the use of resources and inefficient management in the NHS. Our results can be of value to policy makers, researchers, patients and clinicians as the NHS strives towards identifying overuse and underuse of tests.

Written information for patients (or parents of child patients) to reduce the use of antibiotics for acute upper respiratory tract infections in primary care.

BACKGROUND: Acute upper respiratory tract infections (URTIs) are frequently managed in primary care settings. Although many are viral, and there is an increasing problem with antibiotic resistance, antibiotics continue to be prescribed for URTIs. Written patient information may be a simple way to reduce antibiotic use for acute URTIs. OBJECTIVES: To assess if written information for patients (or parents of child patients) reduces the use of antibiotics for acute URTIs in primary care. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, clinical trials.gov, and the World Health Organization (WHO) trials registry up to July 2016 without language or publication restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving patients (or parents of child patients) with acute URTIs, that compared written patient information delivered immediately before or during prescribing, with no information. RCTs needed to have measured our primary outcome (antibiotic use) to be included. DATA COLLECTION AND ANALYSIS: Two review authors screened studies, extracted data, and assessed study quality. We could not meta-analyse included studies due to significant methodological and statistical heterogeneity; we summarised the data narratively. MAIN RESULTS: Two RCTs met our inclusion criteria, involving a total of 827 participants. Both studies only recruited children with acute URTIs (adults were not involved in either study): 558 children from 61 general practices in England and Wales; and 269 primary care doctors who provided data on 33,792 patient-doctor consultations in Kentucky, USA. The UK study had a high risk of bias due to lack of blinding and the US cluster-randomised study had a high risk of bias because the methods to allocate participants to treatment groups was not clear, and there was evidence of baseline imbalance.In both studies, clinicians provided written information to parents of child patients during primary care consultations: one trained general practitioners (GPs) to discuss an eight-page booklet with parents; the other conducted a factorial trial with two comparison groups (written information compared to usual care and written information plus prescribing feedback to clinicians compared to prescribing feedback alone). Doctors in the written information arms received 25 copies of two-page government-sponsored pamphlets to distribute to parents.Compared to usual care, we found moderate quality evidence (one study) that written information significantly reduced the number of antibiotics used by patients (RR 0.53, 95% CI 0.35 to 0.80; absolute risk reduction (ARR) 20% (22% versus 42%)) and had no significant effect on reconsultation rates (RR 0.79, 95% CI 0.47 to 1.32), or parent satisfaction with consultation (RR 0.95, 95% CI 0.87 to 1.03). Low quality evidence (two studies) demonstrated that written information also reduced antibiotics prescribed by clinicians (RR 0.47, 95% CI 0.28 to 0.78; ARR 21% (20% versus 41%); and RR 0.84, 95% CI 0.81 to 0.86; 9% ARR (45% versus 54%)). Neither study measured resolution of symptoms, patient knowledge about antibiotics for acute URTIs, or complications for this comparison.Compared to prescribing feedback, we found low quality evidence that written information plus prescribing feedback significantly increased the number of antibiotics prescribed by clinicians (RR 1.13, 95% CI 1.09 to 1.17; absolute risk increase 6% (50% versus 44%)). Neither study measured reconsultation rate, resolution of symptoms, patient knowledge about antibiotics for acute URTIs, patient satisfaction with consultation or complications for this comparison. AUTHORS' CONCLUSIONS: Compared to usual care, moderate quality evidence from one study showed that trained GPs providing written information to parents of children with acute URTIs in primary care can reduce the number of antibiotics used by patients without any negative impact on reconsultation rates or parental satisfaction with consultation. Low quality evidence from two studies shows that, compared to usual care, GPs prescribe fewer antibiotics for acute URTIs but prescribe more antibiotics when written information is provided alongside prescribing feedback (compared to prescribing feedback alone). There was no evidence addressing resolution of patients' symptoms, patient knowledge about antibiotics for acute URTIs, or frequency of complications.To fill evidence gaps, future studies should consider testing written information on antibiotic use for adults with acute URTIs in high- and low-income settings provided without clinician training and presented in different formats (such as electronic). Future study designs should endeavour to ensure blinded outcome assessors. Study aims should include measurement of the effect of written information on the number of antibiotics used by patients and prescribed by clinicians, patient satisfaction, reconsultation, patients' knowledge about antibiotics, resolution of symptoms, and complications.

Genetic architecture of cardiac dynamic flow volumes.

Cardiac blood flow is a critical determinant of human health. However, the definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep-learning system to extract cardiac flow and volumes from phase-contrast cardiac magnetic resonance imaging. A mixed-linear model applied to 37,653 individuals from the UK Biobank reveals genome-wide significant associations across cardiac dynamic flow volumes spanning from aortic forward velocity to aortic regurgitation fraction. Mendelian randomization reveals a causal role for aortic root size in aortic valve regurgitation. Among the most significant contributing variants, localizing genes (near ELN, PRDM6 and ADAMTS7) are implicated in connective tissue and blood pressure pathways. Here we show that DeepFlow cardiac flow phenotyping at scale, combined with genotyping data, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function.

Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study.

Aims: Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity. Methods and results: We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with ClinicalTrials.gov, NCT03090321. Conclusion: Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.

Constrictive Pericarditis Revealing Rare Case of ALH Amyloidosis With Underlying Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia).

We present a case of pericardial amyloidosis with associated lymphoplasmacytic lymphoma in a patient with chronic worsening shortness of breath and cough. This case highlights the wide variation in the presentation of cardiac amyloidosis, and the rare occurrence of clinically significant light-chain and heavy-chain amyloidosis in the pericardium. (Level of Difficulty: Advanced.).

Interactions of physical activity, muscular fitness, adiposity, and genetic risk for NAFLD.

Genetic predisposition and unhealthy lifestyle are risk factors for nonalcoholic fatty liver disease (NAFLD). We investigated whether the genetic risk of NAFLD is modified by physical activity, muscular fitness, and/or adiposity. In up to 242,524 UK Biobank participants without excessive alcohol intake or known liver disease, we examined cross-sectional interactions and joint associations of physical activity, muscular fitness, body mass index (BMI), and a genetic risk score (GRS) with alanine aminotransferase (ALT) levels and the proxy definition for suspected NAFLD of ALT levels > 30 U/L in women and >40 U/L in men. Genetic predisposition to NAFLD was quantified using a GRS consisting of 68 loci known to be associated with chronically elevated ALT. Physical activity was assessed using accelerometry, and muscular fitness was estimated by measuring handgrip strength. We found that increased physical activity and grip strength modestly attenuate genetic predisposition to elevation in ALT levels, whereas higher BMI markedly amplifies it (all p values < 0.001). Among those with normal weight and high level of physical activity, the odds of suspected NAFLD were 1.6-fold higher in those with high versus low genetic risk (reference group). In those with high genetic risk, the odds of suspected NAFLD were 12-fold higher in obese participants with low physical activity versus those with normal weight and high physical activity (odds ratio for NAFLD = 19.2 and 1.6, respectively, vs. reference group). Conclusion: In individuals with high genetic predisposition for NAFLD, maintaining a normal body weight and increased physical activity may reduce the risk of NAFLD.

Reproducibility in the UK biobank of genome-wide significant signals discovered in earlier genome-wide association studies.

With the establishment of large biobanks, discovery of single nucleotide variants (SNVs, also known as single nucleotide polymorphisms (SNVs)) associated with various phenotypes has accelerated. An open question is whether genome-wide significant SNVs identified in earlier genome-wide association studies (GWAS) are replicated in later GWAS conducted in biobanks. To address this, we examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, "discovery" GWAS and a later, "replication" GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNVs (of which 6289 reached P < 5e-8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0%; although lower for binary than quantitative phenotypes (58.1% versus 94.8% respectively). There was a 18.0% decrease in SNV effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNV effect size, phenotype trait (binary or quantitative), and discovery P value, we built and validated a model that predicted SNV replication with area under the Receiver Operator Curve = 0.90. While non-replication may reflect lack of power rather than genuine false-positives, these results provide insights about which discovered associations are likely to be replicated across subsequent GWAS.

Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals With Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable; however, current risk stratification tools (CHA2DS2-VASc) do not include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS). METHODS: Using data from the largest available genome-wide association study in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank, both independently and integrated with clinical risk factors. The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. RESULTS: Compared with the currently recommended risk tool (CHA2DS2-VASc), the integrated tool significantly improved Net Reclassification Index (2.3% [95% CI, 1.3%-3.0%]) and fit (χ2P=0.002). Using this improved tool, >115 000 people with AF would have improved risk classification in the United States. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (hazard ratio, 1.13 per 1 SD [95% CI, 1.06-1.23]). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson correlation coefficient, -0.018). CONCLUSIONS: In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors; however, the prediction of stroke remains challenging.

Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and Ancestries.

The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE. Most work to date, including the assessment of tools, has focused on performance in individuals of European ancestries. Here we present evidence for the clinical validation of a new integrated risk tool (IRT), ASCVD-IRT, which combines ASCVD-PCE with PRS to predict 10-year risk of ASCVD across diverse ethnicity and ancestry groups. We demonstrate improved predictive performance of ASCVD-IRT over ASCVD-PCE, not only in individuals of self-reported White ethnicities (net reclassification improvement [NRI]; with 95% confidence interval = 2.7% [1.1 to 4.2]) but also Black / African American / Black Caribbean / Black African (NRI = 2.5% [0.6-4.3]) and South Asian (Indian, Bangladeshi or Pakistani) ethnicities (NRI = 8.7% [3.1 to 14.4]). NRI confidence intervals were wider and included zero for ethnicities with smaller sample sizes, including Hispanic (NRI = 7.5% [-1.4 to 16.5]), but PRS effect sizes in these ethnicities were significant and of comparable size to those seen in individuals of White ethnicities. Comparable results were obtained when individuals were analyzed by genetically inferred ancestry. Together, these results validate the performance of ASCVD-IRT in multiple ethnicities and ancestries, and favor their generalization to all ethnicities and ancestries.

Integrated Polygenic Tool Substantially Enhances Coronary Artery Disease Prediction.

BACKGROUND: There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment. METHODS: Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop an integrated risk tool (IRT) that combined our polygenic risk score with established risk tools (either the American Heart Association/American College of Cardiology pooled cohort equations [PCE] or UK QRISK3), and we tested our IRT in an additional, independent set of 186 451 UK Biobank individuals. RESULTS: The novel CAD polygenic risk score shows superior predictive power for CAD events, compared with other published polygenic risk scores, and is largely uncorrelated with PCE and QRISK3. When combined with PCE into an IRT, it has superior predictive accuracy. Overall, 10.4% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, compared with 4.4% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.9% (95% CI, 4.7-7.0). When individuals were stratified into age-by-sex subgroups, the improvement was larger for all subgroups (range, 8.3%-15.4%), with the best performance in 40- to 54-year-old men (15.4% [95% CI, 11.6-19.3]). Comparable results were found using a different risk tool (QRISK3) and also a broader definition of cardiovascular disease. Use of the IRT is estimated to avoid up to 12 000 deaths in the United States over a 5-year period. CONCLUSIONS: An IRT that includes polygenic risk outperforms current risk stratification tools and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person's polygenic risk.

Accuracy of Smartphone Camera Applications for Detecting Atrial Fibrillation: A Systematic Review and Meta-analysis.

Importance: Atrial fibrillation (AF) affects more than 6 million people in the United States; however, much AF remains undiagnosed. Given that more than 265 million people in the United States own smartphones (>80% of the population), smartphone applications have been proposed for detecting AF, but the accuracy of these applications remains unclear. Objective: To determine the accuracy of smartphone camera applications that diagnose AF. Data Sources and Study Selection: MEDLINE and Embase were searched until January 2019 for studies that assessed the accuracy of any smartphone applications that use the smartphone's camera to measure the amplitude and frequency of the user's fingertip pulse to diagnose AF. Data Extraction and Synthesis: Bivariate random-effects meta-analyses were constructed to synthesize data. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) of Diagnostic Test Accuracy Studies reporting guideline. Main Outcomes and Measures: Sensitivity and specificity were measured with bivariate random-effects meta-analysis. To simulate the use of these applications as a screening tool, the positive predictive value (PPV) and negative predictive value (NPV) for different population groups (ie, age ≥65 years and age ≥65 years with hypertension) were modeled. Lastly, the association of methodological limitations with outcomes were analyzed with sensitivity analyses and metaregressions. Results: A total of 10 primary diagnostic accuracy studies, with 3852 participants and 4 applications, were included. The oldest studies were published in 2016 (2 studies [20.0%]), while most studies (4 [40.0%]) were published in 2018. The applications analyzed the pulsewave signal for a mean (range) of 2 (1-5) minutes. The meta-analyzed sensitivity and specificity for all applications combined were 94.2% (95% CI, 92.2%-95.7%) and 95.8% (95% CI, 92.4%-97.7%), respectively. The PPV for smartphone camera applications detecting AF in an asymptomatic population aged 65 years and older was between 19.3% (95% CI, 19.2%-19.4%) and 37.5% (95% CI, 37.4%-37.6%), and the NPV was between 99.8% (95% CI, 99.83%-99.84%) and 99.9% (95% CI, 99.94%-99.95%). The PPV and NPV increased for individuals aged 65 years and older with hypertension (PPV, 20.5% [95% CI, 20.4%-20.6%] to 39.2% [95% CI, 39.1%-39.3%]; NPV, 99.8% [95% CI, 99.8%-99.8%] to 99.9% [95% CI, 99.9%-99.9%]). There were methodological limitations in a number of studies that did not appear to be associated with diagnostic performance, but this could not be definitively excluded given the sparsity of the data. Conclusions and Relevance: In this study, all smartphone camera applications had relatively high sensitivity and specificity. The modeled NPV was high for all analyses, but the PPV was modest, suggesting that using these applications in an asymptomatic population may generate a higher number of false-positive than true-positive results. Future research should address the accuracy of these applications when screening other high-risk population groups, their ability to help monitor chronic AF, and, ultimately, their associations with patient-important outcomes.

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study.

BACKGROUND: Smartphone apps might enable interventions to increase physical activity, but few randomised trials testing this hypothesis have been done. The MyHeart Counts Cardiovascular Health Study is a longitudinal smartphone-based study with the aim of elucidating the determinants of cardiovascular health. We aimed to investigate the effect of four different physical activity coaching interventions on daily step count in a substudy of the MyHeart Counts Study. METHODS: In this randomised, controlled crossover trial, we recruited adults (aged ≥18 years) in the USA with access to an iPhone smartphone (Apple, Cupertino, CA, USA; version 5S or newer) who had downloaded the MyHeart Counts app (version 2.0). After completion of a 1 week baseline period of interaction with the MyHeart Counts app, participants were randomly assigned to receive one of 24 permutations (four combinations of four 7 day interventions) in a crossover design using a random number generator built into the app. Interventions consisted of either daily prompts to complete 10 000 steps, hourly prompts to stand following 1 h of sitting, instructions to read the guidelines from the American Heart Association website, or e-coaching based upon the individual's personal activity patterns from the baseline week of data collection. Participants completed the trial in a free-living setting. Due to the nature of the interventions, participants could not be masked from the intervention. Investigators were not masked to intervention allocation. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in the modified intention-to-treat analysis set, which included all participants who had completed 7 days of baseline monitoring and at least 1 day of one of the four interventions. This trial is registered with ClinicalTrials.gov, NCT03090321. FINDINGS: Between Dec 12, 2016, and June 6, 2018, 2783 participants consented to enrol in the coaching study, of whom 1075 completed 7 days of baseline monitoring and at least 1 day of one of the four interventions and thus were included in the modified intention-to-treat analysis set. 493 individuals completed the full set of assigned interventions. All four interventions significantly increased mean daily step count from baseline (mean daily step count 2914 [SE 74]): mean step count increased by 319 steps (75) for participants in the American Heart Association website prompt group (p<0·0001), 267 steps (74) for participants in the hourly stand prompt group (p=0·0003), 254 steps (74) for participants in the cluster-specific prompts group (p=0·0006), and by 226 steps (75) for participants in the 10 000 daily step prompt group (p=0·0026 vs baseline). INTERPRETATION: Four smartphone-based physical activity coaching interventions significantly increased daily physical activity. These findings suggests that digital interventions delivered via a mobile app have the ability to increase short-term physical activity levels in a free-living cohort. FUNDING: Stanford Data Science Initiative.

The mapping of cancer incidence and mortality trends in the UK from 1980-2013 reveals a potential for overdiagnosis.

The incidence of cancer in the United Kingdom has increased significantly over the last four decades. The aim of this study was to examine trends in UK cancer incidence and mortality by cancer site and assess the potential for overdiagnosis. Using Cancer Research UK incidence and mortality data for the period (1971-2014) we estimated percentage change in incidence and mortality rates and the incidence-mortality ratio (IMR) for cancers in which incidence had increased >50%. Incidence and mortality trend plots were used to assess the potential for overdiagnosis. Incidence rates increased from 67% (uterine) to 375% (melanoma). Change in mortality rates ranged from -69% (cervical) to +239% (liver). The greatest divergences occurred in uterine (IMR = 132), prostate (IMR = 9.6), oral (IMR = 9.8) and thyroid cancer (IMR = 5.3). Only in liver cancer did mortality track incidence (IMR = 1.1). For four cancer sites; uterine, prostate, oral and thyroid, incidence and mortality trends are suggestive of overdiagnosis. Trends in melanoma and kidney cancer suggest potential overdiagnosis and an underlying increase in true risk, whereas for cervical and breast cancer, trends may also reflect improvements in treatments or earlier diagnosis. A more detailed analysis is required to fully understand these patterns.

Verification bias.

This article is part of the Catalogue of Bias series. We present a description of verification bias, and outline its potential impact on research studies and the preventive steps to minimise its risk. We also present teaching slides in the online supplementary file. Verification bias (sometimes referred to as 'work-up bias') concerns the test(s) used to confirm a diagnosis within a diagnostic accuracy study. Verification bias occurs when only a proportion of the study participants receive confirmation of the diagnosis by the reference standard test, or if some participants receive a different reference standard test.

Prevalence and outcomes of incidental imaging findings: umbrella review.

OBJECTIVE: To provide an overview of the evidence on prevalence and outcomes of incidental imaging findings. DESIGN: Umbrella review of systematic reviews. DATA SOURCES: Searches of MEDLINE, EMBASE up to August 2017; screening of references in included papers. ELIGIBILITY CRITERIA: Criteria included systematic reviews and meta-analyses of observational studies that gave a prevalence of incidental abnormalities ("incidentalomas"). An incidental imaging finding was defined as an imaging abnormality in a healthy, asymptomatic patient or an imaging abnormality in a symptomatic patient, where the abnormality was not apparently related to the patient's symptoms. Primary studies that measured the prevalence of incidentalomas in patients with a history of malignancy were also considered in sensitivity analyses. RESULTS: 20 systematic reviews (240 primary studies) were identified from 7098 references from the database search. Fifteen systematic reviews provided data to quantify the prevalence of incidentalomas, whereas 18 provided data to quantify the outcomes of incidentalomas (13 provided both). The prevalence of incidentalomas varied substantially between imaging tests; it was less than 5% for chest computed tomography for incidental pulmonary embolism in patients with and without cancer and whole body positron emission tomography (PET) or PET/computed tomography (for patients with and without cancer). Conversely, incidentalomas occurred in more than a third of images in cardiac magnetic resonance imaging (MRI), chest computed tomography (for incidentalomas of thorax, abdomen, spine, or heart), and computed tomography colonoscopy (for extra-colonic incidentalomas). Intermediate rates occurred with MRI of the spine (22%) and brain (22%). The rate of malignancy in incidentalomas varied substantially between organs; the prevalence of malignancy was less than 5% in incidentalomas of the brain, parotid, and adrenal gland. Extra-colonic, prostatic, and colonic incidentalomas were malignant between 10% and 20% of the time, whereas renal, thyroid, and ovarian incidentalomas were malignant around a quarter of the time. Breast incidentalomas had the highest percentage of malignancy (42%, 95% confidence interval 31% to 54%). Many assessments had high between-study heterogeneity (15 of 20 meta-analyses with I2 >50%). CONCLUSIONS: There is large variability across different imaging techniques both in the prevalence of incidentalomas and in the prevalence of malignancy for specific organs. This umbrella review will aid clinicians and patients weigh up the pros and cons of requesting imaging scans and will help with management decisions after an incidentaloma diagnosis. Our results can underpin the creation of guidelines to assist these decisions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42017075679.

Variation in diagnostic test requests and outcomes: a preliminary metric for OpenPathology.net.

Efforts to reduce healthcare costs have led to the development of metrics to identify unwarranted variation in care. Previous work assessing diagnostic tests is limited, despite their substantial contribution to expenditure. We explored C-reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR) tests ordered across Oxfordshire NHS General Practices, and the proportion of tests that yielded an abnormal result, and identified practices that had a proportion of abnormal CRP and ESR results 3 standard deviations below the mean. We estimated the adjusted average proportion of abnormal CRP and ESR tests that yielded abnormal results from each practice, after adjusting for differences in practice populations. These proportions were plotted against the total CRP and ESR requests per practice. We constructed funnel plots to identify practices 3 standard deviations below the mean proportion of abnormal CRP and ESR tests. We analysed 143,745 CRP and 30,758 ESR requests from 69 practices. Twelve (17%) and 7 (10%) practices were more than 3 standard deviations below the mean for CRP and ESR testing respectively. Two practices (3%) were below the 99.8% limit for both CRP and ESR ordering. Variation in the proportion of tests with an abnormal result shows promise for auditing variation in care.