Feasibility of institution-agnostic, EHR-integrated regional clinical trial matching.

BACKGROUND: A lack of onsite clinical trials is the largest barrier to participation of cancer patients in trials. Development of an automated process for regional trial eligibility screening first requires identification of patient electronic health record data that allows effective trial screening, and evidence that searching for trials regionally has a positive impact compared with site-specific searching. METHODS: To assess a screening framework that would support an automated regional search tool, a set of patient clinical variables was analyzed for prescreening clinical trials. The variables were used to assess regional compared with site-specific screening throughout the United States. RESULTS: Eight core variables from patient electronic health records were identified that yielded likely matches in a prescreen process. Assessment of the screening framework was performed using these variables to search for trials locally and regionally for an 84-patient cohort. The likelihood that a trial returned in this prescreen was a provisional trial match was 45.7%. Expanding the search radius to 20 miles led to a net 91% increase in matches across cancers within the tested cohort. In a U.S. regional analysis, for sparsely populated areas, searching a 100-mile radius using the prescreening framework was needed, whereas for urban areas a 20-mile radius was sufficient. CONCLUSION: A clinical trial screening framework was assessed that uses limited patient data to efficiently and effectively identify prescreen matches for clinical trials. This framework improves trial matching rates when searching regionally compared with locally, although the applicability of this framework may vary geographically depending on oncology practice density. PLAIN LANGUAGE SUMMARY: Clinical trials provide cancer patients the opportunity to participate in research and development of new drugs and treatment approaches. It can be difficult to find available clinical trials for which a patient is eligible. This article describes an approach to clinical trial matching using limited patient data to search for trials regionally, beyond just the patient's local care site. Feasibility testing shows that this process can lead to a net 91% increase in the number of potential clinical trial matches available within 20 miles of a patient. Based on these findings, a software tool based on this model is being developed that will automatically send limited, deidentified information from patient medical records to services that can identify possible clinical trials within a given region.

Should ECG criteria for Low QRS voltage (LQRSV) be specific for Sex?

INTRODUCTION: Low QRS peak-to-nadir voltage (LQRSV) is associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and other cardiomyopathies. Recent studies have proposed criteria for LQRSV when screening athletes for cardiovascular disease. These criteria have not yet been evaluated in a large population of healthy young athletes. METHODS: The target population was 10,728 (42.5% female, 57.5% male, mean age 18.1 ± 4.3 years) athletes who participated in mass ECG screenings between 2014 and 2021 at multiple sites across the United States including grade schools (11%), high schools (32%), colleges (50%), and professional athletic teams (6%) with digitally recorded ECGs and a standardized protocol. Since by design, complete follow up for outcomes and the results of testing were not available. Including only ECGs from initial evaluation among athletes 14-35 years of age and excluding those with right bundle branch block, left bundle branch block, Wolf-Parkinson-White pattern, reversed leads and 3 clinically diagnosed cardiomyopathies at Stanford, 8,679 (58% males, 42% females) remained eligible for analysis. QRS voltage was analyzed for each ECG lead and LQRSV criteria were applied and stratified by sex. RESULTS: QRS voltage was lower in all leads in female athletes compared to male athletes. Using traditional limb lead criteria or precordial lead criteria, the prevalence of LQRSV was significantly lower in males than females (P < .001). Strikingly, LQRSV using the Sokolow-Lyon Index was present in 1.9% of males and 9.8% of females (P < .001). Applying first percentile for LQRS amplitude criteria provided possible values for screening young athletes for LQRSV. CONCLUSIONS: LQRSV is more common among female athletes than male athletes using established criteria. Using first percentile sex-specific cut points should be considered in future analyses. Proposed novel LQRSV criteria in young athletes should be specific for males and females.

Digitized Electrocardiography Measurements Support the Biological Plausibility of the Pathological Significance of ST Segments in Athletes.

OBJECTIVE: ST segment deviations around the isoelectric line are common findings in manifest cardiovascular disease. In athletes, ST elevation is common, while ST depression is considered rare. However, clinical studies in athletes have associated ST depression with myocardial fibrosis and fatty infiltration and ST elevation with pericarditis and myocarditis. This study aims to explore the association between resting ST segment deviations and resting heart rate, an indicator of training and autonomic tone and electrocardiography (ECG) markers of exercise training effect and cardiovascular health R and T wave amplitude. DESIGN: Retrospective analysis of digitized ECG data. SETTING: Institutional setting. PARTICIPANTS: Seven thousand eight hundred thirty-six (male athletes = 4592, female athletes = 3244) healthy asymptomatic athletes (14-35 years). MAIN OUTCOME MEASURES: A series of correlations and regressions were conducted between ST depression (<0.0 µV) and ST elevation (>0.0 µV), on R and T wave amplitudes, and heart rate in leads V2, V5, and aVF. RESULTS: Positive correlations between ST elevation and R and T wave (S wave in V2) amplitudes and leads V5, V2, and aVF in male and female athletes (range of r = 0.1-0.54). In addition, there was a negative correlation between ST elevation and HR for male and female athletes. Finally, there was a negative correlation between ST depression and R wave and HR for male and female athletes in V5 ( P < 0.01). CONCLUSIONS: In athletes, ST segment elevation is correlated with R and T wave amplitudes and negatively correlated with HR. In addition, ST segment elevation is correlated with low heart rate, consistent with its higher prevalence in athletes. ST segment depression is not influenced by HR but is negatively associated with R and T wave amplitudes.

Prevalence and clinical significance of isolated low QRS voltages in young athletes.

AIMS: Low QRS voltages (peak to peak <0.5 mV) in limb leads (LQRSV) on the athlete's electrocardiogram (ECG) may reflect an underlying cardiomyopathy, mostly arrhythmogenic cardiomyopathy (ACM) or non-ischaemic left ventricular scar (NILVS). We studied the prevalence and clinical meaning of isolated LQRSV in a large cohort of competitive athletes. METHODS AND RESULTS: The index group included 2229 Italian competitive athletes [median age 18 years (16-25), 67% males, 97% Caucasian] without major ECG abnormalities at pre-participation screening. Three control groups included Black athletes (N = 1115), general population (N = 1115), and patients with ACM or NILVS (N = 58). Echocardiogram was performed in all athletes with isolated LQRSV and cardiac magnetic resonance (CMR) in those with ventricular arrhythmias or echocardiographic abnormalities. The isolated LQRSV pattern was found in 1.1% index athletes and was associated with increasing age (median age 28 vs. 18 years; P < 0.001), elite status (71% vs. 34%; P < 0.001), body surface area, and body mass index but not with sex, type of sport, and echocardiographic left ventricular mass. The prevalence of isolated LQRSV was 0.2% in Black athletes and 0.3% in young individuals from the general population. Cardiomyopathy patients had a significantly greater prevalence of isolated LQRSV (12%) than index athletes, Black athletes, and general population. Five index athletes with isolated LQSRV and exercise-induced ventricular arrhythmias underwent CMR showing biventricular ACM in 1 and idiopathic NILVS in 1. CONCLUSIONS: Unlike cardiomyopathy patients, the ECG pattern of isolated LQRSV was rarely observed in athletes. This ECG sign should prompt clinical work-up for exclusion of an underlying cardiomyopathy.

Comparison of the Stanford ECG Left Atrial Criteria With the International ECG Criteria for Sports Screening.

OBJECTIVE: Because the International left atrial enlargement electrocardiographic (ECG) screening criteria (ECG-LAE) for athletes are rarely fulfilled in young athletes, we compared it with evidence-based criteria from a recent clinical outcome study of ECG left atrial abnormality (ECG-LAA). DESIGN: Retrospective analyses. SETTING: Routine preparticipation ECG screening in California. PARTICIPANTS: Four thousand four hundred thirty-eight young individuals (18.5 ± 5.4 years, 40% women). ASSESSMENT OF RISK FACTORS: The International criteria for ECG-LAE were applied: prolonged P wave duration of ≥120 ms in leads I or II AND negative portion of ≥1 mm in depth in lead V1. This was compared with Stanford criteria for ECG-LAA: prolonged P wave duration of ≥140 ms odds ratio (OR) negative portion in V1 and V2 greater than 1 mm. MAIN OUTCOME MEASURES: Differences in the classification of abnormal ECGs between the 2 criteria applied to the same population of young athletes. RESULTS: Only 33 (0.7%) of our subjects fulfilled the International criteria for ECG-LAE while 110 (2.5%) fulfilled the ECG-LAA criteria. Adding our new ECG-LAA criterion and considering it a major criterion raised the abnormal ECG prevalence and athletes referred for further evaluation from 2.9% to 4.4%. CONCLUSIONS: The Stanford evidence-based criterion for ECG-LAA incorporating V2 and replacing "or" for "and" regarding P wave duration increased the yield of abnormal classification for P waves. Future follow-up studies are needed to confirm that this new criterion should be included in future ECG screening consensus documents.

Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].

Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Economic evaluation from beef cattle production industry with intensification in Brazil's tropical pastures.

This study aimed to evaluate different scenarios (year, supplementation level) about economic results of beef cattle production during rearing and finishing phase in Brazilian's tropical pastures. Four scenarios were evaluated in combination with fourteen supplements, and it was originated from some research developed inside Forage Crops and Grasslands section from São Paulo State University among years 2011 and 2014. The economic evaluation was analyzed by operating cost, total operational costs, gross revenue, operating profit, and financial net income. Besides profitability, internal rate of return (IRR), benefit/cost ratio (B:C), and simple payback period (SPP) were calculated too. During rearing phase, the best result was observed for scenario 2 (2012), supplement 3.2 (mineral mix) with values of 11 cycles, 26.3%, 9.30%, and 0.39 for SPP, profitability, IRR, and B:C ratio, respectively. Already to finishing phase, the best scenario was 3 (2013), supplement 10 (multiple supplement with supplementation level equal 1.0% body weight), which obtained 4 cycles, 68.7%, 27.00%, and 2.34 for the same variables above mentioned. Results were consistent being that higher IRR and profitability occurred when using low supplementation level. Hence, the economic responses from different scenarios (years and supplements) can alter the final livestock farm financial statement.

QT Corrections for Long QT Risk Assessment: Implications for the Preparticipation Examination.

BACKGROUND: Because sudden cardiac death (SCD) in the young mainly occurs in individuals with structurally normal hearts, improved screening techniques for detecting inherited arrhythmic diseases are needed. The QT interval is an important screening measurement; however, the criteria for detecting an abnormal QT interval are based on Bazett formula and older populations. OBJECTIVE: To define the normal upper limits for QT interval from the electrocardiograms (ECGs) of healthy young individuals, compare the major correction formula and propose new QT interval thresholds for detecting those at risk of SCD. METHODS: Young active individuals underwent ECGs as part of routine preparticipation physical examinations for competitive sports or community screening. This was a nonfunded study using de-identified data with no follow-up. RESULTS: There were 31 558 subjects: 2174 grade school (7%), 18 547 high school (59%), and 10 822 college (34%). Mean age was 17 (12-35 years), 45% were female, 67% white, and 11% of African descent. Bazett performed least favorably for removing the effect of heart rate (HR), whereas Fridericia performed the best. Fridericia correction also closely fit the raw data best (R of 0.65), and at percentile values applicable to screening. The recommended risk cut points using Bazetts correction identified less than half of the athletes in the 99th or 99.5th percentiles of the uncorrected QT by HR range. Use of Fridericia correction increased capture rates by over 50%. CONCLUSION: Our results support the application of the Fridericia-corrected threshold of 460 for men and 470 milliseconds for women (and 485 milliseconds for marked prolongation) rather than Bazett correction for the preparticipation examination.

Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.

Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 × 10-7) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 × 10-6) and one novel region near PPIL2 (HR = 2.47, p = 9.64 × 10-7) with suggestive evidence (p < 10-5). Two known regions (PTPN22: p = 2.25 × 10-6, INS; p = 1.32 × 10-7) and one novel region (PXK/PDHB: p = 8.99 × 10-6) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 × 10-6 and TTC34/PRDM16: 6.45 × 10-6) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1: p = 8.02 × 10-6) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 × 10-7) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 × 10-6 > p > 2.31 × 10-6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.

FTO genotype is associated with phenotypic variability of body mass index.

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Milk feeding and first complementary foods during the first year of life in the TEDDY study.

The aim was to describe milk feeding patterns and first weaning foods during the first year of life in a large prospective birth cohort of infants with increased genetic risk for Type 1 diabetes (T1D) recruited in 4 different countries: the United States, Finland, Germany, and Sweden. All enrolled children with dietary information (n = 8,673) were included in the analyses; 1,307 (15%) children who dropped out before the first birthday were excluded from some analyses. Supplementary milk feeding in the first 3 days of life was common in all the four countries, although the type of the supplementary milk differed by country and by maternal T1D. Donated human milk was commonly used only in Finland. In all the countries, the most common first supplementary food was cow's milk-based infant formula, especially among offspring of mothers with T1D. The use of specific types of infant formulas differed notably by country: Extensively hydrolysed formulas were most used in Finland, partially hydrolysed ones in the United States and in Germany, and soy formulas only in the United States. Infant formulas commonly included probiotics, prebiotics, and starches. During the first year of life, most of the infants received conventional cow's milk. Overall, milk feeding during the first 3 days of life and thereafter until the first birthday differed markedly by maternal T1D status and across countries. These descriptive data may be useful in understanding early infant feeding practices and in planning potential interventions, which affect infant feeding.

Normal computerized Q wave measurements in healthy young athletes.

BACKGROUND: Recent Expert consensus statements have sought to decrease false positive rates of electrocardiographic abnormalities requiring further evaluation when screening young athletes. These statements are largely based on traditional ECG patterns and have not considered computerized measurements. OBJECTIVE: To define the normal limits for Q wave measurements from the digitally recorded ECGs of healthy young athletes. METHODS: All athletes were categorized by sex and level of participation (high school, college, and professional), and underwent screening ECGs with routine pre-participation physicals, which were electronically captured and analyzed. Q wave amplitude, area and duration were recorded for athletes with Q wave amplitudes greater than 0.5mm at standard paper amplitude display (1mV/10mm). ANOVA analyses were performed to determine differences these parameters among all groups. A positive ECG was defined by our Stanford Computerized Criteria as exceeding the 99th percentile for Q wave area in 2 or more leads. Proportions testing was used to compare the Seattle Conference Q wave criteria with our data-driven criteria. RESULTS: 2073 athletes in total were screened. Significant differences in Q wave amplitude, duration and area were identified both by sex and level of participation. When applying our Stanford Computerized Criteria and the Seattle criteria to our cohort, two largely different groups of athletes are identified as having abnormal Q waves. CONCLUSION: Computer analysis of athletes' ECGs should be included in future studies that have greater numbers, more diversity and adequate end points.

HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study.

OBJECTIVES: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS: After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). CONCLUSIONS: HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

Are the QRS duration and ST depression cut-points from the Seattle criteria too conservative?

BACKGROUND: Screening athletes with ECGs is aimed at identifying "at-risk" individuals who may have a cardiac condition predisposing them to sudden cardiac death. The Seattle criteria highlight QRS duration greater than 140 ms and ST segment depression in two or more leads greater than 50 µV as two abnormal ECG patterns associated with sudden cardiac death. METHODS: High school, college, and professional athletes underwent 12 lead ECGs as part of routine pre-participation physicals. Prevalence of prolonged QRS duration was measured using cut-points of 120, 125, 130, and 140 ms. ST segment depression was measured in all leads except leads III, aVR, and V1 with cut-points of 25 µV and 50 µV. RESULTS: Between June 2010 and November 2013, 1595 participants including 297 (167 male, mean age 16.2) high school athletes, 1016 (541 male, mean age 18.8) college athletes, and 282 (mean age 26.6) male professional athletes underwent screening with an ECG. Only 3 athletes (0.2%) had a QRS duration greater than 125 ms. ST segment depression in two or more leads greater than 50 µV was uncommon (0.8%), while the prevalence of ST segment depression in two or more leads increased to 4.5% with a cut-point of 25 µV. CONCLUSION: Changing the QRS duration cut-point to 125 ms would increase the sensitivity of the screening ECG, without a significant increase in false-positives. However, changing the ST segment depression cut-point to 25 µV would lead to a significant increase in false-positives and would therefore not be justified.

Computerized Q wave dimensions in athletes and hypertrophic cardiomyopathy patients.

BACKGROUND: There is controversy regarding Q wave criteria for assessing risk for hypertrophic cardiomyopathy (HCM) in young athletes. METHODS: The 12-lead ECGs from Preparticipation screening in healthy athletes and patients with HCM were studied retrospectively. All 12 leads were measured using the same automated ECG analysis program. RESULTS: There were a total of 225 HCM patients and 1124 athletes with 12-lead electrocardiograms available for analysis. Athletes were on average 20 years of age, 65% were male and 24% were African-American. Patients with HCM were on average 51 years of age, 56% were male and 5.8% were African-American. Q waves by either amplitude, duration or area criteria were more prevalent in males than females, in lateral leads than inferior and in HCM patients than athletes. The most striking difference in Q waves between the groups was in Limb lead I and in the females. Tall, skinny Q waves were rare in athletes and had the highest prevalence of only 3.7% in male HCM patients. CONCLUSION: Q waves are more common in males compared to females and in patients with HCM compared to athletes. Q waves of 30 ms or more in limb lead I appear to offer the greatest discriminatory value for separating patients with HCM from athletes.

Supervised categorical principal component analysis for genome-wide association analyses.

In order to have a better understanding of unexplained heritability for complex diseases in conventional Genome-Wide Association Studies (GWAS), aggregated association analyses based on predefined functional regions, such as genes and pathways, become popular recently as they enable evaluating joint effect of multiple Single-Nucleotide Polymorphisms (SNPs), which helps increase the detection power, especially when investigating genetic variants with weak individual effects. In this paper, we focus on aggregated analysis methods based on the idea of Principal Component Analysis (PCA). The past approaches using PCA mostly make some inherent genotype data and/or risk effect model assumptions, which may hinder the accurate detection of potential disease SNPs that influence disease phenotypes. In this paper, we derive a general Supervised Categorical Principal Component Analysis (SCPCA), which explicitly models categorical SNP data without imposing any risk effect model assumption. We have evaluated the efficacy of SCPCA with the comparison to a traditional Supervised PCA (SPCA) and a previously developed Supervised Logistic Principal Component Analysis (SLPCA) based on both the simulated genotype data by HAPGEN2 and the genotype data of Crohn's Disease (CD) from Wellcome Trust Case Control Consortium (WTCCC). Our preliminary results have demonstrated the superiority of SCPCA over both SPCA and SLPCA due to its modeling explicitly designed for categorical SNP data as well as its flexibility on the risk effect model assumption.

Patterns and prognosis of all components of the J-wave pattern in multiethnic athletes and ambulatory patients.

BACKGROUND: Despite recent concern about the significance of the J-wave pattern (also often referred to as early repolarization) and the importance of screening in athletes, there are limited rigorous prognostic data characterizing the 3 components of the J-wave pattern (ST elevation, J waves, and QRS slurs). We aim to assess the prevalence, patterns, and prognosis of the J-wave pattern among both stable clinical and athlete populations. METHODS: We retrospectively studied 4,041 electrocardiograms from a multiethnic clinical population from 1997 to 1999 at the Veterans Affairs Palo Alto Health Care System. We also examined preparticipation electrocardiograms of 1,114 Stanford University varsity athletes from 2007 to 2008. Strictly defined criteria for components of the J-wave pattern were examined. In clinical subjects, prognosis was assessed using the end point of cardiovascular death after 7 years of follow-up. RESULTS: Components of the J-wave pattern were most prevalent in males; African Americans; and, particularly, athletes, with the greatest variations demonstrated in the lateral leads. ST elevation was the most common. Inferior J waves and slurs, previously linked to cardiovascular risk, were observed in 9.6% of clinical subjects and 12.3% of athletes. J waves, slurs, or ST elevation was not associated with time to cardiovascular death in clinical subjects, and ST-segment slope abnormalities were not prevalent enough in conjunction with them to reach significance. CONCLUSIONS: J waves, slurs, or ST elevation was not associated with increased hazard of cardiovascular death in our large multiethnic, ambulatory population. Even subsets of J-wave patterns, recently proposed to pose a risk of arrhythmic death, occurred at such a high prevalence as to negate their utility in screening.

Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

AIMS: The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. METHODS: This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. RESULTS AND CONCLUSION: Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples.

Classification of Premature Ventricular Contractions in Athletes During Routine Preparticipation Exams.

BACKGROUND: Large-scale data on incidental premature ventricular contraction (PVC) prevalence and morphologies have been lacking, leaving many providers without guidance on further cardiac testing for patients with incidental PVCs on ECG. Athletes offer an intriguing cohort to understand the clinical significance, prevalence, and common morphologies of incidental PVCs because they often undergo ECG screening during preparticipation exams. METHODS: Digital ECGs were obtained from 10 728 screened athletes aged 14 to 35 years during mass screenings in schools and professional sports teams between 2014 and 2021. A retrospective analysis of ECGs with PVCs was performed using the simultaneous display of frontal (limb) and horizontal (precordial) plane leads. PVCs were coded for morphology and categorized as benign or nonbenign using recommended criteria. RESULTS: Twenty-six athletes (0.24%) were found to have at least 1 PVC. Among these, 50% were female, 65% were White, 8% were Asian, 4% were Hispanic, and 23% were Black. Nineteen of the 26 (73%) ECGs had PVCs with a left bundle branch block pattern compared with 7 (27%) with a right bundle branch block pattern. Twenty-four ECGs (96%) had PVCs with benign patterns, including 18 with right ventricular outflow tract, 5 with left anterior fascicle, and 2 with left posterior fascicle morphology. CONCLUSIONS: There is a low prevalence of PVCs on routine ECG screening of young athletes, and most PVCs are of benign morphology in this population. This study highlights the value of using digital ECG recorders with simultaneous lead display to guide decision-making about further cardiac testing and referrals in young athletes with PVCs. Using our results and review of the literature, we propose methods and algorithms of PVC evaluation on screening ECGs to help guide many providers with risk stratification and decision-making about further cardiac testing and electrophysiology referrals in young athletes with PVCs.