Meta-analysis of genome-wide association studies of stable warfarin dose in patients of African ancestry.

Warfarin dose requirements are highly variable due to clinical and genetic factors. While genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWAS) in four African cohorts from Uganda, South Africa, and Zimbabwe, totalling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included two African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n=316) and the University of Alabama at Birmingham (n=199). Following the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci (the CYP2C cluster SNP rs12777823 and CYP2C9 in chromosome 10; VKORC1 in chromosome 16). The genome-wide significance threshold was set at PA revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P=3.64×10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, our meta-analysis of six cohorts of warfarin-treated patients of African ancestry reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements. We also identified a new locus (MALL), that still requires direct evidence of biological plausibility

User‐Centered Design to Develop Automated Short Message Service Messaging for Patient Support of Rheumatic Heart Disease Secondary Antibiotic Prophylaxis

Background The Active Community Case Management Platform is a cloud‐based technology developed to facilitate rheumatic heart disease case management by health care providers. This study aimed to design and pilot an automated short message service (SMS) intervention to support secondary prophylaxis adherence. Methods and Results We developed a concise library of messages to support secondary antibiotic prophylaxis. The SMS intervention used TextIT, an interface that enables users to send out interactive SMS messages at scale. The message bank was piloted in a cohort of 50 patients with rheumatic heart disease randomized into 2 groups. Group 1 received standard support (nurse‐led/Active Community Case Management Platform). Group 2 received standard support plus SMS intervention for 2 months in the Lira and Gulu districts of Northern Uganda. We collected qualitative data on participants' experiences and assessed treatment adherence. Using a sequential user‐centered process consisting of 4 phases (phases 1–4), we developed a message bank (n=43) deployed during our pilot study. There were no between‐group differences in treatment adherence or acceptance. Interviews of participants indicated that the intervention was viewed positively. A total of 75% of SMS recipients responded to the messages, and 25% called the study staff to acknowledge receipt of text messages. Conclusions This study has successfully developed a bank of SMS messages to support secondary antibiotic prophylaxis adherence. We have demonstrated the feasibility and acceptability of SMS technology in rheumatic heart disease care management. Future work will include integrating automated SMS into the Active Community Case Management Platform and a larger study of integrated SMS to reduce health care worker burden for patient support and improve adherence to secondary antibiotic prophylaxis

Pre-intervention wait time and survival in people with rheumatic heart disease in Uganda

BACKGROUND: There is an unmet surgical burden among people living with rheumatic heart disease (RHD) in Uganda. Nevertheless, risk factors associated with time to first intervention and preoperative mortality is poorly understood. METHODS: Individuals with RHD who met indications for valve surgery were identified using the Uganda National RHD Registry (Jan. 2010- Aug. 2022). Kaplan-Meier estimates and multivariable Cox proportional hazard models were utilized. RESULTS: 64% of the cohort with clinical RHD (1452 of 2269) met criteria for index operation. Of those, 13.5% obtained surgical intervention while 30.6% died before surgery. The estimated likelihood of first surgery was 50% at 9.3 years of follow up (95% CI 8.1-upper limit not reached). Intervention was more likely in men vs. women (hazard ratio [HR] 1.78; 95% CI 1.21-2.64), those with post-secondary education vs. primary school or less (HR 3.60; 95% CI 1.88-6.89), and those with history of atrial fibrillation (HR 2.78; 95% CI 1.63-4.76). Surgery was less likely for adults (vs. those \u3c18 years; HR 0.49; 95% CI 0.32-0.77) and those with NYHA class III/IV (vs. I/II; HR 0.51; 95% CI 0.32-0.83). The median preoperative survival time among those awaiting surgery was 4.6 years (95% CI, 3.9-5.7). History of infective endocarditis, RV dysfunction, pericardial effusion, atrial fibrillation, and having surgical indications for multiple valves were associated with increased mortality. CONCLUSIONS: Our analysis revealed a prolonged time to first surgical intervention and high pre-intervention mortality for RHD in Uganda, with factors such as age, sex, and education level remaining barriers to obtaining surgery

Deployment of Point‐of‐Care Echocardiography to Improve Cardiac Diagnostic Access Among American Indians

Background American Indians face significant barriers to diagnosis and management of cardiovascular disease. We sought to develop a real‐world implementation model for improving access to echocardiography within the Indian Health Service, the American Indian Structural Heart Disease Partnership. Methods and Results The American Indian Structural Heart Disease Partnership was implemented and evaluated via a 4‐step process of characterizing the system where it would be instituted, building point‐of‐care echocardiography capacity, deploying active case finding for structural heart disease, and evaluating the approach from the perspective of the clinician and patient. Data were collected and analyzed using a parallel convergent mixed methods approach. Twelve health care providers successfully completed training in point‐of‐care echocardiography. While there was perceived usefulness of echocardiography, providers found it difficult to integrate screening point‐of‐care echocardiography into their workday given competing demands. By the end of 12 months, 6 providers continued to actively utilize point‐of‐care echocardiography. Patients who participated in the study felt it was an acceptable and effective approach. They also identified access to transportation as a notable challenge to accessing echocardiograms. Over the 12‐month period, a total of 639 patients were screened, of which 36 (5.6%) had a new clinically significant abnormal finding. Conclusions The American Indian Structural Heart Disease Partnership model exhibited several promising strategies to improve access to screening echocardiography for American Indian populations. However, competing priorities for Indian Health Service providers' time limited the amount of integration of screening echocardiography into outpatient practice. Future endeavors should explore community‐based solutions to develop a more sustainable model with greater impact on case detection, disease management, and improved outcomes

Stable warfarin dose prediction in sub-Saharan African patients: A machine-learning approach and external validation of a clinical dose-initiation algorithm

Warfarin remains the most widely prescribed oral anticoagulant in sub‐Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine‐learning techniques in predicting stable warfarin dose in sub‐Saharan Black‐African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub‐Saharan Africa (War‐PATH) clinical dose–initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018–July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39–13.76) was the best performing machine‐learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75–19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine‐learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45–14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine‐learning techniques. We have also externally validated our previously developed clinical dose–initiation algorithm, which is being prospectively tested for clinical utility

A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients.

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms

DataSheet2_A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients.XLSX

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.</p

DataSheet1_A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients.zip

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.</p