Functional principal component analysis and sparse-group LASSO to identify associations between biomarker trajectories and mortality among hospitalized SARS-CoV-2 infected individuals.

BACKGROUND: A substantial body of clinical research involving individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evaluated the association between in-hospital biomarkers and severe SARS-CoV-2 outcomes, including intubation and death. However, most existing studies considered each of multiple biomarkers independently and focused analysis on baseline or peak values. METHODS: We propose a two-stage analytic strategy combining functional principal component analysis (FPCA) and sparse-group LASSO (SGL) to characterize associations between biomarkers and 30-day mortality rates. Unlike prior reports, our proposed approach leverages: 1) time-varying biomarker trajectories, 2) multiple biomarkers simultaneously, and 3) the pathophysiological grouping of these biomarkers. We apply this method to a retrospective cohort of 12, 941 patients hospitalized at Massachusetts General Hospital or Brigham and Women's Hospital and conduct simulation studies to assess performance. RESULTS: Renal, inflammatory, and cardio-thrombotic biomarkers were associated with 30-day mortality rates among hospitalized SARS-CoV-2 patients. Sex-stratified analysis revealed that hematogolical biomarkers were associated with higher mortality in men while this association was not identified in women. In simulation studies, our proposed method maintained high true positive rates and outperformed alternative approaches using baseline or peak values only with respect to false positive rates. CONCLUSIONS: The proposed two-stage approach is a robust strategy for identifying biomarkers that associate with disease severity among SARS-CoV-2-infected individuals. By leveraging information on multiple, grouped biomarkers' longitudinal trajectories, our method offers an important first step in unraveling disease etiology and defining meaningful risk strata.

Cis-regulated expression of non-conserved lincRNAs associates with cardiometabolic related traits.

Many complex disease risk loci map to intergenic regions containing long intergenic noncoding RNAs (lincRNAs). The majority of these is not conserved outside humans, raising the question whether genetically regulated expression of non-conserved and conserved lincRNAs has similar rates of association with complex traits. Here we leveraged data from the Genotype-Tissue Expression (GTEx) project and multiple public genome-wide association study (GWAS) resources. Using an established transcriptome-wide association study (TWAS) tool, FUSION, we interrogated the associations between cis-regulated expression of lincRNAs and multiple cardiometabolic traits. We found that cis-regulated expression of non-conserved lincRNAs had a strikingly similar trend of association with complex cardiometabolic traits as conserved lincRNAs. This finding challenges the conventional notion of conservation that has led to prioritization of conserved loci for functional studies and calls attention to the need to develop comprehensive strategies to study the large number of non-conserved human lincRNAs that may contribute to human disease.

Nonconserved Long Intergenic Noncoding RNAs Associate With Complex Cardiometabolic Disease Traits.

OBJECTIVE: Transcriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT (Genetic Investigation of Anthropometric Traits), UK Biobank, GLGC (Global Lipids Genetics Consortium), Cardiogram (Coronary Artery Disease Genome Wide Replication and Meta-Analysis), and DIAGRAM (Diabetes Genetics Replication and Meta-Analysis)/DIAMANTE (Diabetes Meta-Analysis of Trans-Ethnic Association Studies). These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation. CONCLUSIONS: These findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy.

OBJECTIVE: To estimate the prevalence of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) after infection with SARS-CoV-2 during pregnancy and to characterize associated risk factors. METHODS: In a multicenter cohort study (NIH RECOVER [Researching COVID to Enhance Recovery]-Pregnancy Cohort), individuals who were pregnant during their first SARS-CoV-2 infection were enrolled across the United States from December 2021 to September 2023, either within 30 days of their infection or at differential time points thereafter. The primary outcome was PASC, defined as score of 12 or higher based on symptoms and severity as previously published by the NIH RECOVER-Adult Cohort, at the first study visit at least 6 months after the participant's first SARS-CoV-2 infection. Risk factors for PASC were evaluated, including sociodemographic characteristics, clinical characteristics before SARS-CoV-2 infection (baseline comorbidities, trimester of infection, vaccination status), and acute infection severity (classified by need for oxygen therapy). Multivariable logistic regression models were fitted to estimate associations between these characteristics and presence of PASC. RESULTS: Of the 1,502 participants, 61.1% had their first SARS-CoV-2 infection on or after December 1, 2021 (ie, during Omicron variant dominance); 51.4% were fully vaccinated before infection; and 182 (12.1%) were enrolled within 30 days of their acute infection. The prevalence of PASC was 9.3% (95% CI, 7.9-10.9%) measured at a median of 10.3 months (interquartile range 6.1-21.5) after first infection. The most common symptoms among individuals with PASC were postexertional malaise (77.7%), fatigue (76.3%), and gastrointestinal symptoms (61.2%). In a multivariable model, the proportion PASC positive with vs without history of obesity (14.9% vs 7.5%, adjusted odds ratio [aOR] 1.65, 95% CI, 1.12-2.43), depression or anxiety disorder (14.4% vs 6.1%, aOR 2.64, 95% CI, 1.79-3.88) before first infection, economic hardship (self-reported difficulty covering expenses) (12.5% vs 6.9%, aOR 1.57, 95% CI, 1.05-2.34), and treatment with oxygen during acute SARS-CoV-2 infection (18.1% vs 8.7%, aOR 1.86, 95% CI, 1.00-3.44) were associated with increased prevalence of PASC. CONCLUSION: The prevalence of PASC at a median time of 10.3 months after SARS-CoV-2 infection during pregnancy was 9.3% in the NIH RECOVER-Pregnancy Cohort. The predominant symptoms were postexertional malaise, fatigue, and gastrointestinal symptoms. Several socioeconomic and clinical characteristics were associated with PASC after infection during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT05172024.

Cord Blood Plasma Metabolome-wide Associations With Height From Birth to Adolescence.

Although the maternal intrauterine metabolic environment has been recognized to have a profound impact on fetal growth and development with lifelong health implications, to our knowledge, there have been few large-scale birth cohort studies linking the cord metabolome (reflecting both the maternal and fetal metabolic state) with postnatal height measurements across the pediatric age range. Using data from the Boston Birth Cohort, an ongoing prospective birth cohort, this study investigated the association of cord plasma metabolites with children's height from birth to adolescence. Height was analyzed as attained height and longitudinal trajectories. Distinctive cord metabolite types were associated with attained height at different developmental windows: triacylglycerols [TAGs], diacylglycerols [DAGs], cholesterol ester [CEs], phospholipids, amino acids [AAs], acylcarnitines [ACs], and nucleotides in early (age 0-4 years) and middle (age 6-12 years) childhood; various metabolite types other than TAGs in later childhood (after age 14 years). Functional principal component analysis on children's repeated height measurements summarized two typical height trajectory components: loadings on first eigenfunction [FPC1] representing overall height by age, and loadings on second eigenfunction [FPC2] representing speed of pubertal height growth. Although only one cord metabolite was correlated with FPC1 after accounting for multiple testing, the study found 27 metabolites with significant overall effect on FPC2 among females and 18 among males. These metabolites were mostly phospholipids (including phosphatidylethanolamines [PEs], phosphatidylethanolamine plasmalogens [PE_Ps], phosphatidylcholines [PCs], lysophosphatidylethanolamines [LPEs], and lysophosphatidylcholines [LPCs]), AAs, and nucleotides. Their associations with height differed between overweight/obesity (OWO) and non-OWO children, especially among females. In this prospective study of US understudied urban, low-income, racially diverse children, we demonstrated that cord plasma metabolites were significantly associated with postnatal attained height at different age windows as well as height trajectories from birth to adolescence. We also revealed how these associations differed by children's sex and OWO status. Our findings help elucidate metabolic pathways underlying fetal origins of height growth across developmental stages. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Umbilical cord DNA methylation is associated with body mass index trajectories from birth to adolescence.

BACKGROUND: DNA methylation (DNAm) in cord blood has been associated with various prenatal factors and birth outcomes. This study sought to fill an important knowledge gap: the link of cord DNAm with child postnatal growth trajectories from birth to age 18 years (y). METHODS: Using data from a US predominantly urban, low-income, multi-ethnic birth cohort (N = 831), we first applied non-parametric methods to identify body-mass-index percentile (BMIPCT) trajectories from birth to age 18 y (the outcome); then, conducted epigenome-wide association study (EWAS) of the outcome, interrogating over 700,000 CpG sites profiled by the Illumina Infinium MethylationEPIC BeadChip. Multivariate linear regression models and likelihood ratio tests (LRT) were applied to examine the DNAm-outcome association in the overall sample and sex strata. FINDINGS: We identified four distinct patterns of BMIPCT trajectories: normal weight (NW), Early overweight or obesity (OWO), Late OWO, and normal to very late OWO. DNAm at CpG18582997 annotated to TPGS1, CpG15241084 of TLR7, and cg24350936 of RAB31 were associated with BMIPCT at birth-to-3 y, 10 y, and 14 y, respectively (LRT FDR < 0.05 for all). INTERPRETATION: In this prospective birth cohort study, we identified 4 distinct and robust patterns of growth trajectories from birth to 18 y, which were associated with variations in cord blood DNAm at genes implicated in inflammation induction pathways. These findings, if further replicated, raise the possibility that these DNAm markers along with early assessment of BMIPCT trajectories may help identify young children at high-risk for obesity later in life. FUNDING: Detailed in the Acknowledgements section.

Biomarkers of Cardiac Injury, Renal Injury, and Inflammation Are Strong Mediators of Sex-Associated Death in COVID-19.

Background: Studies examining outcomes among individuals with COronaVIrus Disease 2019 (COVID-19) have consistently demonstrated that men have worse outcomes than women, with a higher incidence of myocardial injury, respiratory failure, and death. However, mechanisms of higher morbidity and mortality among men remain poorly understood. We aimed to identify mediators of the relationship between sex and COVID-19-associated mortality. Methods: Patients hospitalized at two quaternary care facilities, New York Presbyterian Hospital (CUIMC/NYPH) and Massachusetts General Hospital (MGH), for SARS-CoV-2 infection between February and May 2020 were included. Five independent biomarkers were identified as mediators of sex effects, including high-sensitivity cardiac troponin T (hs-cTNT), high sensitivity C-reactive protein (hs-CRP), ferritin, D-dimer, and creatinine. Results: In the CUIMC/NYPH cohort (n = 2,626, 43% female), male sex was associated with significantly greater mortality (26 vs. 21%, p = 0.0146) and higher peak hs-cTNT, hs-CRP, ferritin, D-dimer, and creatinine (p < 0.001). The effect of male sex on the primary outcome of death was partially mediated by peak values of all five biomarkers, suggesting that each pathophysiological pathway may contribute to increased risk of death in men. Hs-cTnT, creatinine, and hs-CRP were the strongest mediators. Findings were highly consistent in the MGH cohort with the exception of D-dimer. Conclusions: This study suggests that the effect of sex on COVID-19 outcomes is mediated by cardiac and kidney injury, as well as underlying differences in inflammation and iron metabolism. Exploration of these specific pathways may facilitate sex-directed diagnostic and therapeutic strategies for patients with COVID-19 and provides a framework for the study of sex differences in other complex diseases.

Understanding the Link Between Obesity and Severe COVID-19 Outcomes: Causal Mediation by Systemic Inflammatory Response.

BACKGROUND: Obesity is an established risk factor for severe COVID-19 outcomes. The mechanistic underpinnings of this association are not well-understood. OBJECTIVE: To evaluate the mediating role of systemic inflammation in obesity-associated COVID-19 outcomes. METHODS: This hospital-based, observational study included 3828 SARS-CoV-2-infected patients who were hospitalized February to May 2020 at Massachusetts General Hospital (MGH) or Columbia University Irving Medical Center/New York Presbyterian Hospital (CUIMC/NYP). We use mediation analysis to evaluate whether peak inflammatory biomarkers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], D-dimer, ferritin, white blood cell count and interleukin-6) are in the causal pathway between obesity (BMI ≥ 30) and mechanical ventilation or death within 28 days of presentation to care. RESULTS: In the MGH cohort (n = 1202), obesity was associated with greater likelihood of ventilation or death (OR = 1.73; 95% CI = [1.25, 2.41]; P = 0.001) and higher peak CRP (P < 0.001) compared with nonobese patients. The estimated proportion of the association between obesity and ventilation or death mediated by CRP was 0.49 (P < 0.001). Evidence of mediation was more pronounced in patients < 65 years (proportion mediated = 0.52 [P < 0.001] vs 0.44 [P = 0.180]). Findings were more moderate but consistent for peak ESR. Mediation by other inflammatory markers was not supported. Results were replicated in CUIMC/NYP cohort (n = 2626). CONCLUSION: Findings support systemic inflammatory pathways in obesity-associated severe COVID-19 disease, particularly in patients < 65 years, captured by CRP and ESR. Contextualized in clinical trial findings, these results reveal therapeutic opportunity to target systemic inflammatory pathways and monitor interventions in high-risk subgroups and particularly obese patients.

Cord Blood Metabolome and BMI Trajectory from Birth to Adolescence: A Prospective Birth Cohort Study on Early Life Biomarkers of Persistent Obesity.

There is increasing recognition on the role of early life metabolic programming in childhood obesity. This study sought to investigate whether newborn cord blood metabolome can predict future BMI. It included 946 children in the Boston Birth Cohort, a sample of high-risk yet understudied US urban, low-income, predominantly Black and Hispanic children, who were enrolled at birth and followed prospectively up to age 18 years. A total of 376 metabolites were measured in cord blood plasma. Longitudinal BMI trajectories were defined and categorized into three distinct patterns: early onset overweight and obesity (early-OWO), late onset OWO (late-OWO), and normal weight trajectory (NW). Multinomial logistic regression models were used to identify metabolites individually or as network modules associated with BMI trajectories. Of the 946 children, 388, 254, and 304 were classified as early-OWO, late-OWO, and NW, respectively. Of the seven co-metabolomic network modules defined, two were inversely correlated with early-OWO. Among the 68 metabolites within the two modules, 22 triacylglycerols and diacylglycerols were negatively associated with early-OWO; 5 cholesterol esters were positively associated with early-OWO. In this prospective birth cohort, we demonstrated distinctive longitudinal BMI trajectories and identified multiple cord plasma metabolites in relevant biological pathways that were associated with early-OWO.

Artificial intelligence-based screening for diabetic retinopathy at community hospital.

OBJECTIVES: The purpose of this study is to assess the accuracy of artificial intelligence (AI)-based screening for diabetic retinopathy (DR) and to explore the feasibility of applying AI-based technique to community hospital for DR screening. METHODS: Nonmydriatic fundus photos were taken for 889 diabetic patients who were screened in community hospital clinic. According to DR international classification standards, ophthalmologists and AI identified and classified these fundus photos. The sensitivity and specificity of AI automatic grading were evaluated according to ophthalmologists' grading. RESULTS: DR was detected by ophthalmologists in 143 (16.1%) participants and by AI in 145 (16.3%) participants. Among them, there were 101 (11.4%) participants diagnosed with referable diabetic retinopathy (RDR) by ophthalmologists and 103 (11.6%) by AI. The sensitivity, specificity and area under the curve (AUC) of AI for detecting DR were 90.79% (95% CI 86.4-94.1), 98.5% (95% CI 97.8-99.0) and 0.946 (95% CI 0.935-0.956), respectively. For detecting RDR, the sensitivity, specificity and AUC of AI were 91.18% (95% CI 86.4-94.7), 98.79% (95% CI 98.1-99.3) and 0.950 (95% CI 0.939-0.960), respectively. CONCLUSION: AI has high sensitivity and specificity in detecting DR and RDR, so it is feasible to carry out AI-based DR screening in outpatient clinic of community hospital.

Massachusetts general hospital Covid-19 registry reveals two distinct populations of hospitalized patients by race and ethnicity.

OBJECTIVE: To evaluate differences by race/ethnicity in clinical characteristics and outcomes among hospitalized patients with Covid-19 at Massachusetts General Hospital (MGH). METHODS: The MGH Covid-19 Registry includes confirmed SARS-CoV-2-infected patients hospitalized at MGH and is based on manual chart reviews and data extraction from electronic health records (EHRs). We evaluated differences between White/Non-Hispanic and Hispanic patients in demographics, complications and 14-day outcomes among the N = 866 patients hospitalized with Covid-19 from March 11, 2020-May 4, 2020. RESULTS: Overall, 43% of patients hospitalized with Covid-19 were women, median age was 60.4 [IQR = (48.2, 75)], 11.3% were Black/non-Hispanic and 35.2% were Hispanic. Hispanic patients, representing 35.2% of patients, were younger than White/non-Hispanic patients [median age 51y; IQR = (40.6, 61.6) versus 72y; (58.0, 81.7) (p<0.001)]. Hispanic patients were symptomatic longer before presenting to care (median 5 vs 3d, p = 0.039) but were more likely to be sent home with self-quarantine than be admitted to hospital (29% vs 16%, p<0.001). Hispanic patients had fewer comorbidities yet comparable rates of ICU or death (34% vs 36%). Nonetheless, a greater proportion of Hispanic patients recovered by 14 days after presentation (62% vs 45%, p<0.001; OR = 1.99, p = 0.011 in multivariable adjusted model) and fewer died (2% versus 18%, p<0.001). CONCLUSIONS: Hospitalized Hispanic patients were younger and had fewer comorbidities compared to White/non-Hispanic patients; despite comparable rates of ICU care or death, a greater proportion recovered. These results have implications for public health policy and the design and conduct of clinical trials.

BACE1 partial deletion induces synaptic plasticity deficit in adult mice.

BACE1 is the first enzyme involved in APP processing, thus it is a strong therapeutic target candidate for Alzheimer's disease. The observation of deleterious phenotypes in BACE1 Knock-out (KO) mouse models (germline and conditional) raised some concerns on the safety and tolerability of BACE1 inhibition. Here, we have employed a tamoxifen inducible BACE1 conditional Knock-out (cKO) mouse model to achieve a controlled partial depletion of BACE1 in adult mice. Biochemical and behavioural characterization was performed at two time points: 4-5 months (young mice) and 12-13 months (aged mice). A ~50% to ~70% BACE1 protein reduction in hippocampus and cortex, respectively, induced a significant reduction of BACE1 substrates processing and decrease of Aßx-40 levels at both ages. Hippocampal axonal guidance and peripheral nerve myelination were not affected. Aged mice displayed a CA1 long-term potentiation (LTP) deficit that was not associated with memory impairment. Our findings indicate that numerous phenotypes observed in germline BACE1 KO reflect a fundamental role of BACE1 during development while other phenotypes, observed in adult cKO, may be absent when partially rather than completely deleting BACE1. However, we demonstrated that partial depletion of BACE1 still induces CA1 LTP impairment, supporting a role of BACE1 in synaptic plasticity in adulthood.