Athreya, Arjun P.

ABSTRACT Major depressive disorder (MDD) is a substantial public health challenge. Pharmacogenomics (PGx), which identifies genetic variations that predict drug treatment outcomes, may have utility for clinical practice, but adequate representation of all populations is needed. As precision medicine in psychiatry moves towards the use of Artificial Intelligence (AI) and Machine Learning (ML) to predict treatment outcomes using PGx data, representation of diverse populations will be especially important in order to mitigate algorithmic bias and achieve equitable and generalizable findings. This work sought to quantify population diversity in pharmacogenomic studies of MDD through a systematic review. Data from 390 MDD antidepressant PGx studies were extracted from 5739 articles screened. Studies summarized were predominantly conducted in Europe, East Asia, and North America. Across all global studies, the study population comprised 57.3% White, 36.4% Asian, 1.7% Black, 3.5% Hispanic/Latino, and 0.1% Native American or Indigenous participants. Only sixty‐three (16.2%) studies included Black or Latino/Hispanic patients. Additionally, Black, Asian, Hispanic/Latino, and American Indian/Alaska Native populations were statistically underrepresented in U.S. study populations when compared to national census data, while Asian and Black populations were underrepresented in the United Kingdom. The overrepresentation of participants from a limited number of countries combined with the underrepresentation of Black and Hispanic/Latino populations could impact the extent to which pharmacogenomic testing and associated AI/ML‐based PGx tools could individualize antidepressant medication regimens for treating MDD.

ABSTRACTPharmacogenetics is a promising strategy to facilitate individualized care for patients with Major Depressive Disorder (MDD). Research is ongoing to identify the optimal genetic markers for predicting outcomes to antidepressant therapies. The primary aim of this systematic review was to summarize antidepressant pharmacogenetic studies to enhance understanding of the genes, variants, datatypes/methodologies, and outcomes investigated in the context of MDD. The secondary aim was to identify clinical genetic panels indicated for antidepressant prescribing and summarize their genes and variants. Screening of N = 5793 articles yielded N = 390 for inclusion, largely comprising adult (≥ 18 years) populations. Top‐studied variants identified in the search were discussed and compared with those represented on the N = 34 clinical genetic panels that were identified. Summarization of articles revealed sources of heterogeneity across studies and low rates of replicability of pharmacogenetic associations. Heterogeneity was present in outcome definitions, treatment regimens, and differential inclusion of mediating variables in analyses. Efficacy outcomes (i.e., response, remission) were studied at greater frequency than adverse‐event outcomes. Studies that used advanced analytical approaches, such as machine learning, to integrate variants with complimentary biological datatypes were fewer in number but achieved higher rates of significant associations with treatment outcomes than candidate variant approaches. As large biological datasets become more prevalent, machine learning will be an increasingly valuable tool for parsing the complexity of antidepressant response. This review provides valuable context and considerations surrounding pharmacogenetic associations in MDD which will help inform future research and translation efforts for guiding antidepressant care.

ABSTRACT Adherence in digital health studies with extended observation periods (≥ 12 months) is limited, and participant retention considerably reduces with time. The US Food and Drug Administration has issued guidelines for improving participant engagement, adherence, and diversity in digital health studies combined with decentralized procedures. A decentralized digital health study on well‐being was designed with protocolized procedures to study the feasibility of participant engagement and technology support to facilitate adherence (wearing the smartwatch ≥ 70% of time) sustained over a 12‐month period. At the end of the study, participants were asked about their ease of participation and free‐response questions about how wearing the smartwatches impacted their physical wellness. An inductive thematic analysis (ITA) was performed to assess themes of those responses and association with adherence. A total of 298 participants were recruited between 2022 and 2023 ( n = 129 in Cohort A in October 22, n = 169 in Cohort B in April 23), with 23% non‐white participants accrued. Among the 298 participants accrued, 273 (92% of accrued participants) completed the 12‐month study with an average overall adherence of 77.4% (SD = 32.64) wear‐time across 12 months. Median adherence of participants whose responses exemplified an ITA theme encompassing perceived behavior changes in sleep and physical activity was higher than those who did not have a response exemplifying that theme. Conversely, those expressing perceived discomfort or intrusiveness of the smartwatch had a statistically lower adherence. These results highlight the crucial roles of technology support and robust engagement efforts to enable sustained adherence over extended follow‐up periods in decentralized digital health studies.

Introduction: Identifying patients at risk for ischemic events after percutaneous coronary intervention (PCI) relies on traditional analysis of limited clinical and imaging variables. Machine learning (ML) has shown promise in effectively predicting cardiovascular risk in population studies. While existing ML models mainly predict mortality and incorporate clinical variables, there is a lack of tools that have utilized genetic data and that predict ischemic events. Aims: This study aims to develop and validate a ML model incorporating genotyping and clinical data to enhance prediction of ischemic outcomes for PCI patients utilizing large prospectively derived diverse datasets. Methods: Patients from the TAILOR-PCI trial (n=5302) were utilized for model development. 50% of the sample was utilized for Boruta feature selection and 50% for training and testing using cross validation. Features included demographics, medical history, medications, PCI characteristics, and genetic data (specifically, CYP2C19 *2, *3, *17 alleles). The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. Multiple ML classification algorithms, including Support Vector Machine (SVM) polynomial, Random Forest, Light gradient boost, XG Boost, among others, were benchmarked for their prediction performance on rare events. The top performing classifiers were externally validated on an independent dataset from the PRECISION PCI study (n=3,745). Results: Mean participant age of the training set was 64.2 ± 11.0 years, with 75.4% being male. During follow-up of 12 months, among 4,572 patients in the entire cohort 343 (7.5%) met the primary outcome. The SVM polynomial model demonstrated the highest area under the curve (AUC) of 0.67 for predicting the primary outcome with test dataset. The sensitivity, specificity, precision, and recall were 0.87, 0.28, 0.07, and 0.87 respectively (Figure). Peripheral arterial disease, body mass index, and age were among the top variables by feature importance. Conclusion: ML models incorporating both clinical and genetic data are feasible and highly promising in predicting major adverse cardiac events that may help guide use of anti-platelet drug therapy. The AUC values are reasonable given imbalances and misclassifications in datasets, and further model optimization with prospective utilization of the model will be paramount.

Introduction: Despite advances in obstetric care, postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Prior reviews of studies published through 2016 suggest an association of antidepressant use during late pregnancy and increased risk of PPH. However, a causal link between prenatal antidepressants and PPH remains controversial. Objectives: This systematic literature review aimed to synthesize the empirical evidence on the association of antidepressant exposure in late pregnancy with the risk of PPH, including studies published before and after 2016. Methods: A systematic literature search was conducted using PubMed, OVID Medline, EMBASE, SCOPUS, PsycINFO, and CINAHL from inception to September 9, 2023. Original, peer-reviewed studies (published in English) that reported on the frequency or risk of PPH in women with evidence of antidepressant use during pregnancy and included at least one control group were included. Results: Twenty studies (eight published after 2016) met inclusion criteria, most of which focused on the risks of PPH associated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The main findings from the individual studies were mixed, but the majority documented statistically significant associations of PPH with late prenatal exposure, especially for exposures occurring within 30 days of delivery, compared with unexposed deliveries. Fourteen studies addressed underlying antidepressant indications or their correlates. Few studies focused on prenatal antidepressants and the risk of well-defined severe PPH or on antidepressant dose changes and general PPH risk. None examined competing risks of antidepressant discontinuation on mental health outcomes. Conclusions: Late pregnancy exposure to antidepressants may be a minor risk factor for PPH, but it is unclear to what extent reported associations are causal in nature, as opposed to correlational (effects related to nonpharmacological factors including maternal indication). For patients needing antidepressants during pregnancy, current evidence does not favor routinely discontinuing antidepressants specifically to reduce the risk of PPH.

Abstract Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient‐specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health‐system‐wide, mixed‐methods study. Clinicians representing multiple practices and care settings ( N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient‐specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0–100 points) of each alert, the perceived impact of each alert on stress and decision‐making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision‐making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician‐guided design of PGx alerts in the era of digital medicine.

AbstractObjectivesInterpatient variability in bipolar I depression (BP‐D) symptoms challenges the ability to predict pharmacotherapeutic outcomes. A machine learning workflow was developed to predict remission after 8 weeks of pharmacotherapy (total score of ≤8 on the Montgomery Åsberg Depression Rating Scale [MADRS]).MethodsSupervised machine learning models were trained on data from BP‐D patients treated with olanzapine (N = 168) and were externally validated on patients treated with olanzapine/fluoxetine combination (OFC; N = 131) and lamotrigine (LTG; N = 126). Top predictors were used to develop a prognosis rule informing how many symptoms should change and by how much within 4 weeks to increase the odds of achieving remission.ResultsAn AUC of 0.76 (NIR:0.59; p = 0.17) was established to predict remission in olanzapine‐treated subjects. These trained models achieved AUCs of 0.70 with OFC (NIR:0.52; p < 0.03) and 0.73 with LTG (NIR:0.52; p < 0.003), demonstrating external replication of prediction performance. Week‐4 changes in four MADRS symptoms (reported sadness, reduced sleep, reduced appetite, and concentration difficulties) were top predictors of remission. Across all pharmacotherapies, three or more of these symptoms needed to improve by ≥2 points at Week‐4 to have a 65% chance of achieving remission at 8 weeks (OR: 3.74, 95% CI: 2.45–5.76; p < 9.3E‐11).ConclusionMachine learning strategies achieved cross‐trial and cross‐drug replication in predicting remission after 8 weeks of pharmacotherapy for BP‐D. Interpretable prognoses rules required only a limited number of depressive symptoms, providing a promising foundation for developing simple quantitative decision aids that may, in the future, serve as companions to clinical judgment at the point of care.

Background: Identifying individuals at risk for mild cognitive impairment (MCI) is of urgent clinical need. Objective: This study aimed to determine whether machine learning approaches could harness longitudinal neuropsychology measures, medical data, and APOE ɛ4 genotype to identify individuals at risk of MCI 1 to 2 years prior to diagnosis. Methods: Data from 676 individuals who participated in the ‘APOE in the Predisposition to, Protection from and Prevention of Alzheimer’s Disease’ longitudinal study (N = 66 who converted to MCI) were utilized in supervised machine learning algorithms to predict conversion to MCI. Results: A random forest algorithm predicted conversion 1–2 years prior to diagnosis with 97% accuracy (p = 0.0026). The global minima (each individual’s lowest score) of memory measures from the ‘Rey Auditory Verbal Learning Test’ and the ‘Selective Reminding Test’ were the strongest predictors. Conclusions: This study demonstrates the feasibility of using machine learning to identify individuals likely to convert from normal cognition to MCI.

IMPORTANCE: Meropenem dosing is typically guided by creatinine-based estimated glomerular filtration rate (eGFR), but creatinine is a suboptimal GFR marker in the critically ill. OBJECTIVES: This study aimed to develop and qualify a population pharmacokinetic model for meropenem in critically ill adults and to determine which eGFR equation based on creatinine, cystatin C, or both biomarkers best improves model performance. DESIGN, SETTING, AND PARTICIPANTS: This single-center study evaluated adults hospitalized in an ICU who received IV meropenem from 2018 to 2022. Patients were excluded if they had acute kidney injury, were on kidney replacement therapy, or were treated with extracorporeal membrane oxygenation. Two cohorts were used for population pharmacokinetic modeling: a richly sampled development cohort (n = 19) and an opportunistically sampled qualification cohort (n = 32). MAIN OUTCOMES AND MEASURES: A nonlinear mixed-effects model was developed using parametric methods to estimate meropenem serum concentrations. RESULTS: The best-fit structural model in the richly sampled development cohort was a two-compartment model with first-order elimination. The final model included time-dependent weight normalized to a 70-kg adult as a covariate for volume of distribution (Vd) and time-dependent eGFR for clearance. Among the eGFR equations evaluated, eGFR based on creatinine and cystatin C expressed in mL/min best-predicted meropenem clearance. The mean (se) Vd in the final model was 18.2 (3.5) liters and clearance was 11.5 (1.3) L/hr. Using the development cohort as the Bayesian prior, the opportunistically sampled cohort demonstrated good accuracy and low bias. CONCLUSIONS AND RELEVANCE: Contemporary eGFR equations that use both creatinine and cystatin C improved meropenem population pharmacokinetic model performance compared with creatinine-only or cystatin C-only eGFR equations in adult critically ill patients.