The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

Antibiotics prior to age 2 years have limited association with preschool growth trajectory.

BACKGROUND: Prior studies of early antibiotic use and growth have shown mixed results, primarily on cross-sectional outcomes. This study examined the effect of oral antibiotics before age 24 months on growth trajectory at age 2-5 years. METHODS: We captured oral antibiotic prescriptions and anthropometrics from electronic health records through PCORnet, for children with ≥1 height and weight at 0-12 months of age, ≥1 at 12-30 months, and ≥2 between 25 and 72 months. Prescriptions were grouped into episodes by time and by antimicrobial spectrum. Longitudinal rate regression was used to assess differences in growth rate from 25 to 72 months of age. Models were adjusted for sex, race/ethnicity, steroid use, diagnosed asthma, complex chronic conditions, and infections. RESULTS: 430,376 children from 29 health U.S. systems were included, with 58% receiving antibiotics before 24 months. Exposure to any antibiotic was associated with an average 0.7% (95% CI 0.5, 0.9, p < 0.0001) greater rate of weight gain, corresponding to 0.05 kg additional weight. The estimated effect was slightly greater for narrow-spectrum (0.8% [0.6, 1.1]) than broad-spectrum (0.6% [0.3, 0.8], p < 0.0001) drugs. There was a small dose response relationship between the number of antibiotic episodes and weight gain. CONCLUSION: Oral antibiotic use prior to 24 months of age was associated with very small changes in average growth rate at ages 2-5 years. The small effect size is unlikely to affect individual prescribing decisions, though it may reflect a biologic effect that can combine with others.

Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

PURPOSE: Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. METHODS: We assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate. RESULTS: Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days. CONCLUSIONS: More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient's lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.

Validity of Cardiovascular Data From Electronic Sources: The Multi-Ethnic Study of Atherosclerosis and HealthLNK.

BACKGROUND: Understanding the validity of data from electronic data research networks is critical to national research initiatives and learning healthcare systems for cardiovascular care. Our goal was to evaluate the degree of agreement of electronic data research networks in comparison with data collected by standardized research approaches in a cohort study. METHODS: We linked individual-level data from MESA (Multi-Ethnic Study of Atherosclerosis), a community-based cohort, with HealthLNK, a 2006 to 2012 database of electronic health records from 6 Chicago health systems. To evaluate the correlation and agreement of blood pressure in HealthLNK in comparison with in-person MESA examinations, and body mass index in HealthLNK in comparison with MESA, we used Pearson correlation coefficients and Bland-Altman plots. Using diagnoses in MESA as the criterion standard, we calculated the performance of HealthLNK for hypertension, obesity, and diabetes mellitus diagnosis by using International Classification of Diseases, Ninth Revision codes and clinical data. We also identified potential myocardial infarctions, strokes, and heart failure events in HealthLNK and compared them with adjudicated events in MESA. RESULTS: Of the 1164 MESA participants enrolled at the Chicago Field Center, 802 (68.9%) participants had data in HealthLNK. The correlation was low for systolic blood pressure (0.39; P<0.0001). In comparison with MESA, HealthLNK overestimated systolic blood pressure by 6.5 mm Hg (95% confidence interval, 4.2-7.8). There was a high correlation between body mass index in MESA and HealthLNK (0.94; P<0.0001). HealthLNK underestimated body mass index by 0.3 kg/m2 (95% confidence interval, -0.4 to -0.1). With the use of International Classification of Diseases, Ninth Revision codes and clinical data, the sensitivity and specificity of HealthLNK queries for hypertension were 82.4% and 59.4%, for obesity were 73.0% and 89.8%, and for diabetes mellitus were 79.8% and 93.3%. In comparison with adjudicated cardiovascular events in MESA, the concordance rates for myocardial infarction, stroke, and heart failure were, respectively, 41.7% (5/12), 61.5% (8/13), and 62.5% (10/16). CONCLUSIONS: These findings illustrate the limitations and strengths of electronic data repositories in comparison with information collected by traditional standardized epidemiological approaches for the ascertainment of cardiovascular risk factors and events.

Lessons Learned When Introducing Pharmacogenomic Panel Testing into Clinical Practice.

OBJECTIVES: Implementing new programs to support precision medicine in clinical settings is a complex endeavor. We describe challenges and potential solutions based on the Indiana GENomics Implementation: an Opportunity for the Underserved (INGenious) program at Eskenazi Health-one of six sites supported by the Implementing GeNomics In pracTicE network grant of the National Institutes of Health/National Human Genome Research Institute. INGenious is an implementation of a panel of genomic tests. METHODS: We conducted a descriptive case study of the implementation of this pharmacogenomics program, which has a wide scope (14 genes, 27 medications) and a diverse population (patients who often have multiple chronic illnesses, in a large urban safety-net hospital and its outpatient clinics). CHALLENGES: We placed the clinical pharmacogenomics implementation challenges into six categories: patient education and engagement in care decision making; clinician education and changes in standards of care; integration of technology into electronic health record systems; translational and implementation sciences in real-world clinical environments; regulatory and reimbursement considerations, and challenges in measuring outcomes. A cross-cutting theme was the need for careful attention to workflow. Our clinical setting, a safety-net health care system, presented some distinctive challenges. Patients often had multiple chronic illnesses and sometimes were taking more than one pharmacogenomics-relevant medication. Reaching patients for recruitment or follow-up was another challenge. CONCLUSIONS: New, large-scale endeavors in health care are challenging. A description of the challenges that we encountered and the approaches that we adopted to address them may provide insights for those who implement and study innovations in other health care systems.

Gallbladder Ejection Fraction Is Unrelated to Gallbladder Pathology in Children and Adolescents.

OBJECTIVES: Biliary dyskinesia is a common diagnosis that frequently results in cholecystectomy. In adults, most clinicians use a cut off value for the gallbladder ejection fraction (GBEF) of <35% to define the disease. This disorder is not well characterized in children. Our aim was to determine the relation between GBEF and gallbladder pathology using a large statewide medical record repository. METHODS: We obtained records from all patients of 21 years and younger who underwent hepatic iminodiacetic acid (HIDA) testing within the Indiana Network for Patient Care from 2004 to 2013. GBEF results were obtained from radiology reports using data mining techniques. Age, sex, race, and insurance status were obtained for each patient. Any gallbladder pathology obtained subsequent to an HIDA scan was also obtained and parsed for mention of cholecystitis, cholelithiasis, or cholesterolosis. We performed mixed effects logistic regression analysis to determine the influence of age, sex, race, insurance status, pathologist, and GBEF on the presence of these histologic findings. RESULTS: Two thousand eight hundred forty-one HIDA scans on 2558 patients were found. Of these, 310 patients had a full-text gallbladder pathology report paired with the HIDA scan. GBEF did not correlate with the presence of gallbladder pathology (cholecystitis, cholelithiasis, or cholesterolosis) when controlling for age, sex, race, insurance status, and pathologist using a mixed effects model. CONCLUSIONS: Hypokinetic gallbladders are no more likely to have gallbladder pathology than normal or hyperkinetic gallbladders in the setting of a patient with both a HIDA scan and a cholecystectomy. Care should be used when interpreting the results of HIDA scans in children and adolescents.

Test positivity for chlamydia, gonorrhea, and syphilis infection among a cohort of individuals released from jail in Marion County, Indiana.

BACKGROUND: Individuals entering jails have high rates of sexually transmitted infections (STI), but there are few data on STI in the postincarceration period. This study aimed to describe rates of chlamydia, gonorrhea, and syphilis infection among individuals released from Marion County (Indianapolis), Indiana jails. METHODS: We conducted a retrospective cohort study of individuals incarcerated in Marion County, Indiana jails from 2003 to 2008 (n = 118,670). We linked county jail and public health data to identify individuals with positive STI test results in the 1 year after release from jail. Rates per 100,000 individuals and Cox proportional hazard analyses were performed for each STI, stratified by demographic, STI, and jail characteristics. RESULTS: We found significantly higher rates of STI in this cohort than in the general population, with rates in the 1 year after release being 2 to 7 times higher for chlamydia, 5 to 24 times higher for gonorrhea, and 19 to 32 times higher for syphilis compared with rates in the general population. Characteristics most associated with increased risk of a positive STI test result among this cohort were younger age for chlamydia and gonorrhea, older age for syphilis, black race for men, being jailed for prostitution for women, history of STI, and history of prior incarceration. CONCLUSIONS: This study found high rates of STIs among a cohort of individuals recently released from jail and identified a number of risk factors. Further study is needed to improve targeted STI testing and treatment among this high-risk population.

Epidemiology of Sexually Transmitted Infections Among Offenders Following Arrest or Incarceration.

OBJECTIVES: We sought to estimate rates of sexually transmitted infections (STIs) among criminal offenders in the 1 year after arrest or release from incarceration. METHODS: We performed a retrospective cohort study of risk of having a positive STI (chlamydia, gonorrhea, or syphilis) or incident-positive HIV test in the 1 year following arrest or incarceration in Marion County (Indianapolis), Indiana. Participants were 247,211 individuals with arrest or incarceration in jail, prison, or juvenile detention between 2003 and 2008. RESULTS: Test positivity rates (per 100,000 and per year) were highest for chlamydia (2968) and gonorrhea (2305), and lower for syphilis (278) and HIV (61). Rates of positive STI and HIV were between 1.5 and 2.8 times higher in female than male participants and between 2.7 and 6.9 times higher for Blacks than Whites. Compared with nonoffenders, offenders had a relative risk of 3.9 for chlamydia, 6.6 for gonorrhea, 3.6 for syphilis, and 4.6 for HIV. CONCLUSIONS: The 1-year period following arrest or release from incarceration represents a high-impact opportunity to reduce STI and HIV infection rates at a population level.

Trends in Neonatal Opioid Withdrawal Syndrome and Opioid Exposure Diagnoses Among Infants With Private Health Insurance, 2016-2021: Introduction of the P04.14 ICD-10-CM Code.

OBJECTIVE: The opioid epidemic has led to a surge in diagnoses of neonatal opioid withdrawal syndrome (NOWS). Many states track the incidence of NOWS by using the P96.1 International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code for "neonatal withdrawal symptoms from maternal use of drugs of addiction." In October 2018, an ICD-10-CM code for neonatal opioid exposure (P04.14) was introduced. This code can be used when an infant is exposed to opioids in utero but does not have clinically significant withdrawal symptoms. We analyzed the effect of the P04.14 code on the incidence rate of NOWS (P96.1) and "other" neonatal drug exposure diagnoses (P04.49). METHODS: We used private health insurance data collected for infants in the United States from the first quarter of 2016 through the third quarter of 2021 to describe incidence rates for each code over time and examine absolute and percentage changes before and after the introduction of code P04.14. RESULTS: The exclusive use of code P96.1 declined from an incidence rate per 1000 births of 1.08 in 2016-2018 to 0.70 in 2019-2021, a -35.7% (95% CI, -47.6% to -23.8%) reduction. Use of code P04.49 only declined from an incidence rate of 2.34 in 2016-2018 to 1.64 in 2019-2021, a -30.0% (95% CI, -36.4% to -23.7%) reduction. Use of multiple codes during the course of treatment increased from an average incidence per 1000 births of 0.56 in 2016-2018 to 0.79 in 2019-2021, a 45.5% (95% CI, 24.8%-66.1%) increase. CONCLUSION: The introduction of ICD-10-CM code P04.14 altered the use of other neonatal opioid exposure codes. The use of multiple codes increased, indicating that some ambiguity may exist about which ICD-10-CM code is most appropriate for a given set of symptoms.

A regional informatics platform for coordinated antibiotic-resistant infection tracking, alerting, and prevention.

BACKGROUND: We developed and assessed the impact of a patient registry and electronic admission notification system relating to regional antimicrobial resistance (AMR) on regional AMR infection rates over time. We conducted an observational cohort study of all patients identified as infected or colonized with methicillin-resistant Staphylococcus aureus (MRSA) and/or vancomycin-resistant enterococci (VRE) on at least 1 occasion by any of 5 healthcare systems between 2003 and 2010. The 5 healthcare systems included 17 hospitals and associated clinics in the Indianapolis, Indiana, region. METHODS: We developed and standardized a registry of MRSA and VRE patients and created Web forms that infection preventionists (IPs) used to maintain the lists. We sent e-mail alerts to IPs whenever a patient previously infected or colonized with MRSA or VRE registered for admission to a study hospital from June 2007 through June 2010. RESULTS: Over a 3-year period, we delivered 12 748 e-mail alerts on 6270 unique patients to 24 IPs covering 17 hospitals. One in 5 (22%-23%) of all admission alerts was based on data from a healthcare system that was different from the admitting hospital; a few hospitals accounted for most of this crossover among facilities and systems. CONCLUSIONS: Regional patient registries identify an important patient cohort with relevant prior antibiotic-resistant infection data from different healthcare institutions. Regional registries can identify trends and interinstitutional movement not otherwise apparent from single institution data. Importantly, electronic alerts can notify of the need to isolate early and to institute other measures to prevent transmission.

Impact of dementia on payments for long-term and acute care in an elderly cohort.

BACKGROUND: Older people with dementia have increased risk of nursing home (NH) use and higher Medicaid payments. Dementia's impact on acute care use and Medicare payments is less well understood. OBJECTIVES: Identify trajectories of incident dementia and NH use, and compare Medicare and Medicaid payments for persons having different trajectories. RESEARCH DESIGN: Retrospective cohort of older patients who were screened for dementia in 2000-2004 and were tracked for 5 years. Trajectories were identified with latent class growth analysis. SUBJECTS: A total of 3673 low-income persons aged 65 or older without dementia at baseline. MEASURES: Incident dementia diagnosis, comorbid conditions, dual eligibility, acute and long-term care use and payments based on Medicare and Medicaid claims, medical record systems, and administrative data. RESULTS: Three trajectories were identified based on dementia incidence and short-term and long-term NH use: (1) high incidence of dementia with heavy NH use (5% of the cohort) averaging $56,111/year ($36,361 Medicare, $19,749 Medicaid); (2) high incidence of dementia with little or no NH use (16% of the cohort) averaging $16,206/year ($14,644 Medicare, $1562 Medicaid); and (3) low incidence of dementia and little or no NH use (79% of the cohort) averaging $8475/year ($7558 Medicare, $917 Medicaid). CONCLUSIONS: Dementia and its interaction with NH utilization are major drivers of publicly financed acute and long-term care payments. Medical providers in Accountable Care Organizations and other health care reform efforts must effectively manage dementia care across the care continuum if they are to be financially viable.

Lower provider volume is associated with higher failure rates for endoscopic retrograde cholangiopancreatography.

BACKGROUND: Among physicians who perform endoscopic retrograde cholangiopancreatography (ERCP), the relationship between procedure volume and outcome is unknown. OBJECTIVE: Quantify the ERCP volume-outcome relationship by measuring provider-specific failure rates, hospitalization rates, and other quality measures. RESEARCH DESIGN: Retrospective cohort. SUBJECTS: A total of 16,968 ERCPs performed by 130 physicians between 2001 and 2011, identified in the Indiana Network for Patient Care. MEASURES: Physicians were classified by their average annual Indiana Network for Patient Care volume and stratified into low (<25/y) and high (≥25/y). Outcomes included failed procedures, defined as repeat ERCP, percutaneous transhepatic cholangiography or surgical exploration of the bile duct≤7 days after the index procedure, hospitalization rates, and 30-day mortality. RESULTS: Among 15,514 index ERCPs, there were 1163 (7.5%) failures; the failure rate was higher among low (9.5%) compared with high volume (5.7%) providers (P<0.001). A second ERCP within 7 days (a subgroup of failure rate) occurred more frequently when the original ERCP was performed by a low-volume (4.1%) versus a high-volume physician (2.3%, P=0.013). Patients were more frequently hospitalized within 24 hours when the ERCP was performed by a low-volume (28.3%) versus high-volume physician (14.8%, P=0.002). Mortality within 30 days was similar (low=1.9%, high=1.9%). Among low-volume physicians and after adjusting, the odds of having a failed procedure decreased 3.3% (95% confidence interval, 1.6%-5.0%, P<0.001) with each additional ERCP performed per year. CONCLUSIONS: Lower provider volume is associated with higher failure rate for ERCP, and greater need for postprocedure hospitalization.

Psychiatric medication refill practices of juvenile detainees.

To examine the psychiatric medication fill rates of adolescents after release from juvenile detention. The team reviewed 177 charts. A fill was defined as a psychiatric medication charge to Medicaid 30- or 90-days after release. Differences in demographic characteristics were compared among individuals with fills at 30- or 90-days and those with no medication fills. Forty-five percent of patients were on at least one psychiatric medication. Among detainees on a psychiatric medication, 62 % had a fill by 30 days after release, and 78 % by 90 days. At least 50 % of the adolescents on a psychiatric medication were on an atypical antipsychotic. There was no significant relationship between medication fill and race, age, or sex. Despite the known associations between mental health diagnosis and treatment-seeking with age, sex, and race, it appears that psychiatric medication fill patterns after release from detention are not associated with these factors.

HIV Care Continuum Among People Living With HIV and History of Arrest and Mental Health Diagnosis.

OBJECTIVE: Justice involvement and psychiatric comorbidities contribute to excess HIV morbidity, yet their interaction is poorly understood. We examined associations of this overlap with HIV outcomes among people living with HIV (PLWH). METHODS: We conducted a retrospective cohort study of PLWH aged 13 years and older residing in Marion County (Indianapolis), IN, during 2018 (n = 5730) using linked HIV surveillance, arrest, and clinical data. We used univariable and multivariable regression to evaluate main and interaction effects of 2010-2017 arrest and mental health diagnosis on 2018 linkage to care (LTC), retention in care (RIC), and undetectable viral load (UVL). RESULTS: LTC decreased among those with, versus without, an arrest (P = 0.02), although mental health diagnoses had no significant effect on LTC. When controlling for demographics and substance use disorder, analyses indicated a protective effect of arrest history on odds of RIC (adjusted odds ratio [aOR] = 1.54) and UVL (aOR = 1.26). Mental health diagnosis also increased odds of RIC (aOR = 2.02) and UVL (aOR = 1.95). Post hoc tests demonstrated that these results were mediated by outpatient care utilization, although an arrest or mental health diagnosis did increase odds of RIC among PLWH and a history of low outpatient utilization. CONCLUSIONS: Outpatient care utilization improves HIV outcomes, even among those with justice involvement and psychiatric comorbidities. Holistic approaches to care can increase utilization. Implementation of "no wrong door" approaches, such as integration of mental health care in the primary care setting, simplifies health care navigation and improves access. Among those arrested, access to a Behavioral Court program can improve, rather than disrupt, HIV care.

Perceived or actual barriers to warfarin use in atrial fibrillation based on electronic medical records.

Compared with usual practice, clinical trials often exclude patients with relative contraindications. A study of real-world warfarin use could help inform trials of new medications that could potentially replace warfarin. The objective of this study was to describe potential barriers to warfarin use among patients with atrial fibrillation. This was a retrospective study of electronic medical records (1998-2007) from an inner-city public hospital and affiliated primary care clinics and included adults aged 18 years or more with atrial fibrillation. Exclusions included mitral or aortic valve replacement, hyperthyroidism, or no clinical encounter within 1 year after first diagnosis. Warfarin exposure was defined by electronic pharmacy or physician order data or, in a second definition, international normalized ratio > 1.3. A history of potential barriers to warfarin was defined by International Classification of Diagnoses, 9th revision codes or electronic medical record "dictionary" terms. Among 3329 patients, CHADS2 scores were 0 (17%), 1 (26%), 2-6 (57%). Among 1276 patients with CHADS2 scores >0 who were prescribed warfarin, rates of potential barriers to warfarin were gastrointestinal or genitourinary hemorrhage (20%), alcohol abuse (16%), renal insufficiency (15%), predisposition to falls (8%), cirrhosis/hepatitis (5%), intracranial hemorrhage (1%), other hemorrhage (6%), and age 75 years or more (23%). Among 1475 patients with CHADS2 scores >0 who were not prescribed warfarin, these rates differed by not >3% except for predisposition to falls (16%) and age 75 years or more (43%). In real-world practice, many patients given warfarin have contraindications that would exclude them from clinical trials, and many patients apparently eligible for warfarin do not receive it.

Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.

PURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.

Association of QT interval-prolonging drugs with clinical trial eligibility in patients with advanced cancer.

Introduction: Drug-induced prolongation of the heart rate-corrected QT interval (QTc) is associated with increased risk for the potentially fatal arrhythmia torsades de pointes. Due to arrhythmia risk, clinical trials with cancer therapeutics often exclude patients based on thresholds for QTc prolongation. Our objective was to assess associations between prescriptions for QT-prolonging drugs and the odds of meeting cancer trial exclusionary QTc thresholds in a cohort of adults with advanced cancer. Methods: Electronic health records were retrospectively reviewed for 271 patients seen at our institutional molecular solid tumor clinic. Collected data included demographics, QTc measurements, ventricular arrhythmia-related diagnoses, and all inpatient and outpatient prescriptions. Potential associations were assessed between demographic and clinical variables, including prescriptions for QT-prolonging drugs, and QTc measurements. Results: Women had longer median QTc measurements than men (p = 0.030) and were prescribed more QT-prolonging drugs during the study (p = 0.010). In all patients, prescriptions for QT-prolonging drugs were associated with longer median and maximum QTc measurements at multiple assessed time points (i.e., for QT-prolonging drugs prescribed within 10, 30, 60, and 90 days of QTc measurements). Similarly, the number of QT-prolonging drugs prescribed was correlated with longer median and maximum QTc measurements at multiple time points. Common QTc-related exclusionary criteria were collected from a review of ClinicalTrials.gov for recent cancer clinical trials. Based on common exclusion criteria, prescriptions for QT-prolonging drugs increased the odds of trial exclusion. Conclusion: This study demonstrates that prescriptions for QT-prolonging drugs were associated with longer QTc measurements and increased odds of being excluded from cancer clinical trials.

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

RATIONALE AND OBJECTIVE: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease. STUDY DESIGN: Multicenter, pragmatic, randomized controlled clinical trial. SETTING AND PARTICIPANTS: 6650 individuals with African ancestry and hypertension from 13 health systems. INTERVENTION: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use. OUTCOMES: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months. RESULTS: To date, the trial has enrolled 3423 participants. CONCLUSIONS: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record. TRIAL REGISTRATION: ClinicalTrials.govNCT04191824.