Susan R. Heckbert

Aims: We tested the hypothesis that mitochondrial DNA copy number (CN) is associated with cardiometabolic disease (CMD) traits. Methods and results: We determined the cross-sectional association of mtDNA CN measured in whole blood with several CMD traits in 65,996 individuals (mean age 60, 54% women, and 79% European descent). Cohort- and ancestry/ethnicity-specific association analysis was performed adjusting for trait- and cohort-specific covariates. Age was slightly positively associated with age (0.03 s.d. / 10 years (95% CI=0.01, 0.05)) before 65 years, while every 10 years older age was associated with 0.14 s.d. lower level of mtDNA CN after 65 years (95% CI= -0.18, -0.10). In meta-analysis without adjustment for white blood cell (WBC) and differential count in participants of European descent (N=52,491), low mtDNA CN was associated with increased odds of obesity (OR with 95% CI=1.13 (1.11, 1.16), P=3.3e-30) and hypertension (OR=1.05 (1.03, 1.08), P=4.0e-07). Further adjusting for WBC and differential count in the same participants of European descent (N=44,035), associations became non-significant (P>0.05) for hypertension, attenuated for obesity (OR _{without cell count} =1.15 (1.12, 1.18) versus OR _{cell count} =1.06 (1.03, 1.08)) but strengthened for hyperlipidemia (OR _{without cell counts} =1.03 (1.00, 1.06) versus OR _{cell counts} =1.06 (1.03, 1.09)). The magnitude and directionality of most associations were consistent between participants of European descent and other ethnicity/ancestry origins. Conclusion: Low levels of mtDNA CN in peripheral blood were associated with an increased risk of CMD diseases.

Introduction: Several lines of evidence indicate that some cases of cryptogenic stroke may be due to an atrial cardiopathy that forms a nidus for thrombus formation and embolization even in the absence of atrial fibrillation (AF). Hypothesis: We hypothesized that evidence of atrial cardiopathy other than AF is independently associated with stroke. Methods: We examined the association between several markers of atrial cardiopathy and the risk of ischemic stroke among participants in the Cardiovascular Health Study, which prospectively enrolled community-dwelling adults ≥65 years of age. The exposures of interest were P-wave terminal force in electrocardiogram lead V ₁ (PTFV ₁ ), left atrial dimension on echocardiogram, amino terminal pro-B-type natriuretic peptide (NT-proBNP), and incident AF. The primary outcome was adjudicated ischemic stroke. We used Cox proportional hazards analysis to examine associations with stroke for all four markers together along with adjustment for traditional vascular risk factors. Results: Among 3,723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 patients (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When the four atrial cardiopathy markers were combined in one model along with traditional vascular risk factors, we found significant associations with stroke for PTFV ₁ (hazard ratio [HR] per 1,000 μV*ms, 1.04; 95% confidence interval [CI], 1.0006-1.08), NT-proBNP (HR per doubling of NT-proBNP, 1.09; 95% CI, 1.03-1.16), and incident AF (HR, 2.04; 95% CI, 1.67-2.48), but not left atrial dimension (HR per cm, 0.96; 95% CI, 0.84-1.10). Conclusions: In a large, prospective, longitudinal study, we found that evidence of abnormal atrial substrate, defined more broadly than just AF, was associated with subsequent ischemic stroke. These findings support the hypothesis that left atrial thromboembolism can occur in the absence of AF.

Background We reviewed the results of the Observational Medical Outcomes Research Partnership (OMOP) 2010 Experiment in hopes of finding examples where apparently well‐designed drug studies repeatedly produce anomalous findings. OMOP had applied thousands of designs and design parameters to 53 drug–outcome pairs across 10 electronic data resources. Our intent was to use this repository to elucidate some sources of error in observational studies. Method From the 2010 OMOP Experiment, we sought drug–outcome–method combinations (DOMCs) that met consensus design criteria, yet repeatedly produced results contrary to expectation. We set aside DOMCs for which we could not agree on the suitability of the designs, then selected for an in‐depth scrutiny one drug–outcome pair analyzed by a seemingly plausible methodological approach, whose results consistently disagreed with the a priori expectation. Results The OMOP “all‐by‐all” assessment of possible DOMCs yielded many combinations that would not be chosen by researchers as actual study options. Among those that passed a first level of scrutiny, two of seven drug–outcome pairs for which there were plausible research designs had anomalous results. The use of benzodiazepines was unexpectedly associated with acute renal failure and upper gastrointestinal bleeding. We chose the latter as an example for in‐depth study. The factitious appearance of a bleeding risk may have been partly driven by an excess of procedures on the first day of treatment. A risk window definition that excluded the first day largely removed the spurious association. Conclusion One cause of reproducible “error” may be repeated failure to tie design choices closely enough to the research question at hand. Copyright © 2016 John Wiley & Sons, Ltd.

Introduction: Prompt treatment of severe sepsis in the Emergency Department reduces deaths, but the role of prehospital fluid resuscitation is unknown. We sought to determine the risk-adjusted association between prehospital fluid administration and hospital mortality among emergency medical services (EMS) patients admitted with severe sepsis. Methods: We performed a prospective, observational study of patients hospitalized with severe sepsis on admission among 45,394 adult EMS encounters taken to 15 hospitals from 11/2009 to 12/2010 by a two-tier EMS system in King County, Washington. The region mandated recording of prehospital intravenous catheter and fluid administration in prehospital records, along with detailed demographic, incident, physiologic, and hospital adjustment variables. We determined the effect of prehospital intravenous catheter or fluid versus no catheter or fluid on all-cause mortality using multivariable logistic regression. Results: Of all encounters, 1,350 met criteria for severe sepsis on admission, of whom 205 (15%) died by hospital discharge, 312 (23%) received prehospital intravenous fluid, 90 (7%) received a prehospital catheter alone and 948 (70%) did not receive catheter or fluid. EMS administered a median prehospital fluid volume of 500 mL (interquartile range (IQR): 200, 1000 mL). In adjusted models, the administration of any prehospital fluid was associated with reduced hospital mortality (Odds ratio =0.46; 95% Confidence interval: 0.23, 0.88; P =0.02) compared to no prehospital fluid. The odds of hospital mortality were also lower among severe sepsis patients treated with prehospital intravenous catheter alone (Odds ratio =0.3; 95% Confidence interval: 0.17 to 0.57; P <0.01). Conclusions: In a population-based study, the administration of prehospital fluid and placement of intravenous access were associated with decreased odds of hospital mortality compared with no prehospital catheter or fluid.

Background: It is often assumed that rare genetic variants will improve available risk prediction scores. We aimed to estimate the added predictive ability of rare variants for risk prediction of common diseases in hypothetical scenarios. Methods: In simulated data, we constructed risk models with an area under the ROC curve (AUC) ranging between 0.50 and 0.95, to which we added a single variant representing the cumulative frequency and effect (odds ratio, OR) of multiple rare variants. The frequency of the rare variant ranged between 0.0001 and 0.01 and the OR between 2 and 10. We assessed the resulting AUC, increment in AUC, integrated discrimination improvement (IDI), net reclassification improvement (NRI(>0.01)) and categorical NRI. The analyses were illustrated by a simulation of atrial fibrillation risk prediction based on a published clinical risk model. Results: We observed minimal improvement in AUC with the addition of rare variants. All measures increased with the frequency and OR of the variant, but maximum increment in AUC remained below 0.05. Increment in AUC and NRI(>0.01) decreased with higher AUC of the baseline model, whereas IDI remained constant. In the atrial fibrillation example, the maximum increment in AUC was 0.02 for a variant with frequency = 0.01 and OR = 10. IDI and NRI showed at most minimal increase for variants with frequency greater than or equal to 0.005 and OR greater than or equal to 5. Conclusions: Since rare variants are present in only a minority of affected individuals, their predictive ability is generally low at the population level. To improve the predictive ability of clinical risk models for complex diseases, genetic variants must be common and have substantial effect on disease risk.

Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.

Background: High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation. Methods: We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing &γτ;1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic co-morbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV₁ and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years. Results: The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV₁ and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years. Conclusions: Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.