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Machine Learning Prediction of Pharmacogenetic Testing Uptake Among Opioid-Prescribed Patients Using Electronic Health Records: Retrospective Cohort Study
No full textBackground: Opioids are a widely prescribed class of medication for pain management. However, they have variable efficacy and adverse effects among patients, due to the complex interplay between biological and clinical factors. Pharmacogenetic testing can be used to match patients' genetic profiles to individualize opioid therapy, improving pain relief and reducing the risk of adverse effects. Despite its potential, the pharmacogenetic testing uptake (use of pharmacogenetic testing) remains low due to a range of barriers at the patient, health care provider, infrastructure, and financial levels. Since testing typically involves a shared decision between the provider and patient, predicting the likelihood of a patient undergoing pharmacogenetic testing and understanding the factors influencing that decision can help optimize resource use and improve outcomes in pain management.
Objective: This study aimed to develop machine learning (ML) models, identifying patients' likelihood of pharmacogenetic uptake based on their demographics, clinical variables, medication use, and social determinants of health.
Methods: We used electronic health record data from a single center health care system to identify patients prescribed opioids. We extracted patients' demographics, clinical variables, medication use, and social determinants of health, and developed and validated ML models, including a neural network, logistic regression, random forest, extreme gradient boosting (XGB), naïve Bayes, and support vector machines for pharmacogenetic testing uptake prediction based on procedure codes. We performed 5-fold cross-validation and created an ensemble probability-based classifier using the best-performing ML models for pharmacogenetic testing uptake prediction. Various performance metrics, uptake stratification analysis, and feature importance analysis were used to evaluate the performance of the models.
Results: The ensemble model using XGB and support vector machine-radial basis function classifiers had the highest C-statistics at 79.61%, followed by XGB (78.94%), and neural network (78.05%). While XGB was the best-performing model, the ensemble model achieved a high accuracy (32,699/48,528, 67.38%), recall (537/702, 76.50%), specificity (32,162/47,826, 67.25%), and negative predictive value (32,162/32,327, 99.49%). The uptake stratification analysis using the ensemble model indicated that it can effectively distinguish across uptake probability deciles, where those in the higher strata are more likely to undergo pharmacogenetic testing in the real world (320/4853, 6.59% in the highest decile compared to 6/4853, 0.12% in the lowest). Furthermore, Shapley Additive Explanations value analysis using the XGB model indicated age, hypertension, and household income as the most influential factors for pharmacogenetic testing uptake prediction.
Conclusions: The proposed ensemble model demonstrated a high performance in pharmacogenetic testing uptake prediction among patients using opioids for pain. This model can be used as a decision support tool, assisting clinicians in identifying patients' likelihood of pharmacogenetic testing uptake and guiding appropriate decision-making
Sex-Differences in Early-Onset Alzheimer's Disease
No full textIUIBackground: Prior research in Alzheimer’s disease (AD) suggests female sex is
associated with increased disease risk and pathology burden, but this has not been
examined in Early-onset AD (EOAD; onset <65). Using data from the Longitudinal
Early-Onset Alzheimer’s Disease Study (LEADS), we examined sex and apolipoprotein E
ε4 (APOE ε4) carrier status as predictors of pathological burden.
Methods: Chapter 2 analyses included baseline data from 77 cognitively normal (CN),
230 EOAD, and 70 early-onset non-AD (EOnonAD) LEADS participants. Each
diagnostic group was stratified by sex and then by APOE ε4 carrier status. Imaging
biomarkers were compared across strata, and voxel-wise multiple linear regressions
generated statistical maps of gray matter density, amyloid, and tau PET burden. Chapter 3
analyses evaluated the impact of sex and APOE ε4 on plasma and cerebrospinal fluid
(CSF) AD biomarkers. We included 201 EOAD, 64 EOnonAD, and 86 CN participants
with plasma data; of these, 100 EOAD, 35 EOnonAD, and 38 CN also had CSF data.
Participants were stratified by sex and APOE ε4 genotype. Demographics and biomarker
differences were compared using ANOVA within diagnostic groups, and ANCOVA
models controlled for age and education.
Results: In imaging analyses, EOAD females showed greater amyloid and tau PET
burdens than males. EOAD female APOE ε4 non-carriers exhibited greater amyloid
burden and gray matter atrophy than female ε4 carriers; EOnonAD female non-carriers
also showed greater atrophy. EOAD women had higher plasma NfL and GFAP, with comparable Aβ42/40 and
pTau231 levels relative to men. In CSF, EOAD women had higher neurogranin, tTau,
pTau181, and VILIP1. EOnonAD women had higher plasma GFAP. In CN participants,
women showed higher CSF SNAP25, whereas men showed a trend toward higher plasma
pTau231. APOE ε4 status did not influence plasma or CSF biomarker levels in either sex.
Conclusion: These analyses show that female sex and APOE ε4 status are associated
with greater pathology burden in EOAD. As specific AD fluid biomarkers emerge,
understanding sex-based differences across PET, CSF, and plasma measures is critical
and supports further study of sex- and APOE-ε4–related variation in biomarker
expression and its relevance to EOAD diagnosis and treatment
NCRAD: A Critical Resource for the Alzheimer's Disease and Related Dementias Research Community
No full textBackground:
The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) supports the etiology, early detection, and therapeutic development for Alzheimer's disease and related dementias (ADRD). One of the goals of NCRAD is to continue to offer high‐quality biobanking, biospecimens, standardized ADRD biomarkers, and support for investigators utilizing cutting‐edge methods and assays to advance ADRD research.
Method:
NCRAD currently funds sample processing and banking for ADRD studies, and for AD Research Centers (ADRCs), supports generation of APOE genotype, plasma‐based ADRD biomarkers, and supplemental GWAS data. Rigorous quality control ensures the highest quality biospecimens are processed, banked, and distributed, including: sample tracking; DNA and RNA quality measurements; hemoglobin contamination assessment; DNA fingerprinting to assess sample quality and identity; and whole genome sequencing (WGS) data generated for all banked induced pluripotent stem cell (iPSC) lines. Genetic and biomarker data is shared with data repositories including the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and the National Alzheimer's Coordinating Center (NACC).
Results:
NCRAD currently banks samples for more than 80 studies, including samples from >130,000 participants with sample types including DNA, RNA, whole blood, plasma, serum, CSF, brain tissue, stool, peripheral blood mononuclear cells (PBMCs), lymphoblast cell lines, fibroblasts, and iPSCs. More than 15,000 samples are from paired visits with more than one sample type available, and many studies bank samples from longitudinal participant visits. The repository distributed 20,000 uniform sample collection kits and received, processed, and stored more than 200,000 new aliquots in 2024. Approximately 440,000 sample aliquots have been distributed to nearly 300 researchers thus far. To date, over 1,000 publications have been generated using NCRAD samples and data.
Conclusion:
NCRAD has played a key role in development of best practices, protocol development, and uniform sample collection for ADRD studies. NCRAD continues to support cutting‐edge research in genetics, genomics, and biomarker research and, more recently, implementation of the Alzheimer's Association Revised Criteria for diagnosing AD by making plasma biomarker data broadly available for ADRC participants. As such, NCRAD has and continues to play a vital part in the advancement of translational ADRD research
A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects
No full textFailure of septation of the interventricular septum (IVS) is the most common congenital heart defect, but mechanisms for patterning the IVS are largely unknown. Here we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors causes IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the congenital heart defect transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes ventricular septation defects and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects
Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models
No full textSrc homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease
Sex, education and race/ethnicity have distinct effects on amyloid and tau‐PET status
No full textBackground:
Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide.
Method:
Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 (N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education (N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant.
Result:
Female sex was associated with an APOEε4‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex*APOE interactions were observed.
In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:βinteraction=0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2).
In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:βinteraction=‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3).
Conclusion:
In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology
Degradation of the TEAD•YAP/TAZ Transcription Factor Complex by Heterobifunctional Small Molecules that Bind to the TEAD Allosteric Lipid Pocket
No full textCentral kinases of the Hippo tumor suppressor pathway phosphorylate the transcriptional coactivators YAP and TAZ to sequester them in the cytoplasm. In cancer, Hippo pathway kinases have reduced activity, leading to translocation of YAP and TAZ into the nucleus where they engage TEADs and other transcription factors. Here, we explore whether heterobifunctional small molecules that bind to the TEAD allosteric lipid-binding pocket can degrade the TEAD•YAP/TAZ complex. We design and synthesize heterobifunctional molecules that consist of flufenamic acid analogs that bind to the allosteric TEAD lipid pocket, a long and flexible linker, and thalidomide to engage E3 ubiquitin ligase component cereblon. The bifunctional compounds promote ternary complex formation in biochemical assays and mammalian cells but exhibited modest degradation of TEAD, YAP, and TAZ in cancer cells. Methyl ester analogs of these compounds led to substantial proteasomal degradation of the TEAD•YAP/TAZ complex in cancer cells. This work provides a strategy for depletion of nuclear YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities in vivo
Omega-3 supplementation in addition to prenatal vitamins during pregnancy is associated with lower rates of preterm birth and small for gestational age
No full textOmega-3 fatty acids and prenatal vitamins support fetal growth, but most studies assess omega-3 supplementation without accounting for baseline prenatal vitamin use during pregnancy. In this secondary analysis, we obtained data from the large, prospective Nulliparous Mother-to-be (nuMoM2b) cohort study of 9,461 nulliparous individuals. Participants were enrolled through eight clinical sites across the United States. We compared adverse birth outcomes between those taking additional omega-3 supplements beyond standard prenatal vitamin intake (PNV-OM) vs. prenatal vitamins alone (PNV). PNV-OM intake was associated with significantly lower rates of preterm birth (5.04 vs. 8.41%, P < 0.001) and SGA (2.84 vs. 4.48%, P = 0.004). After adjustment for demographic and clinical differences, PNV-OM use remained associated with reduced odds of preterm birth (aOR 0.64, 95% CI: 0.47-0.86, P = 0.004) and SGA (aOR 0.64, 95% CI: 0.42-0.95, P = 0.03). However, given substantial socioeconomic differences between groups and the potential for residual confounding, these findings should be interpreted with caution. Supplemental omega-3 intake during pregnancy may provide an additive benefit beyond prenatal vitamins alone, but randomized trials are needed to determine whether this relationship is causal
P-460. Clinical Presentations and Outcomes of Pediatric Mycoplasma pneumoniae: A Retrospective Chart Review
No full textBackground:
Mycoplasma pneumoniae causes a self-resolving illness in children, but it can also cause severe illness requiring hospitalization. Cases fell during the COVID-19 pandemic, but then surged in Asia in late 2023 and spread globally in 2024. This study aimed to characterize presentations, diagnostic challenges, and outcomes for hospitalized children with confirmed M. pneumoniae infections over 12 months.
Methods:
A retrospective cohort study was conducted at Riley Hospital for Children of all patients admitted to pediatric units with confirmed M. pneumoniae infection from February 2024 to February 2025. Inclusion required a positive PCR of nasopharyngeal swab, bronchoalveolar lavage, or cerebrospinal fluid; a multiplex respiratory panel; or serology. Demographics, comorbidities, clinical presentations, diagnostic workup, treatment regimens, and outcomes were extracted to REDCap. A comparative analysis was done using data from February 2023 to January 2024.
Results:
Analysis identified 122 clinical encounters with 148 positive tests. There were 112/2573 (4.35%) positive molecular respiratory tests for M. pneumoniae, a 20.7-fold increase from the prior 12 months (5/2363; 0.21%), Figure 1. The mean age was 10.0 years (range 1 month-25 years), with 25 (20.3%) under 5 years old. An overview of presentations and M. pneumoniae PCR and serologic test results is available in Table 1. Notable findings include that 26 (21%) patients had isolated extrapulmonary (EP) involvement. Of isolated EP cases, 54% dermatologic and 33% CNS cases were PCR-negative but serology-positive. Viral coinfections were present in 22 cases (18%).
Intensive care unit (ICU) admission was needed for 28 cases (25%), mainly for pulmonary complications (23/28, 82%). Macrolides were given to 91 patients (75%), but 28 (23%) exhibited clinical non-response, requiring escalation to doxycycline or fluoroquinolone. One death occurred (0.8%).
Conclusion:
This study highlights a resurgence of pediatric M. pneumoniae infections in 2024–2025, Extrapulmonary manifestations, especially dermatologic and CNS, were frequent and often PCR-negative, reinforcing the need for serologic testing. Clinicians should be aware of atypical Mycoplasma presentations, diagnostic limitations, and treatment resistance patterns
Real-world comparison of mechanical thrombectomy vs. catheter-directed thrombolysis for the treatment of pulmonary embolism: a single-center retrospective study
No full textA recent multi-site randomized controlled trial, PEERLESS, demonstrated superiority of FlowTriever mechanical thrombectomy (FTMT) to catheter-directed thrombolysis (CDT) in the treatment of intermediate-risk pulmonary embolism using a 5-point composite outcome. The purpose of our study is to review clinical outcomes between these two procedures in actual clinical practice without the use of a composite endpoint using a large sample size. This is a retrospective, single-center analysis of 461 patients who presented with submassive or massive PE and underwent treatment with either FTMT or CDT. No significant difference was observed in 7-day (RR 0.495; p = 0.25) or 30-day mortality (RR 1.347; p = 0.67). There was significantly less risk of procedure-related decompensations within the FTMT group (RR 0.221; p = 0.01). Non-procedure-related decompensations were similar between treatment options (RR 1.091; p = 0.51). ICU LOS was significantly lower for FTMT (mean 1.87 vs. 3.07; p < 0.001) however total LOS was longer within the FTMT (mean 6.85 vs. 5.68; p = 0.008). Similar to PEERLESS, we observed decreased ICU utilization with FTMT in our real-world retrospective data, likely reflecting our practice of ICU admission during thrombolytic administration. We observed slightly lower risk of procedure-related decompensations within the FTMT group, suggesting lower periprocedural morbidity; however, overall mortality between groups was not different