Schizophrenia (SCZ) and related psychoses occur in all human populations, but are diagnosed most frequently among Black and African ancestry individuals. Environmental exposures and adversities, ...disparities in access to care, and historical trends of over- and racialized diagnosis contribute to this discrepancy. Nonetheless, African diaspora populations remain underrepresented in large scale research initiatives, limiting the potential benefit of new biological insights to the communities most burdened by these illnesses.
Building on our recent work in the Million Veteran Program (MVP), we undertook a collaborative effort to compile and harmonize extant genotypic and phenotypic data for admixed African ancestry individuals. These studies included the new All of Us (AOU) initiative, and the historic BiGS, COGS, GPC, PAARTNERS, and MGS studies; 15,101 SCZ, 11643 bipolar I (BIP), and 63,212 control participants were available for analysis. We applied a range of genomic methodologies including trans-ancestry meta-analysis and fine-mapping, polygenic risk score (PRS) profiling, TWAS, and genome-based restricted maximum likelihood (GREML). We combined African ancestry results with published findings based on European and East Asian populations to explore convergent (and divergent) effects in the most diverse genetic analysis of these disorders to date.
In the discovery phase, we identified a secondary association in GRIN2A (P=5.05e-8); four loci attained genome-wide significance in the African ancestry meta-analysis. Across 270 PGC3 loci, 65% showed the same direction of allelic effect in African American veterans (P=1e-7), compared to 90% in European Americans (P=9e-48); importantly, when considering only European or African ancestry tracts (i.e., haplotypes) in African Americans, 69% (P=3.4e-10) and 58% (P=0.007) of index SNPs showed a consistent direction of allelic effect. We observed fewer total and novel associations when combining African results with published European findings than observed when combining European or East Asian datasets. More intriguingly, fine-mapping of PGC3 loci saw the total number of credible SNPs reduced by 13% following meta-analysis with African ancestry based results, and by 20% when only African tracts were analyzed. We also observed more drastic improvements in fine-mapping resolution, including narrowing a gene-dense signal at 12q24.3 down to a single locus, BCL7A, and honing of gene-spanning signal at CACNA1I to a singular intron. Notably, we did not observe cross-ancestry support for the MHC locus on chromosome 6p21; imputation of structural C4 alleles highlighted a remarkable "shift" with respect to copy number distributions, reflecting duplication event subsequent to human migrations out-of-Africa.
Our expanded analyses of SCZ and BIP in African ancestry populations highlight challenges and opportunities of enhanced diversity in neuropsychiatric genetics research. We explore the implications of ancestry-based disparities in representation and generalizability of genetic effects. Leveraging two large-scale EHRs, we explore the broad pleiotropy of SCZ and BIP risk alleles, and benchmark the relevance of current instruments for risk stratification, and predicting hospitalization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Observational studies are used for estimating vaccine effectiveness under real-world conditions. The practical performance of two common approaches-cohort and test-negative designs-need to be ...compared for COVID-19 vaccines.
We compared the cohort and test-negative designs to estimate the effectiveness of the BNT162b2 vaccine against COVID-19 outcomes using nationwide data from the United States Department of Veterans Affairs. Specifically, we (1) explicitly emulated a target trial using follow-up data and evaluated the potential for confounding using negative controls and benchmarking to a randomized trial, (2) performed case-control sampling of the cohort to confirm empirically that the same estimate is obtained, (3) further restricted the sampling to person-days with a test, and (4) implemented additional features of a test-negative design. We also compared their performance in limited datasets.
Estimated BNT162b2 vaccine effectiveness was similar under all four designs. Empirical results suggested limited residual confounding by healthcare-seeking behavior. Analyses in limited datasets showed evidence of residual confounding, with estimates biased downward in the cohort design and upward in the test-negative design.
Vaccine effectiveness estimates under a cohort design with explicit target trial emulation and a test-negative design were similar when using rich information from the VA healthcare system, but diverged in opposite directions when using a limited dataset. In settings like ours with sufficient information on confounders and other key variables, the cohort design with explicit target trial emulation may be preferable as a principled approach that allows estimation of absolute risks and facilitates interpretation of effect estimates.
IMPORTANCE: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. OBJECTIVE: Individuals with African ...ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19–associated AKI and death. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information. EXPOSURES: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). MAIN OUTCOMES AND MEASURES: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2). RESULTS: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio OR, 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021. CONCLUSIONS AND RELEVANCE: In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.
COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute ...COVID-19 in preventing the development of PCCs.
To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs.
Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment.
Veterans Health Administration (VHA).
Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022.
Nirmatrelvir-ritonavir treatment for acute COVID-19.
Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms.
Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (
= 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 95% CI, 0.44 to 0.97; cumulative incidence difference, -0.29 percentage points CI, -0.52 to -0.05 percentage points).
Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance.
Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir.
U.S. Department of Veterans Affairs.
Assessment instruments commonly used in clinical trials to measure functional outcomes in substance users may lack sensitivity to detect change during treatment, potentially limiting findings ...regarding benefits of reduced drug use. This study evaluated the sensitivity of the Addiction Severity Index (ASI) to detect change in psychiatric functioning among cocaine users.
Data were pooled across five clinical trials for cocaine use disorder (N = 492) that included a 12-week treatment period and 6-month follow-up. Within-person cohen’s d′ was used to evaluate effect size of change on the Psychiatric Composite Score of the ASI (ASI-Psych) and Global Severity Index (GSI) of the Brief Symptom Inventory, as well as cocaine use.
Effect sizes were larger for GSI than ASI-Psych from baseline to week 12 (GSI d′ = 0.59; ASI-Psych d′ = 0.16), and 6-month follow-up (GSI d′ = 0.48; ASI-Psych d′ = 0.10). For those with non-zero ASI-Psych at baseline (n = 252), medium effect sizes were found over the 12-week period (d′ = 0.53) and 6-month follow-up (d′ = 0.47). Effect sizes for change in days of cocaine use were most similar to GSI in either sample.
The ASI Psychiatric Composite Score may have limited sensitivity to detect change in psychiatric functioning among clinical trial participants who reduce cocaine use. It may be useful for detecting change amongst those reporting some psychiatric problems at the start of treatment. Future research should consider an instrument’s sensitivity to change when assessing the potential functional benefits of reducing cocaine use.
•This study evaluated the effect size of change in psychiatric functioning.•Cocaine users had limited change on ASI psychiatric domain during clinical trial.•The Global Severity Index (GSI) from BSI showed medium effect size of change.•Effect sizes for change in days of cocaine use were most similar to GSI.•Assessing benefits of reduced cocaine use should consider sensitivity to change.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
HIV management among older people living with HIV (PLWH) may be complicated by the presence of multiple comorbidities and polypharmacy. This study evaluated effectiveness and ...durability of modern 3-drug antiretroviral regimens among older PLWH.
Methods
Using data from the Veterans Aging Cohort Study (VACS), PLWH ≥50 years old initiating a dolutegravir (DTG), bictegravir (BIC), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV)-based 3-drug regimen for the first time between January 1, 2014, and March 31, 2020 were followed from regimen initiation (baseline) until regimen discontinuation (d/c), death, loss to follow-up, or end of study (September 30, 2020). Suppression viral load (VL)< 50 copies/mL, change in CD4 cell count, and regimen d/c were compared between regimens 6- and 12-months post-baseline using multivariable logistic or linear regression. Virologic failure (VF; 2 consecutive VLs ≥ 200 copies/ml, or 1VL ≥ 200 copies/ml followed by regimen d/c) was evaluated over 12 months. For all outcomes, DTG-based regimens were compared to each other regimen. Outcomes were stratified by treatment experience (ART-naïve and ART-experienced).
Results
2,489 ART-naive (DTG: 912, BIC: 432, EVG: 751, RAL: 159, DRV: 235) and 13,810 ART-experienced (DTG: 5097, BIC: 1765, EVG: 3582, RAL: 1486, DRV: 1880) individuals were included. Included PLWH were 97% male and 30% were ≥65 years old (Table 1). For both naive and experienced PLWH, those on DTG were more likely suppressed and had greater increases in CD4 counts at 6 and 12 months compared to those on DRV or RAL (Table 2). Odds of VF did not differ by regimen for ART-naive. For ART-experienced, DTG showed reduced likelihood of VF compared to DRV and RAL. Discontinuations within the first year were higher for RAL and DRV compared to DTG. For ART-experienced PLWH, 6-month d/c was greater for DTG vs. EVG. Regardless of treatment status, no other statistical differences in outcomes were observed between DTG-, BIC-, and EVG-based regimens.
Conclusion
For both ART-naïve and ART-experienced PLWH >50 years old, treatment responses during the first 12 months of follow-up were similar for those taking DTG-, BIC-, and EVG-based regimens. DTG-based regimens demonstrated greater effectiveness and durability compared to DRV- or RAL-based regimens.
Disclosures
Cassidy Henegar, PhD, MSPH, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare: full-time employee Charles Hicks, MD, MD, ViiV Healthcare: I am a full time employee of ViiV Healthcare. Vani Vannappagari, MBBS, MPH, PhD, ViiV Healthcare: I am full time employee of ViiV Healthcare and receive GlaxoSmithKline stock as part of my compensation package|ViiV Healthcare: Stocks/Bonds.
Abstract
The course of posttraumatic stress disorder (PTSD) symptoms varies among veterans of war zones, but sources of variation in long‐term symptom course remain poorly understood. Modeling of ...symptom growth trajectories facilitates the understanding of predictors of individual outcomes over time. Although growth mixture modeling (GMM) has been applied to military populations, few studies have incorporated both predeployment and follow‐up measurements over an extended time. In this prospective study, 1,087 U.S. Army soldiers with varying military occupational specialties and geographic locations were assessed before and after deployment to the Iraq war zone, with long‐term follow‐up assessment occurring at least 5 years after return from deployment. The primary outcome variable was the PTSD Checklist–Civilian Version summary score. GMM yielded four latent profiles, characterized as primarily asymptomatic (
n =
194, 17.8%); postdeployment worsening symptoms (
n =
84, 7.7%); mild symptoms (
n =
320, 29.4%); and preexisting, with a chronic postdeployment elevation of symptoms (
n =
489, 45.0%). Regression models comparing the primarily asymptomatic class to the symptomatic classes revealed that chronic symptom classes were associated with higher degrees of stress exposure, less predeployment social support, military reservist or veteran status at the most recent assessment, and poorer predeployment visual memory,
OR
s = 0.98–2.90. PTSD symptom course varies considerably over time after military deployment and is associated with potentially modifiable biopsychosocial factors that occur early in its course in addition to exposures and military status.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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