Clinical associations with a polygenic predisposition to benign lower white blood cell counts.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Clinical consequences of a polygenic predisposition to benign lower white blood cell counts: Consequences of benign WBC count genetics.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is undefined. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio=0.55 per standard deviation increase in PGSWBC [95%CI, 0.30 - 0.94], p=0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n=1,724, hazard ratio [HR]=0.78 [0.69 - 0.88], p=4.0×10-5) or immunosuppressant (n=354, HR=0.61 [0.38 - 0.99], p=0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n=1,466, HR=0.62 [0.44 - 0.87], p=0.006). Collectively, these findings suggest that a WBC count polygenic score identifies individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Genome-Wide Association Study of CKD Progression.

SIGNIFICANCE STATEMENT: Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease. BACKGROUND: Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified. METHODS: We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter. RESULTS: In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54. CONCLUSIONS: Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.

Correlates of Taxane-Induced Neuropathy, an Electronic Health Record Based Observational Study.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common therapeutic complication affecting cancer patients' quality-of-life. We evaluated clinical characteristics, demographics, and lifestyle factors in association with CIPN following taxane treatment. METHODS: Data were extracted from the electronic health record of 3387 patients diagnosed with a primary cancer and receiving taxane (i.e., paclitaxel or docetaxel) at Vanderbilt University Medical Center. Neuropathy was assessed via a validated computer algorithm. Univariate and multivariate regression models were applied to evaluate odds ratios (ORs) and 95% confidence intervals (CIs) of CIPN-associated factors. RESULTS: Female sex (OR = 1.28, 95% CI = 1.01-1.62), high body-mass index (BMI) (OR = 1.31, 95% CI = 1.06-1.61 for overweight, and OR = 1.49, 95% CI = 1.21-1.83 for obesity), diabetes (OR = 1.66, 95% CI = 1.34-2.06), high mean taxane dose (OR = 1.05, 95% CI = 1.03-1.08 per 10 mg/m2), and more treatment cycles (1.12, 95% CI = 1.10-1.14) were positively associated with CIPN. Concurrent chemotherapy (OR = 0.74, 95% CI = 0.58-0.94) and concurrent radiotherapy (OR = 0.77, 95% CI = 0.59-1.00) were inversely associated with CIPN. Obesity and diabetes both had a stronger association with docetaxel CIPN compared to paclitaxel, although interaction was only significant for diabetes and taxane (p = 0.019). Increased BMI was associated with CIPN only among non-diabetic patients (OR:1.34 for overweight and 1.68 for obesity), while diabetes increased CIPN risk across all BMI strata (ORs were 2.65, 2.41, and 2.15 for normal weight, overweight, and obese, respectively) compared to normal-weight non-diabetic patients (p for interaction = 0.039). CONCLUSIONS: Female sex, obesity, and diabetes are significantly associated with taxine-induced CIPN. Further research is needed to identify clinical and pharmacologic strategies to prevent and mitigate CIPN in at-risk patient populations.

Trends in characteristics, management, and outcomes of patients presenting with gastrointestinal bleeding to emergency departments in the United States from 2006 to 2019.

BACKGROUND: Recent epidemiologic studies of trends in gastrointestinal bleeding (GIB) provided results through 2014 or earlier and assessed only hospitalised patients, excluding patients presenting to emergency departments (EDs) who are not hospitalised. AIMS: To provide the first U.S. nationwide epidemiological evaluation of all patients presenting to EDs with GIB METHODS: We used the Nationwide Emergency Department Sample for 2006-2019 to calculate yearly projected incidence of patients presenting to EDs with primary diagnoses of GIB, categorised by location and aetiology. Outcomes were assessed with multivariable analyses. RESULTS: The age/sex-adjusted incidence for GIB increased from 378.4 to 397.5/100,000 population from 2006 to 2019. Upper gastrointestinal bleeding (UGIB) incidence decreased from 2006 to 2014 (112.3-94.4/100,000) before increasing to 116.2/100,000 by 2019. Lower gastrointestinal bleeding (LGIB) incidence increased from 2006 to 2015 (146.0 to 161.0/100,000) before declining to 150.2/100,000 by 2019. The proportion of cases with one or more comorbidities increased from 27.4% to 35.9% from 2006 to 2019. Multivariable analyses comparing 2019 to 2006 showed increases in ED discharges (odds ratio [OR] = 1.45; 95% confidence interval [CI] = 1.43-1.48) and decreases in red blood cell (RBC) transfusions (OR = 0.62; 0.61-0.63), endoscopies (OR = 0.60; 0.59-0.61), death (OR = 0.51; 0.48-0.54) and length of stay (relative ratio [RR] = 0.81; 0.80-0.82). Inpatient cost decreased from 2012 to 2019 (RR = 0.92; 0.91-0.93). CONCLUSIONS: The incidence of GIB in the U.S. is increasing. UGIB incidence has been increasing since 2014 while LGIB incidence has been decreasing since 2015. Despite a more comorbid population in 2019, case fatality rate, length of stay and costs have decreased. More patients are discharged from the ED and the rate of RBC transfusions has decreased, possibly reflecting changing clinical practice in response to updated guidelines.

An updated, computable MEDication-Indication resource for biomedical research.

The MEDication-Indication (MEDI) knowledgebase has been utilized in research with electronic health records (EHRs) since its publication in 2013. To account for new drugs and terminology updates, we rebuilt MEDI to overhaul the knowledgebase for modern EHRs. Indications for prescribable medications were extracted using natural language processing and ontology relationships from six publicly available resources: RxNorm, Side Effect Resource 4.1, Mayo Clinic, WebMD, MedlinePlus, and Wikipedia. We compared the estimated precision and recall between the previous MEDI (MEDI-1) and the updated version (MEDI-2) with manual review. MEDI-2 contains 3031 medications and 186,064 indications. The MEDI-2 high precision subset (HPS) includes indications found within RxNorm or at least three other resources. MEDI-2 and MEDI-2 HPS contain 13% more medications and over triple the indications compared to MEDI-1 and MEDI-1 HPS, respectively. Manual review showed MEDI-2 achieves the same precision (0.60) with better recall (0.89 vs. 0.79) compared to MEDI-1. Likewise, MEDI-2 HPS had the same precision (0.92) and improved recall (0.65 vs. 0.55) than MEDI-1 HPS. The combination of MEDI-1 and MEDI-2 achieved a recall of 0.95. In updating MEDI, we present a more comprehensive medication-indication knowledgebase that can continue to facilitate applications and research with EHRs.

Racial disparity in taxane-induced neutropenia among cancer patients.

BACKGROUND: Large interindividual variations have been reported in chemotherapy-induced toxicities. Little is known whether racial disparities exist in neutropenia associated with taxanes. METHODS: Patients with a diagnosis of primary cancer who underwent chemotherapy with taxanes were identified from Vanderbilt University Medical Center's Synthetic Derivative. Multinomial regression models were applied to evaluate odds ratios (ORs) and 95% confidence intervals (CIs) of neutropenia associated with race, with adjustments for demographic variables, baseline neutrophil count, chemotherapy-related information, prior treatments, and cancer site. RESULTS: A total of 3492 patients were included in the study. Compared with White patients, grade 2 or higher neutropenia was more frequently recorded among Black patients who received taxanes overall (42.2% vs. 32.7%, p < 0.001) or paclitaxel (43.0% vs. 36.7%, p < 0.001) but not among those who received docetaxel (32.0% vs. 30.2%, p = 0.821). After adjustments for multiple covariates, Black patients who received chemotherapy with any taxanes had significantly higher risk of grade 2 (OR = 1.53; 95% CI = 1.09-2.14) and grade 3 (OR = 1.91; 95% CI = 1.36-2.67) neutropenia but comparable risk of grade 4 neutropenia (OR = 1.19; 95% CI = 0.79-1.79). Similar association patterns were observed for Black patients who specifically received paclitaxel, but a null association was found for those treated with docetaxel. CONCLUSION: Black cancer patients treated with taxanes for any cancer had a higher risk of neutropenia compared with their White counterparts, especially those who received paclitaxel. More research is needed to understand the mechanism(s) underlying this racial disparity in order to enhance the delivery of patient-centered oncology.

High-throughput framework for genetic analyses of adverse drug reactions using electronic health records.

Understanding the contribution of genetic variation to drug response can improve the delivery of precision medicine. However, genome-wide association studies (GWAS) for drug response are uncommon and are often hindered by small sample sizes. We present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions (ADRs) using "drug allergy" labels from electronic health records (EHRs). As a proof-of-concept, we conducted GWAS for ADRs to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Center's BioVU DNA Biobank. We identified 7 genetic loci associated with ADRs at P < 5 × 10-8, including known genetic associations such as CYP2D6 and OPRM1 for CYP2D6-metabolized opioid ADR. Additional expression quantitative trait loci and phenome-wide association analyses added evidence to the observed associations. Our high-throughput framework is both scalable and portable, enabling impactful pharmacogenomic research to improve precision medicine.

Diverse functional autoantibodies in patients with COVID-19.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

Diverse Functional Autoantibodies in Patients with COVID-19.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the "exoproteome"). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.

A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19.

OBJECTIVE: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data. MATERIALS AND METHODS: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis. RESULTS: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online. CONCLUSION: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes.

PheMap: a multi-resource knowledge base for high-throughput phenotyping within electronic health records.

OBJECTIVE: Developing algorithms to extract phenotypes from electronic health records (EHRs) can be challenging and time-consuming. We developed PheMap, a high-throughput phenotyping approach that leverages multiple independent, online resources to streamline the phenotyping process within EHRs. MATERIALS AND METHODS: PheMap is a knowledge base of medical concepts with quantified relationships to phenotypes that have been extracted by natural language processing from publicly available resources. PheMap searches EHRs for each phenotype's quantified concepts and uses them to calculate an individual's probability of having this phenotype. We compared PheMap to clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network for type 2 diabetes mellitus (T2DM), dementia, and hypothyroidism using 84 821 individuals from Vanderbilt Univeresity Medical Center's BioVU DNA Biobank. We implemented PheMap-based phenotypes for genome-wide association studies (GWAS) for T2DM, dementia, and hypothyroidism, and phenome-wide association studies (PheWAS) for variants in FTO, HLA-DRB1, and TCF7L2. RESULTS: In this initial iteration, the PheMap knowledge base contains quantified concepts for 841 disease phenotypes. For T2DM, dementia, and hypothyroidism, the accuracy of the PheMap phenotypes were >97% using a 50% threshold and eMERGE case-control status as a reference standard. In the GWAS analyses, PheMap-derived phenotype probabilities replicated 43 of 51 previously reported disease-associated variants for the 3 phenotypes. For 9 of the 11 top associations, PheMap provided an equivalent or more significant P value than eMERGE-based phenotypes. The PheMap-based PheWAS showed comparable or better performance to a traditional phecode-based PheWAS. PheMap is publicly available online. CONCLUSIONS: PheMap significantly streamlines the process of extracting research-quality phenotype information from EHRs, with comparable or better performance to current phenotyping approaches.

A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women.

Haptoglobin (HP) protein plays a critical role in binding and removing free hemoglobin from blood. A deletion in the HP gene affects the protein structure and function. A recent study developed a novel method to impute this variant and discovered significant association of this variant with low-density lipoprotein (LDL) and total cholesterol levels among European descendants. In the present study, we investigated this variant among 3608 Chinese women. Consistent with findings from Europeans, we found significant associations between the deletion with lower cholesterol levels; women homozygous for the deletion allele (HP1-HP1), had a lower level of total cholesterol (-4.24 mg dl-1, P=0.02) and LDL cholesterol (-3.43 mg dl-1, P=0.03) than those not carrying the deletion allele (HP2-HP2). Especially, women carrying the HP1S-HP1S, had an even lower level of total cholesterol (-5.59 mg dl-1, P=7.0 × 10-3) and LDL cholesterol (-4.68 mg dl-1, P=8.0 × 10-3) compared to those carrying HP2-HP2. These associations remained significant after an adjustment for an established cholesterol level-related variant, rs2000999. Our study extends the previous findings regarding the association of HP structure variant with blood cholesterol levels to East Asians and affirms the validity of the new methodology for assessing HP structure variation.