Gene set proximity analysis: expanding gene set enrichment analysis through learned geometric embeddings, with drug-repurposing applications in COVID-19.

MOTIVATION: Gene set analysis methods rely on knowledge-based representations of genetic interactions in the form of both gene set collections and protein-protein interaction (PPI) networks. However, explicit representations of genetic interactions often fail to capture complex interdependencies among genes, limiting the analytic power of such methods. RESULTS: We propose an extension of gene set enrichment analysis to a latent embedding space reflecting PPI network topology, called gene set proximity analysis (GSPA). Compared with existing methods, GSPA provides improved ability to identify disease-associated pathways in disease-matched gene expression datasets, while improving reproducibility of enrichment statistics for similar gene sets. GSPA is statistically straightforward, reducing to a version of traditional gene set enrichment analysis through a single user-defined parameter. We apply our method to identify novel drug associations with SARS-CoV-2 viral entry. Finally, we validate our drug association predictions through retrospective clinical analysis of claims data from 8 million patients, supporting a role for gabapentin as a risk factor and metformin as a protective factor for severe COVID-19. AVAILABILITY: GSPA is available for download as a command-line Python package at https://github.com/henrycousins/gspa. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.

OBJECTIVE: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection. DESIGN: Retrospective cohort study. SETTING: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results. PARTICIPANTS: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490). MAIN OUTCOME MEASURES: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19. RESULTS: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae. CONCLUSIONS: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.

Unmanaged Pharmacogenomic and Drug Interaction Risk Associations with Hospital Length of Stay among Medicare Advantage Members with COVID-19: A Retrospective Cohort Study.

Unmanaged pharmacogenomic and drug interaction risk can lengthen hospitalization and may have influenced the severe health outcomes seen in some COVID-19 patients. To determine if unmanaged pharmacogenomic and drug interaction risks were associated with longer lengths of stay (LOS) among patients hospitalized with COVID-19, we retrospectively reviewed medical and pharmacy claims from 6025 Medicare Advantage members hospitalized with COVID-19. Patients with a moderate or high pharmacogenetic interaction probability (PIP), which indicates the likelihood that testing would identify one or more clinically actionable gene-drug or gene-drug-drug interactions, were hospitalized for 9% (CI: 4-15%; p < 0.001) and 16% longer (CI: 8-24%; p < 0.001), respectively, compared to those with low PIP. Risk adjustment factor (RAF) score, a commonly used measure of disease burden, was not associated with LOS. High PIP was significantly associated with 12-22% longer LOS compared to low PIP in patients with hypertension, hyperlipidemia, diabetes, or chronic obstructive pulmonary disease (COPD). A greater drug-drug interaction risk was associated with 10% longer LOS among patients with two or three chronic conditions. Thus, unmanaged pharmacogenomic risk was associated with longer LOS in these patients and managing this risk has the potential to reduce LOS in severely ill patients, especially those with chronic conditions.

Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers With the Risk of Hospitalization and Death in Hypertensive Patients With COVID-19.

Background Despite its clinical significance, the risk of severe infection requiring hospitalization among outpatients with severe acute respiratory syndrome coronavirus 2 infection who receive angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) remains uncertain. Methods and Results In a propensity score-matched outpatient cohort (January-May 2020) of 2263 Medicare Advantage and commercially insured individuals with hypertension and a positive outpatient SARS-CoV-2, we determined the association of ACE inhibitors and ARBs with COVID-19 hospitalization. In a concurrent inpatient cohort of 7933 hospitalized with COVID-19, we tested their association with in-hospital mortality. The robustness of the observations was assessed in a contemporary cohort (May-August). In the outpatient study, neither ACE inhibitors (hazard ratio [HR], 0.77; 0.53-1.13, P=0.18) nor ARBs (HR, 0.88; 0.61-1.26, P=0.48) were associated with hospitalization risk. ACE inhibitors were associated with lower hospitalization risk in the older Medicare group (HR, 0.61; 0.41-0.93, P=0.02), but not the younger commercially insured group (HR, 2.14; 0.82-5.60, P=0.12; P-interaction 0.09). Neither ACE inhibitors nor ARBs were associated with lower hospitalization risk in either population in the validation cohort. In the primary inpatient study cohort, neither ACE inhibitors (HR, 0.97; 0.81-1.16; P=0.74) nor ARBs (HR, 1.15; 0.95-1.38, P=0.15) were associated with in-hospital mortality. These observations were consistent in the validation cohort. Conclusions ACE inhibitors and ARBs were not associated with COVID-19 hospitalization or mortality. Despite early evidence for a potential association between ACE inhibitors and severe COVID-19 prevention in older individuals, the inconsistency of this observation in recent data argues against a role for prophylaxis.

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study.

OBJECTIVE: To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65. DESIGN: Retrospective cohort study. SETTING: Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database. PARTICIPANTS: Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness. MAIN OUTCOME MEASURES: More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated. RESULTS: 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group. CONCLUSIONS: The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.