COVID-19 subphenotypes at hospital admission are associated with mortality: a cross-sectional study.

BACKGROUND: We have an incomplete understanding of COVID-19 characteristics at hospital presentation and whether underlying subphenotypes are associated with clinical outcomes and therapeutic responses. METHODS: For this cross-sectional study, we extracted electronic health data from adults hospitalized between 1 March and 30 August 2020 with a PCR-confirmed diagnosis of COVID-19 at five New York City Hospitals. We obtained clinical and laboratory data from the first 24 h of the patient's hospitalization. Treatment with tocilizumab and convalescent plasma was assessed over hospitalization. The primary outcome was mortality; secondary outcomes included intubation, intensive care unit (ICU) admission and length of stay (LOS). First, we employed latent class analysis (LCA) to identify COVID-19 subphenotypes on admission without consideration of outcomes and assigned each patient to a subphenotype. We then performed robust Poisson regression to examine associations between COVID-19 subphenotype assignment and outcome. We explored whether the COVID-19 subphenotypes had a differential response to tocilizumab and convalescent plasma therapies. RESULTS: A total of 4620 patients were included. LCA identified six subphenotypes, which were distinct by level of inflammation, clinical and laboratory derangements and ranged from a hypoinflammatory subphenotype with the fewest derangements to a hyperinflammatory with multiorgan dysfunction subphenotypes. Multivariable regression analyses found differences in risk for mortality, intubation, ICU admission and LOS, as compared to the hypoinflammatory subphenotype. For example, in multivariable analyses the moderate inflammation with fever subphenotype had 3.29 times the risk of mortality (95% CI 2.05, 5.28), while the hyperinflammatory with multiorgan failure subphenotype had 17.87 times the risk of mortality (95% CI 11.56, 27.63), as compared to the hypoinflammatory subphenotype. Exploratory analyses suggested that subphenotypes may differential respond to convalescent plasma or tocilizumab therapy. CONCLUSION: COVID-19 subphenotype at hospital admission may predict risk for mortality, ICU admission and intubation and differential response to treatment.KEY MESSAGEThis cross-sectional study of COVID patients admitted to the Mount Sinai Health System, identified six distinct COVID subphenotypes on admission. Subphenotypes correlated with ICU admission, intubation, mortality and differential response to treatment.

Perspectives of diverse Spanish- and English-speaking patients on the clinical use of polygenic risk scores.

PURPOSE: As polygenic risk scores (PRS) emerge as promising tools to inform clinical care, there is a pressing need for patient-centered evidence to guide their implementation, particularly in diverse populations. Here, we conducted in-depth interviews of diverse Spanish- and English-speaking patients to explore their perspectives on clinical PRS. METHODS: We enrolled 30 biobank participants aged 35-50 years through a purposive sampling strategy, ensuring that >75% self-reported as African/African American or Hispanic/Latinx and half were Spanish-speaking. Semistructured interviews in Spanish or English explored attitudes toward PRS, barriers to adoption, and communication preferences. Data were analyzed using an inductive thematic analysis approach. RESULTS: Perceived utility of clinical PRS focused on the potential for personal health benefits, and most participants stated that high-risk results would prompt physician consultations and health behavior changes. There was little concern among participants about the limited predictive power of PRS for non-European populations. Barriers to uptake of PRS testing and adoption of PRS-related recommendations included socioeconomic factors, insurance status, race, ethnicity, language, and inadequate understanding of PRS. Participants favored in-person PRS result disclosure by their physician. CONCLUSION: Findings provide valuable insight into diverse patients' attitudes and potential barriers related to clinical PRS, guiding future research and patient-centered clinical implementation.

Implementing genomic screening in diverse populations.

BACKGROUND: Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented in genomic medicine research. Therefore, we implemented a pilot genomic screening program in the BioMe Biobank in New York City, where the majority of participants are of non-European ancestry. METHODS: We initiated genomic screening for well-established genes associated with hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). We evaluated and included an additional gene (TTR) associated with hereditary transthyretin amyloidosis (hATTR), which has a common founder variant in African ancestry populations. We evaluated the characteristics of 74 participants who received results associated with these conditions. We also assessed the preferences of 7461 newly enrolled BioMe participants to receive genomic results. RESULTS: In the pilot genomic screening program, 74 consented participants received results related to HBOC (N = 26), LS (N = 6), FH (N = 8), and hATTR (N = 34). Thirty-three of 34 (97.1%) participants who received a result related to hATTR were self-reported African American/African (AA) or Hispanic/Latinx (HL), compared to 14 of 40 (35.0%) participants who received a result related to HBOC, LS, or FH. Among the 7461 participants enrolled after the BioMe protocol modification to allow the return of genomic results, 93.4% indicated that they would want to receive results. Younger participants, women, and HL participants were more likely to opt to receive results. CONCLUSIONS: The addition of TTR to a pilot genomic screening program meant that we returned results to a higher proportion of AA and HL participants, in comparison with genes traditionally included in genomic screening programs in the USA. We found that the majority of participants in a multi-ethnic biobank are interested in receiving genomic results for medically actionable conditions. These findings increase knowledge about the perspectives of diverse research participants on receiving genomic results and inform the broader implementation of genomic medicine in underrepresented patient populations.

Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis.

The TTR V142I variant associated with hereditary transthyretin amyloidosis (hATTR) is present in up to 4% of African American (AA) and 1% of Hispanic/Latinx (HL) individuals and increases risk for heart failure. Delayed and missed diagnoses could potentiate health disparities in these populations. We evaluated whether population-based genomic screening could effectively identify individuals at risk for hATTR and prompt initiation of risk management. We identified participants of the BioMe Biobank in New York City who received TTR V142I results through a pilot genomic screening program. We performed a retrospective medical record review to evaluate for the presence hATTR-related systemic features, uptake of recommended follow-up, and short-term outcomes. Thirty-two AA (N = 17) and HL (N = 15) individuals received a TTR V142I result (median age 57, 81% female). None had a previous diagnosis of hATTR. Eighteen (56%) had hATTR-related systemic features, including 4 (13%) with heart failure, 10 (31%) with carpal tunnel syndrome, and 10 (31%) with spinal stenosis. Eighteen (56%) pursued follow-up with a cardiologist within 8 months. One person received a diagnosis of hATTR. Thus, we found that the majority of V142I-positive individuals had hATTR-related systemic features at the time of result disclosure, including well-described red flags. Genomic screening can help identify hATTR risk and guide management early on, avoiding potential delays in diagnosis and treatment.