Validating a predictive algorithm for suicide risk with Alaska Native populations.

INTRODUCTION: The American Indian/Alaska Native (AI/AN) suicide rate in Alaska is twice the state rate and four times the U.S. rate. Healthcare systems need innovative methods of suicide risk detection. The Mental Health Research Network (MHRN) developed suicide risk prediction algorithms in a general U.S. METHODS: We applied MHRN predictors and regression coefficients to electronic health records of AI/AN patients aged ≥13 years with behavioral health diagnoses and primary care visits between October 1, 2016, and March 30, 2018. Logistic regression assessed model accuracy for predicting and stratifying risk for suicide attempt within 90 days after a visit. We compared expected to observed risk and assessed model performance characteristics. RESULTS: 10,864 patients made 47,413 primary care visits. Suicide attempt occurred after 589 (1.2%) visits. Visits in the top 5% of predicted risk accounted for 40% of actual attempts. Among visits in the top 0.5% of predicted risk, 25.1% were followed by suicide attempt. The best fitting model had an AUC of 0.826 (95% CI: 0.809-0.843). CONCLUSIONS: The MHRN model accurately predicted suicide attempts among AI/AN patients. Future work should develop clinical and operational guidance for effective implementation of the model with this population.

VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People.

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype-phenotype relationships were assessed by multivariate regression analysis, adjusted for self-reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 -1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e-05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self-reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.

Clonal analysis of HIV-1 genotype and function associated with virologic failure in treatment-experienced persons receiving maraviroc: Results from the MOTIVATE phase 3 randomized, placebo-controlled trials.

Detailed clonal phenotypic/genotypic analyses explored viral-escape mechanisms during maraviroc-based therapy in highly treatment-experienced participants from the MOTIVATE trials. To allow real-time assessment of samples while maintaining a blind trial, the first 267 enrolled participants were selected for evaluation. At failure, plasma samples from 20/50 participants (16/20 maraviroc-treated) with CXCR4-using virus and all 38 (13 maraviroc-treated) with CCR5-tropic virus were evaluated. Of those maraviroc-treated participants with CXCR4-using virus at failure, genotypic and phenotypic clonal tropism determinations showed >90% correspondence in 14/16 at Day 1 and 14/16 at failure. Phylogenetic analysis of clonal sequences detected pre-treatment progenitor CXCR4-using virus, or on-treatment virus highly divergent from the Day 1 R5 virus, excluding possible co-receptor switch through maraviroc-mediated evolution. Re-analysis of pre-treatment samples using the enhanced-sensitivity Trofile® assay detected CXCR4-using virus pre-treatment in 16/20 participants failing with CXCR4-using virus. Post-maraviroc reversion of CXCR4-use to CCR5-tropic occurred in 7/8 participants with follow-up, suggesting selective maraviroc inhibition of CCR5-tropic variants in a mixed-tropic viral population, not emergence of de novo mutations in CCR5-tropic virus, as the main virologic escape mechanism. Maraviroc-resistant CCR5-tropic virus was observed in plasma from 5 treated participants with virus displaying reduced maximal percent inhibition (MPI) but no evidence of IC50 change. Env clones with reduced MPI showed 1-5 amino acid changes specific to each V3-loop region of env relative to Day 1. However, transferring on-treatment resistance-associated changes using site-directed mutagenesis did not always establish resistance in Day 1 virus, and key 'signature' mutation patterns associated with reduced susceptibility to maraviroc were not identified. Evolutionary divergence of the CXCR4-using viruses is confirmed, emphasizing natural selection not influenced directly by maraviroc; maraviroc simply unmasks pre-existing lineages by inhibiting the R5 virus. For R5-viral failure, resistance development through drug selection pressure was uncommon and manifested through reduced MPI and with virus strain-specific mutational patterns.