Publications by authors named "Joseph A C Delaney"

73 Publications

Semi-parametric Estimation of Biomarker Age Trends with Endogenous Medication Use in Longitudinal Data.

Obs Stud 2021 May 27;7:127-147. Epub 2021 May 27.

Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA.

In cohort studies, non-random medication use can pose barriers to estimation of the natural history trend in a mean biomarker value-namely, the association between a predictor of interest and a biomarker outcome that would be observed in the total absence of biomarker-specific treatment. Common causes of treatment and outcomes are often unmeasured, obscuring our ability to easily account for medication use with assumptions commonly invoked in causal inference such as conditional ignorability. Further, without a high degree of confidence in the availability of a variable satisfying the exclusion restriction, use of instrumental variable approaches may be difficult to justify. Heckman's hybrid model with structural shift (sometimes referred to less specifically as the treatment effects model) can be used to correct endogeneity bias via a homogeneity assumption (i.e., that average treatment effects do not vary across covariates) and parametric specification of a joint model for the outcome and treatment. In recent work, we relaxed the homogeneity assumption by allowing observed covariates to serve as treatment effect modifiers. While this method has been shown to be reasonably robust in settings of cross-sectional data, application of this methodology to settings of longitudinal data remains unexplored. We demonstrate how the assumptions of the treatment effects model can be extended to accommodate clustered data arising from longitudinal studies. Our proposed approach is semi-parametric in nature in that valid inference can be obtained without the need to specify any component of the longitudinal correlation structure. As an illustrative example, we use data from the Multi-Ethnic Study of Atherosclerosis to evaluate trends in low-density lipoprotein by age and gender. Results from a collection of simulation studies, as well as our illustrative example, confirm that our generalization of the treatment effects model can serve as a useful tool to uncover natural history trends in longitudinal data that are obscured by endogenous treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232347PMC
May 2021

Types of Stroke Among People Living With HIV in the United States.

J Acquir Immune Defic Syndr 2021 04;86(5):568-578

Neurology, University of Washington, Seattle, WA.

Background: Most studies of stroke in people living with HIV (PLWH) do not use verified stroke diagnoses, are small, and/or do not differentiate stroke types and subtypes.

Setting: CNICS, a U.S. multisite clinical cohort of PLWH in care.

Methods: We implemented a centralized adjudication stroke protocol to identify stroke type, subtype, and precipitating conditions identified as direct causes including infection and illicit drug use in a large diverse HIV cohort.

Results: Among 26,514 PLWH, there were 401 strokes, 75% of which were ischemic. Precipitating factors such as sepsis or same-day cocaine use were identified in 40% of ischemic strokes. Those with precipitating factors were younger, had more severe HIV disease, and fewer traditional stroke risk factors such as diabetes and hypertension. Ischemic stroke subtypes included cardioembolic (20%), large vessel atherosclerosis (13%), and small vessel (24%) ischemic strokes. Individuals with small vessel strokes were older, were more likely to have a higher current CD4 cell count than those with cardioembolic strokes and had the highest mean blood pressure of the ischemic stroke subtypes.

Conclusion: Ischemic stroke, particularly small vessel and cardioembolic subtypes, were the most common strokes among PLWH. Traditional and HIV-related risk factors differed by stroke type/subtype. Precipitating factors including infections and drug use were common. These results suggest that there may be different biological phenomena occurring among PLWH and that understanding HIV-related and traditional risk factors and in particular precipitating factors for each type/subtype may be key to understanding, and therefore preventing, strokes among PLWH.
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http://dx.doi.org/10.1097/QAI.0000000000002598DOI Listing
April 2021

Drug and alcohol use among people living with HIV in care in the United States by geographic region.

AIDS Care 2021 Jan 23:1-8. Epub 2021 Jan 23.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Substance use in the U.S. varies by geographic region. Opioid prescribing practices and marijuana, heroin, and methamphetamine availability are evolving differently across regions. We examined self-reported substance use among people living with HIV (PLWH) in care at seven sites from 2017-2019 to understand current regional substance use patterns. We calculated the percentage and standardized percentage of PLWH reporting current drug use and at-risk and binge alcohol use by U.S. Census Bureau geographic region and examined associations in adjusted logistic regression analyses. Among 7,686 PLWH, marijuana use was the most prevalent drug (30%), followed by methamphetamine/crystal (8%), cocaine/crack (7%), and illicit opioids (3%). One-third reported binge alcohol use (32%). Differences in percent of current use by region were seen for marijuana (24-41%) and methamphetamine/crystal (2-15%), with more use in the West and Northeast, and binge alcohol use (26-40%). In adjusted analyses, PLWH in the Midwest were significantly less likely to use methamphetamine/crystal (aOR: 0.13;0.06-0.25) or illicit opioids (aOR:0.16;0.05-0.53), and PLWH in the Northeast were more likely to use cocaine/crack (aOR:1.59;1.16-2.17), compared to PLWH in the West. Understanding differences in substance use patterns in the current era, as policies continue to evolve, will enable more targeted interventions in clinical settings among PLWH.
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http://dx.doi.org/10.1080/09540121.2021.1874274DOI Listing
January 2021

Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA).

BMC Cardiovasc Disord 2021 01 22;21(1):45. Epub 2021 Jan 22.

Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

Background: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP).

Methods: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level.

Results: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14CD16) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 T helper cell subsets with average systolic blood pressure.

Conclusion: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.
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http://dx.doi.org/10.1186/s12872-021-01857-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821496PMC
January 2021

Brief Report: Differences in Types of Myocardial Infarctions Among People Aging With HIV.

J Acquir Immune Defic Syndr 2021 02;86(2):208-212

University of Washington, Seattle, WA.

Background: Type 1 myocardial infarctions (T1MIs) result from atherosclerotic plaque instability, rupture, and/or erosion. Type 2 MIs (T2MIs) are secondary to causes such as sepsis and cocaine-induced vasospasm resulting in an oxygen demand-supply mismatch and are associated with higher mortality than T1MIs. T2MIs account for a higher proportion of MIs among people living with HIV (PLWH) compared with the general population. We compared MI rates by type among aging PLWH. We hypothesized that increases in MI rates with older age would differ by MI types, and T2MIs would be more common than T1MIs in younger individuals.

Methods: Potential MIs from 6 sites were centrally adjudicated using physician notes, electrocardiograms, procedure results, and laboratory results. Reviewers categorized MIs by type and identified causes of T2MIs. We calculated T1MI and T2MI incidence rates. Incidence rate ratios were calculated for T2MI vs. T1MI rates per decade of age.

Results: We included 462 T1MIs (52%) and 413 T2MIs (48%). T1MI rates increased with older age, although T1MIs occurred in all age decades including young adults. T2MI rates were significantly higher than T1MI rates for PLWH younger than 40 years. T1MI rates were similar or higher than T2MI rates among those older than 40 years (significantly higher for those aged 50-59 and 60-69 years).

Conclusions: Rates of T2MIs were higher than T1MIs until age 40 years among PLWH, differing from the general population, but rates of both were high among older PLWH. Given prognostic differences between MI types, these results highlight the importance of differentiating MI types among PLWH.
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http://dx.doi.org/10.1097/QAI.0000000000002534DOI Listing
February 2021

Brief Report: Weight Gain Following ART Initiation in ART-Naïve People Living With HIV in the Current Treatment Era.

J Acquir Immune Defic Syndr 2021 03;86(3):339-343

University of Washington, Seattle, WA.

Objectives: Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era.

Methods: Between 2012 and 2019, 3232 ART-naïve PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time.

Results: Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens.

Conclusions: There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naïve PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.
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http://dx.doi.org/10.1097/QAI.0000000000002556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878311PMC
March 2021

Changing Patterns of Alcohol Use and Probability of Unsuppressed Viral Load Among Treated Patients with HIV Engaged in Routine Care in the United States.

AIDS Behav 2021 Apr 16;25(4):1072-1082. Epub 2020 Oct 16.

Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

We examined HIV viral load non-suppression ([Formula: see text] 200 copies/mL) subsequent to person-periods (3-18 months) bookended by two self-reports of alcohol use on a standardized patient reported outcome assessment among adults in routine HIV care. We examined the relative risk (RR) of non-suppression associated with increases and decreases in alcohol use (relative to stable use), stratified by use at the start of the person-period. Increases in drinking from abstinence were associated with higher risk of viral non-suppression (low-risk without binge: RR 1.16, 95% CI 1.03, 1.32; low-risk with binge: RR 1.35, 95% CI 1.11, 1.63; high-risk: RR 1.89, 95% CI 1.16, 3.08). Decreases in drinking from high-risk drinking were weakly, and not statistically significantly associated with lower risk of viral non-suppression. Other changes in alcohol use were not associated with viral load non-suppression. Most changes in alcohol consumption among people using alcohol at baseline were not strongly associated with viral non-suppression.
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http://dx.doi.org/10.1007/s10461-020-03065-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979457PMC
April 2021

Substantial decline in heavily treated therapy-experienced persons with HIV with limited antiretroviral treatment options.

AIDS 2020 11;34(14):2051-2059

Department of Medicine, Division of Allergy & Infectious Diseases, University of Washington, Seattle, Washington.

Objective: Historically, a high burden of resistance to antiretroviral therapy (ART) in heavily treatment-experienced (HTE) persons with HIV (PWH) resulted in limited treatment options (LTOs). We evaluated the prevalence, risk factors, and virologic control of HTE PWH with LTO throughout the modern ART era.

Design: We examined all ART-experienced PWH in care between 2000 and 2017 in the Centers for AIDS Research Network of Integrated Clinical Systems cohort.

Methods: We computed the annual prevalence of HTE PWH with LTO defined as having two or less available classes with two or less active drugs per class based on genotypic data and cumulative antiretroviral resistance. We used multivariable Cox proportional hazards models to examine risk of LTO by 3-year study entry periods adjusting for demographic and clinical characteristics.

Results: Among 27 133 ART-experienced PWH, 916 were classified as having LTO. The prevalence of PWH with LTO was 5.2-7.5% in 2000-2006, decreased to 1.8% in 2007, and remained less than 1% after 2012. Persons entering the study in 2009-2011 had an 80% lower risk of LTO compared with those entering in 2006-2008 (adjusted hazard ratio 0.20; 95% confidence interval: 0.09-0.42). We found a significant increase in undetectable HIV viral loads among PWH ever classified as having LTO from less than 30% in 2001 to more than 80% in 2011, comparable with persons who never had LTO.

Conclusion: Results of this large multicenter study show a dramatic decline in the prevalence of PWH with LTO to less than 1% with the availability of more potent drugs and a marked increase in virologic suppression in the current ART era.
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http://dx.doi.org/10.1097/QAD.0000000000002679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606534PMC
November 2020

Hazardous alcohol use, antiretroviral therapy receipt, and viral suppression in people living with HIV who inject drugs in the United States, India, Russia, and Vietnam.

AIDS 2020 12;34(15):2285-2294

Department of Community Health Sciences, Jonathan and Karin Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, USA.

Objectives: In high-income countries, hazardous alcohol use is associated with reduced receipt of antiretroviral therapy (ART) and viral suppression among people living with HIV (PLHIV) who inject drugs. These associations are less understood in lower middle-income countries (LMIC) and upper middle-income countries.

Design: We examined associations between hazardous alcohol use, ART receipt, and viral suppression among PLHIV who reported current or former injection drug use. Participants were from nine studies in the United States (high-income country), India (LMIC), Russia (upper middle-income country), and Vietnam (LMIC).

Methods: Hazardous alcohol use was measured via Alcohol Use Disorders Identification Test. Outcomes were HIV viral suppression (viral load of <1000 RNA copies/ml) and self-reported ART receipt. Logistic regression assessed associations between hazardous alcohol use and both outcome variables, controlling for age and sex, among participants with current and former injection drug use.

Results: Among 2790 participants, 16% were women, mean age was 37.1 ± 9.5 years. Mean Alcohol Use Disorders Identification Test scores were 4.6 ± 8.1 (women) and 6.2 ± 8.3 (men); 42% reported ART receipt; 40% had viral suppression. Hazardous alcohol use was significantly associated with reduced ART receipt in India (adjusted odds ratio = 0.59, 95% confidence interval: 0.45-0.77, P < 0.001); and lower rates of viral suppression in Vietnam (adjusted odds ratio = 0.51, 95% confidence interval: 0.31-0.82, P = 0.006).

Conclusion: Associations between hazardous alcohol use, ART receipt, and viral suppression varied across settings and were strongest in LMICs. Addressing hazardous alcohol use holds promise for improving HIV continuum of care outcomes among PLHIV who inject drugs. Specific impact and intervention needs may differ by setting.
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http://dx.doi.org/10.1097/QAD.0000000000002716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951611PMC
December 2020

Antiretroviral drug class and anaemia risk in the current treatment era among people living with HIV in the USA: a clinical cohort study.

BMJ Open 2020 03 19;10(3):e031487. Epub 2020 Mar 19.

Department of Epidemiology, University of Washington, Seattle, Washington, USA.

Objective: Anaemia is common among people living with HIV (PLWH) and has been associated with certain, often older, antiretroviral medications. Information on current antiretroviral therapy (ART) and anaemia is limited. The objective was to compare the associations between anaemia incidence or haemoglobin change with core ART classes in the current ART era.

Design: Retrospective cohort study.

Setting: USA-based prospective clinical cohort of PLWH aged 18 and above receiving care at eight sites between January 2010 and March 2018.

Participants: 16 505 PLWH were included in this study.

Main Outcome Measures: Anaemia risk and haemoglobin change were estimated among PLWH for person-time on a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI)-based regimen, relative to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based reference. We also examined PLWH on regimens containing multiple core classes. Cox proportional hazards regression analyses were conducted to measure the associations between time-updated ART classes and incident anaemia or severe anaemia. Linear mixed effects models were used to examine the relationships between ART classes and haemoglobin change.

Results: During a median of 4.9 years of follow-up, 1040 developed anaemia and 488 developed severe anaemia. Compared with NNRTI use, INSTI-based regimens were associated with an increased risk of anaemia (adjusted HR (aHR) 1.26, 95% CI 1.00 to 1.58) and severe anaemia (aHR 1.51, 95% CI 1.07 to 2.11) and a decrease in haemoglobin level. Time on multiple core classes was also associated with increased anaemia risk (aHR 1.39, 95% CI 1.13 to 1.70), while no associations were found for PI use.

Conclusion: These findings suggest INSTI use may increase the risk of anaemia. If confirmed, screening for anaemia development in users of INSTIs may be beneficial. Further research into the underlying mechanisms is warranted.
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http://dx.doi.org/10.1136/bmjopen-2019-031487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103836PMC
March 2020

Incorporating sampling weights into robust estimation of Cox proportional hazards regression model, with illustration in the Multi-Ethnic Study of Atherosclerosis.

BMC Med Res Methodol 2020 03 14;20(1):62. Epub 2020 Mar 14.

Department of Epidemiolgy, University of Washington, Seattle, WA, USA.

Background: Cox proportional hazards regression models are used to evaluate associations between exposures of interest and time-to-event outcomes in observational data. When exposures are measured on only a sample of participants, as they are in a case-cohort design, the sampling weights must be incorporated into the regression model to obtain unbiased estimating equations.

Methods: Robust Cox methods have been developed to better estimate associations when there are influential outliers in the exposure of interest, but these robust methods do not incorporate sampling weights. In this paper, we extend these robust methods, which already incorporate influence weights, so that they also accommodate sampling weights.

Results: Simulations illustrate that in the presence of influential outliers, the association estimate from the weighted robust method is closer to the true value than the estimate from traditional weighted Cox regression. As expected, in the absence of outliers, the use of robust methods yields a small loss of efficiency. Using data from a case-cohort study that is nested within the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort study, we illustrate differences between traditional and robust weighted Cox association estimates for the relationships between immune cell traits and risk of stroke.

Conclusions: Robust weighted Cox regression methods are a new tool to analyze time-to-event data with sampling, e.g. case-cohort data, when exposures of interest contain outliers.
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http://dx.doi.org/10.1186/s12874-020-00945-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071747PMC
March 2020

The association of prediagnosis social support with survival after heart failure in the Cardiovascular Health Study.

Ann Epidemiol 2020 02 9;42:73-77. Epub 2020 Jan 9.

School of Biological & Population Health Sciences, Oregon State University, Corvallis; Department of Epidemiology and Population Health, Stanford University, Stanford, CA. Electronic address:

Purpose: Although social support has been shown to be associated with survival among persons with cardiovascular disease, little research has focused on whether social support, measured before the onset of heart failure, can enhance survival after diagnosis. The objective of this study was to assess the association between prediagnosis social support and postdiagnosis survival among older adults with heart failure.

Methods: We obtained the data from the Cardiovascular Health Study, which included noninstitutionalized adults aged 65 years or older from four sites in the United States with primary enrollment in 1989-1990. We used two measures of social support, the Lubben Social Network Scale and the Interpersonal Support Evaluation List. The analytic data set included 529 participants with a social support measure within two years before diagnosis of heart failure.

Results: After adjustment for demographic covariates, cardiovascular risk factors, and general health status, mortality rates were lower among participants in the highest tertile of social network scores (HR 0.74, 95% CI: 0.59, 0.93) and the middle tertile (HR 0.73 [0.58, 0.90]), compared with the lowest tertile. Results with interpersonal support were null.

Conclusions: These findings suggest that prediagnosis structural social support may modestly buffer heart failure patients from mortality.
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http://dx.doi.org/10.1016/j.annepidem.2019.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060020PMC
February 2020

Associations of diet quality and blood serum lipoprotein levels in a population at high risk for diabetes: the Strong Heart Family Study.

Eur J Clin Nutr 2020 07 5;74(7):1084-1090. Epub 2019 Dec 5.

Department of Epidemiology, University of Washington, Seattle, WA, USA.

Background/objectives: Previous studies consistently report that diet quality is inversely associated with risk of cardiovascular disease (CVD) and type 2 diabetes. However, few studies have assessed the association of diet quality with serum lipoproteins, an intermediate marker of cardio-metabolic health, or assessed whether type 2 diabetes modifies these associations. This study assessed associations of diet quality (evaluated using the Alternative Healthy Eating Index (AHEI)), and the interaction of diet quality with diabetes, on total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), apolipoprotein A (apoA1), and apolipoprotein B (apoB) among American Indians (AIs).

Subjects/methods: Participants comprised AIs who participated in the Strong Heart Family Study (SHFS)-a study of CVD and its risk factors in 12 AI communities. Generalized estimated equations (GEEs) were used to examine the following associations: (1) the cross-sectional associations of diet quality (as determined by AHEI) with serum lipoproteins (n = 2200); and (2) the prospective associations of the AHEI measured at baseline with serum lipoproteins (n = 1899).

Results: In cross-sectional analyses, associations of AHEI with TC (p < 0.0001) LDL-C (p = 0.005), and ApoB (p = 0.002) differed according to diabetes status. In prospective analysis, AHEI was associated with more favorable levels of TC (p = 0.029) and LDL-C (p = 0.008) among participants with diabetes independent of other demographic, behavioral, and health factors; associations of diet quality with TC, LDL-C, and ApoB were much weaker among participants without diabetes. There was no association of diet quality with TG, HDL-C, or ApoA.

Conclusions: The associations of diet quality with TC, LDL-C, and ApoB differ according to diabetes status.
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http://dx.doi.org/10.1038/s41430-019-0539-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272258PMC
July 2020

Proton Pump Inhibitors, H Blocker Use, and Risk of Inflammatory Bowel Disease in Children.

J Pediatr Pharmacol Ther 2019 Nov-Dec;24(6):489-496

Objectives: Evidence suggests use of proton pump inhibitors (PPIs) and H blockers may provoke disease flares in individuals with established inflammatory bowel disease (IBD); however, there are no studies investigating the relationship of these medications with risk of developing pediatric IBD. The hypothesis was that use of acid suppression therapy in children might be associated with development of pediatric IBD.

Methods: This was a nested case-control study of 285 Kaiser Permanente Northern California members, age ≤21 years diagnosed with IBD from 1996 to 2016. Four controls without IBD were matched to each case on age, race, and membership status at the case's index date. Disease risk scores (DRS) were computed for each subject. Odds ratios and 95% confidence intervals were calculated by using conditional logistic regression models adjusted for DRS.

Results: The children's mean age was 15.1 ± 2.6 years and 49.5% were female. Six cases (n = 3 Crohn's disease [CD], n = 3 ulcerative colitis [UC]) and 6 controls were prescribed PPIs and 10 cases (n = 7 CD, n = 3 UC) and 28 controls were prescribed H2 blockers. The OR for the association of at least 1 PPI or H blocker prescription with subsequent IBD was 3.6 (95% CI, 1.1-11.7) for PPIs and 1.6 (95% CI, 0.7-3.7) for H blockers.

Conclusions: Early-life PPI use appears to be associated with subsequent IBD risk. These findings have implications for clinical treatment of children with gastrointestinal symptoms and warrant further investigation in a larger cohort.
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http://dx.doi.org/10.5863/1551-6776-24.6.489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836698PMC
November 2019

Association Between Bilirubin, Atazanavir, and Cardiovascular Disease Events Among People Living With HIV Across the United States.

J Acquir Immune Defic Syndr 2019 08;81(5):e141-e147

Department of Epidemiology, University of Washington, Seattle, WA.

Objective: Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is associated with decreased cardiovascular events in HIV-uninfected populations. We examined these associations in people living with HIV (PLWH).

Methods: Potential myocardial infarctions (MIs) and strokes were centrally adjudicated. We examined MI types: type 1 MI (T1MI) from atherosclerotic plaque instability and type 2 MI (T2MI) in the setting of oxygen demand/supply mismatch such as sepsis. We used multivariable Cox regression analyses to determine associations between total bilirubin levels and outcomes adjusting for traditional and HIV-specific risk factors. To minimize confounding by hepatobiliary disease, we conducted analyses limited to bilirubin values <2.1 mg/dL; among those with fibrosis-4 values <3.25; and among everyone. We repeated analyses stratified by hepatitis C status and time-updated atazanavir use.

Results: Among 25,816 PLWH, there were 392 T1MI and 356 T2MI during follow-up. Adjusted hazard ratios for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. By contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (hazard ratio 0.56:0.33-1.00). Higher bilirubin levels among those on atazanavir were associated with fewer T1MI combined with ischemic stroke.

Limitations: Analyses were conducted with total rather than unconjugated bilirubin.

Conclusions: Among PLWH, higher bilirubin levels were associated with T2MI among some subgroups. However, among those on atazanavir, there was a protective association between bilirubin and T2MI. These findings demonstrate different associations between outcomes and elevated bilirubin due to diverse causes and the importance of distinguishing MI types.
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http://dx.doi.org/10.1097/QAI.0000000000002071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625840PMC
August 2019

Virologic Failure Among People Living With HIV Initiating Dolutegravir-Based Versus Other Recommended Regimens in Real-World Clinical Care Settings.

J Acquir Immune Defic Syndr 2019 08;81(5):572-577

Department of Medicine, University of Washington, Seattle, WA.

Background: Guidelines for initial antiretroviral treatment (ART) regimens have evolved, with integrase strand transfer inhibitors (INSTIs) increasingly prominent. Research on virologic failure (VF) with INSTI therapy is predominantly from clinical trials not care settings, especially for recently approved medications including dolutegravir. We compared outcomes among people living with HIV (PLWH) who initiated recommended regimens in clinical care across the United States.

Setting: We examined 2 groups of PLWH at 8 clinics who initiated ART regimens (August 1, 2013-March 31, 2017): those ART treatment-naive at initiation, and those treatment-experienced.

Methods: The outcome in this longitudinal cohort study was VF, defined as a viral load of ≥400 copies/mL ≥6 months after ART initiation. We examined the proportion of individuals who remained on, switched, or discontinued the regimen. Associations between regimens and outcomes were examined with adjusted Cox proportional hazards models.

Results: Among 5177 PLWH, a lower proportion experienced VF on dolutegravir- versus other INSTI- or darunavir-based regimens for previously treatment-naive (7% vs. 12% vs. 28%) and treatment-experienced PLWH (6% vs. 10% vs. 21%). In adjusted analyses, hazard ratios were similar across regimens for the combined outcome of regimen discontinuation or treatment switch. The hazard ratios for VF comparing dolutegravir- to darunavir-based regimens was 0.30 (95% CI: 0.2 to 0.6) among previously treatment-naive PLWH and was 0.60 (95% CI: 0.4 to 0.8) among treatment-experienced PLWH.

Conclusions: The proportion of previously treatment-naive PLWH remaining on recommended ART regimens did not differ by regimen. The likelihood of VF was lower with dolutegravir- than darunavir-based regimens for previously treatment-naive and treatment-experienced PLWH.
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http://dx.doi.org/10.1097/QAI.0000000000002075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649666PMC
August 2019

Impact of Abstinence and of Reducing Illicit Drug Use Without Abstinence on Human Immunodeficiency Virus Viral Load.

Clin Infect Dis 2020 02;70(5):867-874

Department of Biostatistics, University of Washington, Collaborative Health Studies Coordinating Center, Seattle.

Background: Substance use is common among people living with human immunodeficiency virus (PLWH) and a barrier to achieving viral suppression. Among PLWH who report illicit drug use, we evaluated associations between HIV viral load (VL) and reduced use of illicit opioids, methamphetamine/crystal, cocaine/crack, and marijuana, regardless of whether or not abstinence was achieved.

Methods: This was a longitudinal cohort study of PLWH from 7 HIV clinics or 4 clinical studies. We used joint longitudinal and survival models to examine the impact of decreasing drug use and of abstinence for each drug on viral suppression. We repeated analyses using linear mixed models to examine associations between change in frequency of drug use and VL.

Results: The number of PLWH who were using each drug at baseline ranged from n = 568 (illicit opioids) to n = 4272 (marijuana). Abstinence was associated with higher odds of viral suppression (odds ratio [OR], 1.4-2.2) and lower relative VL (ranging from 21% to 42% by drug) for all 4 drug categories. Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with VL suppression (OR, 2.2, 1.6, respectively). Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with lower relative VL (47%, 38%, respectively).

Conclusions: Abstinence was associated with viral suppression. In addition, reducing use of illicit opioids or methamphetamine/crystal, even without abstinence, was also associated with viral suppression. Our findings highlight the impact of reducing substance use, even when abstinence is not achieved, and the potential benefits of medications, behavioral interventions, and harm-reduction interventions.
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http://dx.doi.org/10.1093/cid/ciz299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319266PMC
February 2020

Approaches for creating comparable measures of alcohol use symptoms: Harmonization with eight studies of criminal justice populations.

Drug Alcohol Depend 2019 01 23;194:59-68. Epub 2018 Oct 23.

Yale School of Medicine, United States. Electronic address:

Background: With increasing data archives comprised of studies with similar measurement, optimal methods for data harmonization and measurement scoring are a pressing need. We compare three methods for harmonizing and scoring the AUDIT as administered with minimal variation across 11 samples from eight study sites within the STTR (Seek-Test-Treat-Retain) Research Harmonization Initiative. Descriptive statistics and predictive validity results for cut-scores, sum scores, and Moderated Nonlinear Factor Analysis scores (MNLFA; a psychometric harmonization method) are presented.

Methods: Across the eight study sites, sample sizes ranged from 50 to 2405 and target populations varied based on sampling frame, location, and inclusion/exclusion criteria. The pooled sample included 4667 participants (82% male, 52% Black, 24% White, 13% Hispanic, and 8% Asian/ Pacific Islander; mean age of 38.9 years). Participants completed the AUDIT at baseline in all studies.

Results: After logical harmonization of items, we scored the AUDIT using three methods: published cut-scores, sum scores, and MNLFA. We found greater variation, fewer floor effects, and the ability to directly address missing data in MNLFA scores as compared to cut-scores and sum scores. MNLFA scores showed stronger associations with binge drinking and clearer study differences than did other scores.

Conclusions: MNLFA scores are a promising tool for data harmonization and scoring in pooled data analysis. Model complexity with large multi-study applications, however, may require new statistical advances to fully realize the benefits of this approach.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312501PMC
January 2019

Differentiation of Type 1 and Type 2 Myocardial Infarctions Among HIV-Infected Patients Requires Adjudication Due to Overlap in Risk Factors.

AIDS Res Hum Retroviruses 2018 11 21;34(11):916-921. Epub 2018 Aug 21.

11 Department of Epidemiology, University of Washington, Seattle, Washington.

The Universal Myocardial infarction (MI) definition divides MIs into different types. Type 1 MIs (T1MI) result spontaneously from atherosclerotic plaque instability. Type 2 MIs (T2MI) are due to secondary causes of myocardial oxygen demand/supply mismatch such as occurs with sepsis. T2MI are much more common among those with HIV than in the general population. T1MI and T2MI have different mechanisms, risk factors, and potential treatments suggesting that they should be distinguished to achieve a better scientific understanding of MIs in HIV. We sought to determine whether MI type could be accurately predicted by patient characteristics without adjudication in HIV-infected individuals. We developed a statistical model to predict T2MI versus T1MI using adjudicated events from six sites utilizing demographic characteristics, traditional cardiovascular, and HIV-related risk factors. Validation was assessed in a seventh site via mean calibration, and discrimination level was assessed by the area under the curve (AUC). Of 812 MIs, 388 were T2MI. HIV-related factors including hepatitis C infection were predictive of T2MI, whereas traditional cardiovascular risk factors including total cholesterol predicted T1MI. The score predicted 69 T2MI in the validation sample resulting in poor calibration, given that 90 T2MIs were observed. The development sample AUC was 0.75 versus 0.65 in the validation sample, suggesting relatively poor discrimination. The level of discrimination to predict MI type based on patient characteristics is insufficient for individual level prediction. Adjudication is required to distinguish MI types, which is necessary to advance understanding of this important outcome among HIV populations.
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http://dx.doi.org/10.1089/AID.2018.0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238602PMC
November 2018

Perceived access and barriers to care among illicit drug users and hazardous drinkers: findings from the Seek, Test, Treat, and Retain data harmonization initiative (STTR).

BMC Public Health 2018 03 20;18(1):366. Epub 2018 Mar 20.

Division of HIV, ID and Global Medicine, Zuckerberg San Francisco General, University of California San Francisco, 995 Potrero Ave, 4th Floor, San Francisco, CA, 94110, USA.

Background: Illicit drug use (DU) and hazardous drinking (HD) among marginalized populations may be associated with greater barriers to care.

Methods: We used baseline data on the participants of the Seek, Test, Treat, and Retain data harmonization initiative. DU includes use of any illicit drugs within the past 6 months. HD was defined as scores ≥8 for men and ≥ 7 for women on Alcohol Use Disorders Identification Test within the past 12 months. Social support scores were assigned by summing scores from individual questions related to social support. Two outcomes for multivariable regression models and mediation analysis were perceived access to care and perceived barriers to care scores, calculated from summated points from individual questions within each domain. All models were adjusted for age, gender, race/ethnicity, and social support and stratified by HIV status.

Results: Among 1403 illicit drug users and 4984 non-drug users, the mean age was 39.6 ± 12.2 years old, 71% were male, 57% African Americans, and 39% Hispanic/Latinos. Over 25% reported difficulties in covering medical costs and finding transportation to health care facilities and greater proportions of drug users and hazardous drinkers reported these issues than non-DU/non-HD. In multivariable models, DU and HD were both independently associated with having greater barriers to care (β: 0.49 (95% confidence interval: 0.19 to 0.79) p < 0.01; 0.31 (0.18 to 0.45) < 0.01) in HIV-negative participants. Neither DU nor HD was strongly associated with barriers to care for HIV-positive participants. Social support was associated with better perceived access to care and fewer barriers to care in the HIV-negative participants.

Conclusion: The current study found that financial burdens of care, logistical difficulties in accessing care, and low social support were common challenges among individuals using illicit drugs and/or drinking hazardously. Addressing structural barriers and strengthening social support may be important strategies to improve health care among marginalized populations, regardless of HIV status.
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http://dx.doi.org/10.1186/s12889-018-5291-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859651PMC
March 2018

Risk of sudden sensorineural hearing loss in adults using phosphodiesterase type 5 inhibitors: Population-based cohort study.

Pharmacoepidemiol Drug Saf 2018 06 7;27(6):587-595. Epub 2018 Mar 7.

Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Purpose: The objective of the study was to determine the risk of sudden sensorineural hearing loss (SNHL) associated with use of phosphodiesterase type 5 (PDE5) inhibitors.

Methods: We conducted a retrospective cohort study in the MarketScan Commercial Claims and Encounters Database including adult men who initiated a PDE5 inhibitor (n = 377,722) and 1,957,233 nonusers between 1998 and 2007. Periods of drug exposure were assessed on a weekly basis based on pharmacy billing records, assuming use of 1 dose per week (current use). Incident sudden SNHL was defined based on inpatient or outpatient visits with International Classification of Diseases, Ninth Revision, Clinical Modification codes 389.1x, 389.2x, or 388.2 plus ≥2 procedure codes for audiometric hearing testing within ±30 days of sudden SNHL diagnosis. We used age- and propensity score-adjusted Cox proportional hazards model to evaluate the risk of sudden SNHL during periods of current or recent use compared with that of nonuse. We conducted sensitivity analyses by varying the assumed drug utilization frequency and sudden SNHL case definition.

Results: We evaluated 1233 sudden SNHL cases, resulting in an incidence of 4.35, 5.58, and 2.38 per 10,000 person-years for current, recent, and nonuse of PDE5 inhibitors, respectively. Compared with nonuse, the adjusted hazard ratio was 1.25 (1.01-1.55) for current use with a risk difference of 1.97 (1.12-2.82) per 10,000 person-years. For recent use, the adjusted hazard ratio was 1.60 (1.33-1.94) and risk difference was 3.19 (2.24-4.14). Estimates were consistent across the sensitivity analyses.

Conclusions: Use of PDE5 inhibitors is associated with a small but significantly increased risk of sudden SNHL.
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http://dx.doi.org/10.1002/pds.4405DOI Listing
June 2018

Increased Risk of Myocardial Infarction in HIV-Infected Individuals in North America Compared With the General Population.

J Acquir Immune Defic Syndr 2017 08;75(5):568-576

*Department of Medicine, University of Washington School of Medicine, Seattle, WA; †Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; ‡Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC; §Department of Medicine, University of Alabama School of Medicine, Birmingham, AL; ‖Department of Medicine, University of California San Diego, San Diego, CA; ¶Kaiser Permanente Division of Research, Oakland, CA; #Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; **Department of Epidemiology, University of Washington School of Public Health, Seattle, WA; ††Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; ‡‡Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; §§Department of Medicine, George Washington University School of Medicine, Washington, DC; ‖‖Department of Clinical Investigations, Whitman Walker Health, Washington, DC; ¶¶Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA; ##Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA; ***Department of Medicine, Yale School of Public Health, New Haven, CT; †††Department of Infectious Diseases, San Leandro Medical Center, San Leandro, CA; and ‡‡‡Department of Medicine, Johns Hopkins University, Baltimore, MD.

Background: Previous studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort.

Methods: We ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC.

Results: Among 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/μL: ref; 350-499 cells/μL: aIRR = 1.32 (0.98 to 1.77); 200-349 cells/μL: aIRR = 1.37 (1.01 to 1.86); 100-199 cells/μL: aIRR = 1.60 (1.09 to 2.34); <100 cells/μL: aIRR = 2.19 (1.44 to 3.33)]. Risk associated with detectable HIV RNA [<400 copies/mL: ref; ≥400 copies/mL: aIRR = 1.36 (1.06 to 1.75)] was significantly increased only when CD4 was excluded.

Conclusions: The higher incidence of T1MI in HIV-infected individuals and increased risk associated with lower CD4 count and detectable HIV RNA suggest that early suppressive antiretroviral treatment and aggressive management of traditional CVD risk factors are necessary to maximally reduce MI risk.
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http://dx.doi.org/10.1097/QAI.0000000000001450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522001PMC
August 2017

Prevalence and Factors Associated with Hazardous Alcohol Use Among Persons Living with HIV Across the US in the Current Era of Antiretroviral Treatment.

AIDS Behav 2017 Jul;21(7):1914-1925

Department of Medicine, University of Washington, 325 9th Ave Box 359931, Seattle, WA, USA.

Hazardous alcohol use is associated with detrimental health outcomes among persons living with HIV (PLWH). We examined the prevalence and factors associated with hazardous alcohol use in the current era using several hazardous drinking definitions and binge drinking defined as ≥5 drinks for men versus ≥4 for women. We included 8567 PLWH from 7 U.S. sites from 2013 to 2015. Current hazardous alcohol use was reported by 27% and 34% reported binge drinking. In adjusted analyses, current and past cocaine/crack (odd ratio [OR] 4.1:3.3-5.1, p < 0.001 and OR 1.3:1.1-1.5, p < 0.001 respectively), marijuana (OR 2.5:2.2-2.9, p < 0.001 and OR 1.4:1.2-1.6, p < 0.001), and cigarette use (OR 1.4:1.2-1.6, p < 0.001 and OR 1.3:1.2-1.5, p < 0.001) were associated with increased hazardous alcohol use. The prevalence of hazardous alcohol use remains high in the current era, particularly among younger men. Routine screening and targeted interventions for hazardous alcohol use, potentially bundled with interventions for other drugs, remain a key aspect of HIV care.
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http://dx.doi.org/10.1007/s10461-017-1740-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628735PMC
July 2017

HIV Provider Documentation and Actions Following Patient Reports of At-risk Behaviors and Conditions When Identified by a Web-Based Point-of-Care Assessment.

AIDS Behav 2017 Nov;21(11):3111-3121

Department of Medicine, Harborview Medical Center, University of Washington, 325 9th Ave, Box 359931, Seattle, WA, 98104, USA.

We compared same-day provider medical record documentation and interventions addressing depression and risk behaviors before and after delivering point-of-care patient-reported outcomes (PROs) feedback for patients who self-reported clinically relevant levels of depression or risk behaviors. During the study period (1 January 2006-15 October 2010), 2289 PRO assessments were completed by HIV-infected patients. Comparing the 8 months before versus after feedback implementation, providers were more likely to document depression (74% before vs. 87% after feedback, p = 0.02) in patients with moderate-to-severe depression (n = 317 assessments), at-risk alcohol use (41 vs. 64%, p = 0.04, n = 155) and substance use (60 vs. 80%, p = 0.004, n = 212). Providers were less likely to incorrectly document good adherence among patients with inadequate adherence after feedback (42 vs. 24%, p = 0.02, n = 205). While PRO feedback of depression and adherence were followed by increased provider intervention, other domains were not. Further investigation of factors associated with the gap between awareness and intervention are needed in order to bridge this divide.
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http://dx.doi.org/10.1007/s10461-017-1718-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021024PMC
November 2017

Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification and its Progression Among Older Adults: 10-Year Follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA).

J Am Heart Assoc 2016 10 11;5(10). Epub 2016 Oct 11.

Division of Cardiology, Johns Hopkins University, Baltimore, MD

Background: Recent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, we assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC).

Methods And Results: We studied 5448 adults free of clinically diagnosed CVD (52% female; aged 45-84 years) from the Multi-Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles. Baseline CAC was measured by computed tomography, and CAC measurements were repeated in 2742 participants ≈10 years later. At baseline, mean calcium intakes across quintiles were 313.3, 540.3, 783.0, 1168.9, and 2157.4 mg/day. Women had higher calcium intakes than men. After adjustment for potential confounders, among 1567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake, were 1 (reference), 0.95 (0.79-1.14), 1.02 (0.85-1.23), 0.86 (0.69-1.05), and 0.73 (0.57-0.93). After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR=1.22 [1.07-1.39]). No relation was found between baseline calcium intake and 10-year changes in log-transformed CAC among those participants with baseline CAC >0.

Conclusions: High total calcium intake was associated with a decreased risk of incident atherosclerosis over long-term follow-up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC.
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http://dx.doi.org/10.1161/JAHA.116.003815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121484PMC
October 2016

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

Am J Hum Genet 2016 Jul 16;99(1):56-75. Epub 2016 Jun 16.

Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
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http://dx.doi.org/10.1016/j.ajhg.2016.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005440PMC
July 2016

Short Communication: Effect of Antiretroviral Therapy on Circulating Damage-Associated Molecular Pattern Molecules and CD4 Immune Reconstitution in HIV-Infected Individuals.

AIDS Res Hum Retroviruses 2016 09 13;32(9):876-8. Epub 2016 Jun 13.

1 Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington , Seattle, Washington.

We examined levels of the damage-associated molecular pattern molecules, HMGB1 and S100A9, in individuals for whom stored samples were available before and after antiretroviral therapy (ART) initiation, to determine their association with CD4 reconstitution. Mean HMGB1 levels (1.95 ng/ml vs. 3.02 ng/ml) and the proportion of individuals with detectable S100A9 (19.6% vs. 43.1%) significantly increased after ART. Detectable post-ART S100A9 was independently associated with impaired immune reconstitution.
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http://dx.doi.org/10.1089/AID.2016.0059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028901PMC
September 2016

Evaluating the treatment effects model for estimation of cross-sectional associations between risk factors and cardiovascular biomarkers influenced by medication use.

Pharmacoepidemiol Drug Saf 2015 Dec 30;24(12):1286-96. Epub 2015 Sep 30.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Purpose: In cross-sectional observational data, evaluation of biomarker-to-exposure associations is often complicated by nonrandom medication use. Traditional approaches often lead to biased estimates, consistent with known results involving confounding by indication. More sophisticated, yet easy to implement approaches such as inverse probability weighting and censored normal regression can address medication use in certain settings but have poor performance when medication use depends on off-medication biomarker values. More sophisticated approaches are necessary.

Methods: Heckman's treatment effects model resembles the process that gives rise to cross-sectional data. In this study, we conduct a variety of simulation studies to illustrate why traditional approaches are inappropriate when medication use depends on underlying biomarker values. We illustrate how Heckman's model can accommodate this feature. We also apply the models to data from the Multi-Ethnic Study of Atherosclerosis.

Results: Inverse probability weighting and censored normal regression are sensitive to how strongly medication use is associated with untreated biomarker values (the untreated value acts as an unmeasured predictor of medication use in this context). Heckman's model can often adequately remove bias and is robust to certain forms of model misspecification but relies on knowing important predictors of medication use, even when they are independent of the biomarker. The advantages of Heckman's model can be negated if the effect of medication on biomarker values is proportionate to the underlying biomarker.

Conclusions: If predictors of medication use are measured, data are cross-sectional, and effects are approximately additive, then Heckman's model is more accurate relative to alternative approaches.
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http://dx.doi.org/10.1002/pds.3876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278897PMC
December 2015

Validation of secondary data sources to identify Parkinson disease against clinical diagnostic criteria.

Am J Epidemiol 2015 Feb 29;181(3):185-90. Epub 2014 Dec 29.

Parkinson disease (PD) is the second most common neurodegenerative disorder. Its diagnosis relies solely on a clinical examination and is not straightforward because no diagnostic test exists. Large, population-based, prospective cohort studies designed to examine other outcomes that are more common than PD might provide cost-efficient alternatives for studying the disease. However, most cohort studies have not implemented rigorous systematic screening for PD. A majority of epidemiologic studies that utilize population-based prospective designs rely on secondary data sources to identify PD cases. Direct validation of these secondary sources against clinical diagnostic criteria is lacking. The Framingham Heart Study has prospectively screened and evaluated participants for PD based on clinical diagnostic criteria. We assessed the predictive value of secondary sources for PD identification relative to clinical diagnostic criteria in the Framingham Heart Study (2001-2012). We found positive predictive values of 1.0 (95% confidence interval: 0.868, 1.0), 1.0 (95% confidence interval: 0.839, 1.0), and 0.50 (95% confidence interval: 0.307, 0.694) for PD identified from self-report, use of antiparkinsonian medications, and Medicare claims, respectively. The negative predictive values were all higher than 0.99. Our results highlight the limitations of using only Medicare claims data and suggest that population-based cohorts may be utilized for the study of PD determined via self-report or medication inventories while preserving a high degree of confidence in the validity of PD case identification.
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http://dx.doi.org/10.1093/aje/kwu326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312428PMC
February 2015
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