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1. Comparisons of Polyexposure, Polygenic, and Clinical Risk Scores in Risk Prediction of Type 2 Diabetes

   https://doi.org/10.2337/dc20-2049  

   He, Yixuan ; Lakhani, Chirag M. ; Rasooly, Danielle ; Manrai, Arjun K. ; Tzoulaki, Ioanna ; Patel, Chirag J. ( February 2021 , Diabetes Care)

   To establish a polyexposure score (PXS) for type 2 diabetes (T2D) incorporating 12 nongenetic exposures and examine whether a PXS and/or a polygenic risk score (PGS) improves diabetes prediction beyond traditional clinical risk factors.

   We identified 356,621 unrelated individuals from the UK Biobank of White British ancestry with no prior diagnosis of T2D and normal HbA1c levels. Using self-reported and hospital admission information, we deployed a machine learning procedure to select the most predictive and robust factors out of 111 nongenetically ascertained exposure and lifestyle variables for the PXS in prospective T2D. We computed the clinical risk score (CRS) and PGS by taking a weighted sum of eight established clinical risk factors and >6 million single nucleotide polymorphisms, respectively.

   In the study population, 7,513 had incident T2D. The C-statistics for the PGS, PXS, and CRS models were 0.709, 0.762, and 0.839, respectively. Individuals in the top 10% of PGS, PXS, and CRS had 2.00-, 5.90-, and 9.97-fold greater risk, respectively, compared to the remaining population. Addition of PGS and PXS to CRS improved T2D classification accuracy, with a continuous net reclassification index of 15.2% and 30.1% for cases, respectively, and 7.3% and 16.9% for controls, respectively.

   For T2D, the PXS provides modest incremental predictive value over established clinical risk factors. However, the concept of PXS merits further consideration in T2D risk stratification and is likely to be useful in other chronic disease risk prediction models.

    

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2. Polygenic scores for tobacco use provide insights into systemic health risks in a diverse EHR-linked biobank in Los Angeles

   https://doi.org/10.1038/s41398-024-02743-z  

   Venkateswaran, Vidhya ; Boulier, Kristin ; Ding, Yi ; Johnson, Ruth ; Bhattacharya, Arjun ; Pasaniuc, Bogdan ( January 2024 , Translational Psychiatry)

   Tobacco use is a major risk factor for many diseases and is heavily influenced by environmental factors with significant underlying genetic contributions. Here, we evaluated the predictive performance, risk stratification, and potential systemic health effects of tobacco use disorder (TUD) predisposing germline variants using a European- ancestry-derived polygenic score (PGS) in 24,202 participants from the multi-ancestry, hospital-based UCLA ATLAS biobank. Among genetically inferred ancestry groups (GIAs), TUD-PGS was significantly associated with TUD in European American (EA) (OR: 1.20, CI: [1.16, 1.24]), Hispanic/Latin American (HL) (OR:1.19, CI: [1.11, 1.28]), and East Asian American (EAA) (OR: 1.18, CI: [1.06, 1.31]) GIAs but not in African American (AA) GIA (OR: 1.04, CI: [0.93, 1.17]). Similarly, TUD-PGS offered strong risk stratification across PGS quantiles in EA and HL GIAs and inconsistently in EAA and AA GIAs. In a cross-ancestry phenome-wide association meta-analysis, TUD-PGS was associated with cardiometabolic, respiratory, and psychiatric phecodes (17 phecodes atP < 2.7E-05). In individuals with no history of smoking, the top TUD-PGS associations with obesity and alcohol-related disorders (P = 3.54E-07, 1.61E-06) persist. Mendelian Randomization (MR) analysis provides evidence of a causal association between adiposity measures and tobacco use. Inconsistent predictive performance of the TUD-PGS across GIAs motivates the inclusion of multiple ancestry populations at all levels of genetic research of tobacco use for equitable clinical translation of TUD-PGS. Phenome associations suggest that TUD-predisposed individuals may require comprehensive tobacco use prevention and management approaches to address underlying addictive tendencies.

    

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3. A prospective cohort study of preconception COVID-19 vaccination and miscarriage

   https://doi.org/10.1093/humrep/dead211  

   Yland, Jennifer J. ; Wesselink, Amelia K. ; Regan, Annette K. ; Hatch, Elizabeth E. ; Rothman, Kenneth J. ; Savitz, David A. ; Wang, Tanran R. ; Huybrechts, Krista F. ; Hernández-Díaz, Sonia ; Eisenberg, Michael L. ; et al ( October 2023 , Human Reproduction)

   To what extent is preconception maternal or paternal coronavirus disease 2019 (COVID-19) vaccination associated with miscarriage incidence?

   COVID-19 vaccination in either partner at any time before conception is not associated with an increased rate of miscarriage.

   Several observational studies have evaluated the safety of COVID-19 vaccination during pregnancy and found no association with miscarriage, though no study prospectively evaluated the risk of early miscarriage (gestational weeks [GW] <8) in relation to COVID-19 vaccination. Moreover, no study has evaluated the role of preconception vaccination in both male and female partners.

   An Internet-based, prospective preconception cohort study of couples residing in the USA and Canada. We analyzed data from 1815 female participants who conceived during December 2020–November 2022, including 1570 couples with data on male partner vaccination.

   Eligible female participants were aged 21–45 years and were trying to conceive without use of fertility treatment at enrollment. Female participants completed questionnaires at baseline, every 8 weeks until pregnancy, and during early and late pregnancy; they could also invite their male partners to complete a baseline questionnaire. We collected data on COVID-19 vaccination (brand and date of doses), history of SARS-CoV-2 infection (yes/no and date of positive test), potential confounders (demographic, reproductive, and lifestyle characteristics), and pregnancy status on all questionnaires. Vaccination status was categorized as never (0 doses before conception), ever (≥1 dose before conception), having a full primary sequence before conception, and completing the full primary sequence ≤3 months before conception. These categories were not mutually exclusive. Participants were followed up from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss to follow-up, 20 weeks’ gestation), whichever occurred first. We estimated incidence rate ratios (IRRs) for miscarriage and corresponding 95% CIs using Cox proportional hazards models with GW as the time scale. We used propensity score fine stratification weights to adjust for confounding.

   Among 1815 eligible female participants, 75% had received at least one dose of a COVID-19 vaccine by the time of conception. Almost one-quarter of pregnancies resulted in miscarriage, and 75% of miscarriages occurred <8 weeks’ gestation. The propensity score-weighted IRR comparing female participants who received at least one dose any time before conception versus those who had not been vaccinated was 0.85 (95% CI: 0.63, 1.14). COVID-19 vaccination was not associated with increased risk of either early miscarriage (GW: <8) or late miscarriage (GW: 8–19). There was no indication of an increased risk of miscarriage associated with male partner vaccination (IRR = 0.90; 95% CI: 0.56, 1.44).

   The present study relied on self-reported vaccination status and infection history. Thus, there may be some non-differential misclassification of exposure status. While misclassification of miscarriage is also possible, the preconception cohort design and high prevalence of home pregnancy testing in this cohort reduced the potential for under-ascertainment of miscarriage. As in all observational studies, residual or unmeasured confounding is possible.

   This is the first study to evaluate prospectively the relation between preconception COVID-19 vaccination in both partners and miscarriage, with more complete ascertainment of early miscarriages than earlier studies of vaccination. The findings are informative for individuals planning a pregnancy and their healthcare providers.

   This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Health [R01-HD086742 (PI: L.A.W.); R01-HD105863S1 (PI: L.A.W. and M.L.E.)], the National Institute of Allergy and Infectious Diseases (R03-AI154544; PI: A.K.R.), and the National Science Foundation (NSF-1914792; PI: L.A.W.). The funders had no role in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. L.A.W. is a fibroid consultant for AbbVie, Inc. She also receives in-kind donations from Swiss Precision Diagnostics (Clearblue home pregnancy tests) and Kindara.com (fertility apps). M.L.E. received consulting fees from Ro, Hannah, Dadi, VSeat, and Underdog, holds stock in Ro, Hannah, Dadi, and Underdog, is a past president of SSMR, and is a board member of SMRU. K.F.H. reports being an investigator on grants to her institution from UCB and Takeda, unrelated to this study. S.H.-D. reports being an investigator on grants to her institution from Takeda, unrelated to this study, and a methods consultant for UCB and Roche for unrelated drugs. The authors report no other relationships or activities that could appear to have influenced the submitted work.

   N/A.

    

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4. The association of criminal justice supervision setting with overdose mortality: a longitudinal cohort study

   https://doi.org/10.1111/add.15077  

   Binswanger, Ingrid A. ; Nguyen, Anh P. ; Morenoff, Jeffrey D. ; Xu, Stanley ; Harding, David J. ( May 2020 , Addiction)

   Despite the high prevalence of substance use among people in the US criminal justice system, little is known about the incidence of overdose mortality by use patterns, drug convictions and supervision setting. We examined the associations between these characteristics and overdose mortality.

   Retrospective cohort study.

   Individuals sentenced to prison, jail, probation or jail plus probation for a felony conviction in Michigan, USA from 2003 to 2006.

   Using the National Death Index, we assessed overdose mortality to December 2012. We calculated overdose mortality rates by pre‐sentence opioid use, drug convictions and supervision setting. Multivariable analyses were conducted using competing risks regression with time‐varying covariates.

   Among 140 266 individuals followed over a mean of 7.84 years [standard deviation (SD) = 1.52], 14.9% of the 1131 deaths were due to overdose (102.8 per 100 000 person‐years). Over the follow‐up, more than half of overdose deaths occurred in the community (57.7%), nearly a third (28.8%) on probation and 12.8% on parole. The adjusted risk of overdose death was lower on probation [hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.60, 0.85] than in the community without probation or parole (HR = 1.00) but not significantly different on parole (HR = 1.13, 95% CI = 0.87, 1.47). Pre‐sentence daily opioid use (HR = 3.54, 95% CI = 3.24, 3.87) was associated with an increased risk. Drug possession (HR = 1.11, 95% CI = 0.93, 1.31) and delivery convictions (HR = 0.92, 95% CI = 0.77, 1.09) were not significantly associated with overdose mortality.

   Based on the absolute or relative risk, parole, probation and community settings are appropriate settings for enhanced overdose prevention interventions. Ensuring that individuals with pre‐sentence opioid use have access to harm reduction and drug treatment services may help to prevent overdose among people involved with the criminal justice system.

    

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5. Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease

   https://doi.org/10.1097/HC9.0000000000000076  

   Yu, Lei ; Yousuf, Sarim ; Yousuf, Shahrukh ; Yeh, Jeffrey ; Biggins, Scott W. ; Morishima, Chihiro ; Shyu, Irene ; O’Shea-Stone, Galen ; Eilers, Brian ; Waldum, Annie ; et al ( March 2023 , Hepatology Communications)

   Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways.

   We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men.

   The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%,p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18–9.82,p=0.023).

   In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.

    

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