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.

Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients.

CYP3A5 genetic variants are associated with tacrolimus metabolism. Controversy remains on whether CYP3A4 increased [*1B (rs2740574), *1 G (rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This retrospective cohort study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Heart transplanted patients (n = 177, between 2008 and 2020) were included and median age was 54 years old. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*1B or *1 G variants (Group 3) compared to CYP3A4*1/*1 (Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.

Association Between Neighborhood Socioeconomic Factors and Length of Stay After Surgery for Congenital Heart Disease.

OBJECTIVES: Neighborhood socioeconomic status, as measured by area deprivation index (ADI) is associated with longer length of stay (LOS) after surgery for hypoplastic left heart syndrome. We tested the hypothesis that LOS is associated with ADI in a large cohort of congenital heart disease (CHD) surgical cases of varying severity and sought to determine which other components of the ADI accounted for any associations. DESIGN: Retrospective analysis of a curated dataset. The Brokamp ADI was determined using residential addresses. Overall, ADI and each of its six individual components were dichotomized, and LOS compared between groups above versus below the median for the entire cohort and after stratifying by surgical The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) severity category. SETTING: Single-center academic pediatric teaching hospital. PATIENTS: CHD patients who underwent surgical repair/palliation between September 2007 and August 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 2462 patients (52.7% male) were included. Median age was 254 (interquartile range [IQR] 95-1628) days and median LOS in the hospital was 8 (IQR 5-18) days. We failed to identify an association between Brokamp ADI, above versus below the median for the entire cohort, and LOS; nor in STAT categories 1-4. However, in STAT category 5 (n = 129) those with ADI above the median (more deprived) had a significantly longer LOS (48 [20-88] vs. 36 [18-49] d, p = 0.034). Of the individual components of the ADI, only percent below poverty level and percent vacant houses were associated with LOS in STAT category 5. CONCLUSIONS: LOS after CHD surgery is associated with Brokamp ADI in STAT category 5 cases, we failed to identify an association in lower-risk cardiac operations.

Developing and evaluating pediatric phecodes (Peds-Phecodes) for high-throughput phenotyping using electronic health records.

OBJECTIVE: Pediatric patients have different diseases and outcomes than adults; however, existing phecodes do not capture the distinctive pediatric spectrum of disease. We aim to develop specialized pediatric phecodes (Peds-Phecodes) to enable efficient, large-scale phenotypic analyses of pediatric patients. MATERIALS AND METHODS: We adopted a hybrid data- and knowledge-driven approach leveraging electronic health records (EHRs) and genetic data from Vanderbilt University Medical Center to modify the most recent version of phecodes to better capture pediatric phenotypes. First, we compared the prevalence of patient diagnoses in pediatric and adult populations to identify disease phenotypes differentially affecting children and adults. We then used clinical domain knowledge to remove phecodes representing phenotypes unlikely to affect pediatric patients and create new phecodes for phenotypes relevant to the pediatric population. We further compared phenome-wide association study (PheWAS) outcomes replicating known pediatric genotype-phenotype associations between Peds-Phecodes and phecodes. RESULTS: The Peds-Phecodes aggregate 15 533 ICD-9-CM codes and 82 949 ICD-10-CM codes into 2051 distinct phecodes. Peds-Phecodes replicated more known pediatric genotype-phenotype associations than phecodes (248 vs 192 out of 687 SNPs, P < .001). DISCUSSION: We introduce Peds-Phecodes, a high-throughput EHR phenotyping tool tailored for use in pediatric populations. We successfully validated the Peds-Phecodes using genetic replication studies. Our findings also reveal the potential use of Peds-Phecodes in detecting novel genotype-phenotype associations for pediatric conditions. We expect that Peds-Phecodes will facilitate large-scale phenomic and genomic analyses in pediatric populations. CONCLUSION: Peds-Phecodes capture higher-quality pediatric phenotypes and deliver superior PheWAS outcomes compared to phecodes.

Next-generation phenotyping: introducing phecodeX for enhanced discovery research in medical phenomics.

MOTIVATION: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure. RESULTS: Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology-and is a more robust representation of the medical phenome for global use in discovery research. AVAILABILITY AND IMPLEMENTATION: phecodeX is available at https://github.com/PheWAS/phecodeX.

Developing and Evaluating Pediatric Phecodes (Peds-Phecodes) for High-Throughput Phenotyping Using Electronic Health Records.

Objective: Pediatric patients have different diseases and outcomes than adults; however, existing phecodes do not capture the distinctive pediatric spectrum of disease. We aim to develop specialized pediatric phecodes (Peds-Phecodes) to enable efficient, large-scale phenotypic analyses of pediatric patients. Materials and Methods: We adopted a hybrid data- and knowledge-driven approach leveraging electronic health records (EHRs) and genetic data from Vanderbilt University Medical Center to modify the most recent version of phecodes to better capture pediatric phenotypes. First, we compared the prevalence of patient diagnoses in pediatric and adult populations to identify disease phenotypes differentially affecting children and adults. We then used clinical domain knowledge to remove phecodes representing phenotypes unlikely to affect pediatric patients and create new phecodes for phenotypes relevant to the pediatric population. We further compared phenome-wide association study (PheWAS) outcomes replicating known pediatric genotype-phenotype associations between Peds-Phecodes and phecodes. Results: The Peds-Phecodes aggregate 15,533 ICD-9-CM codes and 82,949 ICD-10-CM codes into 2,051 distinct phecodes. Peds-Phecodes replicated more known pediatric genotype-phenotype associations than phecodes (248 versus 192 out of 687 SNPs, p<0.001). Discussion: We introduce Peds-Phecodes, a high-throughput EHR phenotyping tool tailored for use in pediatric populations. We successfully validated the Peds-Phecodes using genetic replication studies. Our findings also reveal the potential use of Peds-Phecodes in detecting novel genotype-phenotype associations for pediatric conditions. We expect that Peds-Phecodes will facilitate large-scale phenomic and genomic analyses in pediatric populations. Conclusion: Peds-Phecodes capture higher-quality pediatric phenotypes and deliver superior PheWAS outcomes compared to phecodes.

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.

Current Practices in Pharmacogenomics.

Pharmacogenomics, where genomic information is used to tailor medication management, is a strategy to maximize drug efficacy and minimize toxicity. Although pediatric evidence is less robust than for adults, medications influenced by pharmacogenomics are prescribed to children and adolescents. Evidence-based guidelines and drug label annotations are available from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Pharmacogenomics Knowledgebase (PharmGKB). Some pediatric health care facilities use pharmacogenomics to provide dosing recommendations to pediatricians. Herein, we use a case-based approach to illustrate the use of pharmacogenomic data in pediatric clinical care and provide resources for finding and using pharmacogenomic guidelines.

Population genetic testing and SERPINA1 sequencing identifies unidentified alpha-1 antitrypsin deficiency alleles and gene-environment interaction with hepatitis C infection.

Alpha-1 antitrypsin deficiency (AATD), a relatively common autosomal recessive genetic disorder, is underdiagnosed in symptomatic individuals. We sought to compare the risk of liver transplantation associated with hepatitis C infection with AATD heterozygotes and homozygotes and determine if SERPINA1 sequencing would identify undiagnosed AATD. We performed a retrospective cohort study in a deidentified Electronic Health Record (EHR)-linked DNA biobank with 72,027 individuals genotyped for the M, Z, and S alleles in SERPINA1. We investigated liver transplantation frequency by genotype group and compared with hepatitis C infection. We performed SERPINA1 sequencing in carriers of pathogenic AATD alleles who underwent liver transplantation. Liver transplantation was associated with the Z allele (ZZ: odds ratio [OR] = 1.31, p<2e-16; MZ: OR = 1.02, p = 1.2e-13) and with hepatitis C (OR = 1.20, p<2e-16). For liver transplantation, there was a significant interaction between genotype and hepatitis C (ZZ: interaction OR = 1.23, p = 4.7e-4; MZ: interaction OR = 1.11, p = 6.9e-13). Sequencing uncovered a second, rare, pathogenic SERPINA1 variant in six of 133 individuals with liver transplants and without hepatitis C. Liver transplantation was more common in individuals with AATD risk alleles (including heterozygotes), and AATD and hepatitis C demonstrated evidence of a gene-environment interaction in relation to liver transplantation. The current AATD screening strategy may miss diagnoses whereas SERPINA1 sequencing may increase diagnostic yield for AATD, stratify risk for liver disease, and inform clinical management for individuals with AATD risk alleles and liver disease risk factors.

Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influences on tacrolimus dose adjusted concentration in adult heart transplant recipients.

CYP3A5 genetic variants are associated with tacrolimus metabolism. Controversy remains on whether CYP3A4 increased [* 1B (rs2740574), *1G (rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*7Bor *7G variants (Group 3) compared to CYP3A4*1/*1 (Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.

Variant-based heritability assessment of dexmedetomidine and fentanyl clearance in pediatric patients.

Despite complex pathways of drug disposition, clinical pharmacogenetic predictors currently rely on only a few high effect variants. Quantification of the polygenic contribution to variability in drug disposition is necessary to prioritize target drugs for pharmacogenomic approaches and guide analytic methods. Dexmedetomidine and fentanyl, often used in postoperative care of pediatric patients, have high rates of inter-individual variability in dosing requirements. Analyzing previously generated population pharmacokinetic parameters, we used Bayesian hierarchical mixed modeling to measure narrow-sense (additive) heritability ( h SNP 2 ) of dexmedetomidine and fentanyl clearance in children and identify relative contributions of small, moderate, and large effect-size variants to h SNP 2 . We used genome-wide association studies (GWAS) to identify variants contributing to variation in dexmedetomidine and fentanyl clearance, followed by functional analyses to identify associated pathways. For dexmedetomidine, median clearance was 33.0 L/h (interquartile range [IQR] 23.8-47.9 L/h) and h SNP 2 was estimated to be 0.35 (90% credible interval 0.00-0.90), with 45% of h SNP 2 attributed to large-, 32% to moderate-, and 23% to small-effect variants. The fentanyl cohort had median clearance of 8.2 L/h (IQR 4.7-16.7 L/h), with estimated h SNP 2 of 0.30 (90% credible interval 0.00-0.84). Large-effect variants accounted for 30% of h SNP 2 , whereas moderate- and small-effect variants accounted for 37% and 33%, respectively. As expected, given small sample sizes, no individual variants or pathways were significantly associated with dexmedetomidine or fentanyl clearance by GWAS. We conclude that clearance of both drugs is highly polygenic, motivating the future use of polygenic risk scores to guide appropriate dosing of dexmedetomidine and fentanyl.

Pediatric Persistent Inflammation, Immunosuppression, and Catabolism Syndrome Prevalence in Sepsis-Related Mortalities: A 23-Year Institutional History.

BACKGROUND: Delayed mortality in sepsis often is linked to a lack of resolution in the inflammatory cascade termed persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Limited research exists on PICS in pediatric patients with sepsis. RESEARCH QUESTION: What is the prevalence of pediatric PICS (pPICS) in patients who died of sepsis-related causes and what associated pathogen profiles and comorbidities did they have compared with those patients without pPICS who died from sepsis? STUDY DESIGN AND METHODS: A retrospective study of a single institution using a de-identified database from 1997 through 2020 for all patients aged 21 years or younger who died of culture-positive sepsis from a known source and who had laboratory data available were evaluated for the presence of pPICS. RESULTS: Among records extracted from the institutional database, 557 patients had culture-positive sepsis, with 262 patients having pPICS (47%). Patients with pPICS were more likely to have underlying hematologic or oncologic disease or cardiac disease. In addition, patients who had pPICS showed increased odds of associated fungal infection compared with those patients who did not (OR, 2.69; 95% CI, 1.59-4.61; P < .001). When assessing laboratory criteria, having a sustained absolute lymphocyte count of < 1.0 × 103/µL was most closely associated with having pPICS compared with other laboratory parameters. Finally, the results of multivariate logistic regression analysis indicated that patients with pPICS were more common in the cardiac ICU, as opposed to the PICU (OR, 3.43; CI, 1.57-7.64; P = .002). INTERPRETATION: Pediatric patients who died of a sepsis-related cause have a pPICS phenotype nearly one-half of the time. These patients are more likely to be in the cardiac ICU than the pediatric ICU and have associated fungal infections. Special attention should be directed toward this population in future research.

Pediatric considerations for pharmacogenetic selective serotonin reuptake inhibitors clinical decision support.

Pharmacogenetic testing for psychiatry is growing at a rapid pace, with multiple sites utilizing results to help clinical decision-making. Genotype-guided dosing and drug selection have been implemented at several sites, including Vanderbilt University Medical Center, where clinical decision support (CDS) based on pharmacogenetic results went live for selective serotonin reuptake inhibitors in 2020 for both adult and pediatric patients. Effective and appropriate implementation of CYP2D6- and CYP2C19-guided CDS for the pediatric population requires consideration of the evidence for the pharmacogenetic associations, medication indications, and appropriate alternative therapies to be used when a pharmacogenetic contraindication is identified. In this article, we review these pediatric pharmacogenetic considerations for selective serotonin reuptake inhibitor CDS. We include a case study, the current literature supporting clinical recommendations, considerations when designing pediatric CDS, future implications, and examples of sertraline, (es)citalopram, paroxetine, and fluvoxamine alerts.

Tutorial: Using Community Engagement Studios to Enhance Pharmacogenetic Study Design for Maximizing Enrollment of Diverse Children and Pregnant People.

Most pharmacogenetic research is conducted in adult, non-pregnant populations of European ancestry. Study of more diverse and special populations is necessary to validate findings and improve health equity. However, there are significant barriers to recruitment of diverse populations for genetic studies, such as mistrust of researchers due to a history of unethical research and ongoing social inequities. Engaging communities and understanding community members' perspectives may help to overcome these barriers and improve research quality. Here, we highlight one method for engaging communities, the Community Engagement Studio (CES), a consultative session that allows researchers to obtain guidance and feedback based on community members' lived experiences. We also provide an example of its use in pharmacogenetic studies. In designing a survey study of knowledge and attitudes around pharmacogenetic testing among children with chronic conditions and pregnant individuals, we sought input from diverse community stakeholders through CESs at Vanderbilt University Medical Center. We participated in two CESs with community stakeholders representing study target populations. Our goals were to learn specific concerns about pharmacogenetic testing and preferred recruitment strategies for these communities. Concerns were expressed about how genetic information would be used beyond the immediate study. Participants emphasized the importance of clarity and transparency in communication to overcome participation hesitancy and mistrust of the study team. Recruitment strategy recommendations ranged from informal notices posted in healthcare settings to provider referrals. The CES enabled us to modify our recruitment methods and research materials to better communicate with populations currently under-represented in pharmacogenetics research.

Pediatric CYP2D6 metabolizer status and post-tonsillectomy nausea and vomiting after ondansetron.

The goal of this study was to determine whether CYP2D6 metabolizer status within the ondansetron-treated pediatric tonsillectomy population is associated with risk of postoperative nausea and vomiting (PONV) in the post-anesthesia care unit. We conducted a retrospective cohort study of pediatric patients (<18 years) who underwent tonsillectomy and received ondansetron on the day of the procedure. Data were obtained from BioVU, an institutional biobank that links DNA to de-identified electronic health record data. Subjects were tested for 10 CYP2D6 allelic variants and copy number variation, and genotype data translated into CYP2D6 metabolizer status. The cohort included 652 individuals, 105 (16.1%) of whom had PONV. Rates of PONV were similar across groups: ultrarapid metabolizers (UMs), 1 of 9 (11.1%); normal metabolizers (NMs), 64 of 354 (18.1%); intermediate metabolizers (IMs), 33 of 234 (14.1%); poor metabolizers (PMs), 6 of 39 (15.4%); and ambiguous phenotypes, 1 of 16 (6.3%). In multivariable analysis adjusted for age, sex, and time under anesthesia, CYP2D6 metabolizer status was not associated with PONV, with an odds ratio of 1.37 (95% confidence interval 0.9, 2.1) when comparing PM/IM versus NM/UM. In this large pediatric population, no significant differences were detected for PONV based on CYP2D6 metabolizer status. Further investigation is needed to determine mechanisms for ondansetron inefficacy in children.

Direct-to-patient telehealth equity: Reaching diverse pediatric populations in primary care.

INTRODUCTION: Telehealth is the use of electronic information and technology for long-distance clinical care. In direct-to-patient (DTP) telehealth, the patient initiates care from a personal computer or mobile device to a medical provider. While information on standard clinic-to-clinic telehealth exists, less is known about DTP telehealth in pediatric populations. Using quantitative and qualitative data, we examined DTP telehealth for low-income pediatric patient-families and compared the experience of English and non-English speakers. METHOD: Telehealth visits for acute and preventive care took place from April 2020 to May 2020 at a pediatric primary care clinic (80% Medicaid-insured, 40% non-English-speaking). Patients and primary care providers conducted the visit through the clinic's portal or other platforms (WhatsApp, FaceTime, Zoom). Providers completed an electronic survey with patient feedback about the telehealth experience and their own observations. An iterative inductive/deductive approach informed a coding scheme for free-text survey responses consisting of five domains. RESULTS: REDCap surveys were completed for 258 (52%) of telehealth visits. There was an overrepresentation of English visits compared to the overall clinic population and the majority of visits were via mobile phone. Visits with English speakers utilized the patient portal and had positive process ease ratings more often than those with non-English speakers. Providers rated most telehealth visits as satisfactory, with contributing elements including family call environment, technology process and experience, value added, and barriers. DISCUSSION: Expanding telehealth in pediatrics without worsening health disparities requires building digital health that is user-friendly on mobile technology, facilitating patient preferred language, and simplifying logistical processes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Bronchopulmonary dysplasia is associated with polyhydramnios in a scan for novel perinatal risk factors.

BACKGROUND: The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial, and there are limited data about prenatal exposures and risk of BPD. STUDY DESIGN: Our study performed parallel analyses using a logistic regression model in a cohort of 4527 infants with data from a curated registry and using a phenome wide association study (PheWAS) based on ICD9/10-based phecodes. We examined 20 prenatal exposures from a neonatal intensive care unit (NICU) curated registry database related to pregnancy and maternal health as well as 94 maternal diagnosis phecodes with a PheWAS analysis. RESULT: In both the curated registry and PheWAS analyses, polyhydramnios was associated with an increased risk of BPD (OR 5.70, 95% CI 2.78-11.44, p = 1.37 × 10-6). CONCLUSION: Our data suggest that polyhydramnios may be a clinical indicator of premature infants at increased risk for bronchopulmonary dysplasia. Combining curated registry data with PheWAS analysis creates a valuable tool to generate hypotheses. IMPACT: Polyhydramnios was significantly associated with bronchopulmonary dysplasia in both a curated registry and by ICD coding analysis with a phenome wide association study (PheWAS). Preterm polyhydramnios may be a clinical indicator of infants at increased risk for developing bronchopulmonary dysplasia after preterm birth. Combining curated registry with PheWAS analysis creates a valuable tool to generate hypotheses about perinatal risk factors and morbidities associated with preterm birth.