Clinical Consortium Research Articles

Patterns of pharmacogenetic variation in nine biogeographic groups.

Frequencies of pharmacogenetic (PGx) variants are known to differ substantially across populations but much of the available PGx literature focuses on one or a few population groups, often defined in nonstandardized ways, or on a specific gene or variant. Guidelines produced by the Clinical Pharmacogenetic Implementation Consortium (CPIC) provide consistent methods of literature extraction, curation, and reporting, including comprehensive curation of allele frequency data across nine defined "biogeographic groups" from the PGx literature. We extracted data from 23 CPIC guidelines encompassing 19 genes to compare the sizes of the populations from each group and allele frequencies of altered function alleles across groups. The European group was the largest in the curated literature for 16 of the 19 genes, while the American and Oceanian groups were the smallest. Nearly 200 alleles were detected in nonreference groups that were not reported in the largest (reference) group. The genes CYP2B6 and CYP2C9 were more likely to have higher frequencies of altered function alleles in nonreference groups compared to the reference group, while the genes CYP4F2, DPYD, SLCO1B1, and UGT1A1 were less likely to have higher frequencies in nonreference groups. PGx allele frequencies and function differ substantially across nine biogeographic groups, all but two of which are underrepresented in available PGx data. Awareness of these differences and increased efforts to characterize the breadth of global PGx variation are needed to ensure that implementation of PGx-guided drug selection does not further widen existing health disparities among populations currently underrepresented in PGx data.

Sensitivity of Advanced Magnetic Resonance Imaging to Progression over Six Months in Early Spinocerebellar Ataxia.

Clinical trials for upcoming disease-modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes. READISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations. A total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3-T MR scanning at baseline and a median [interquartile range] follow-up of 6.2 [5.9-6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6-month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate. Rate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls (P < 0.005), with high effect sizes (Cohen's d = 1-2) and moderate-to-high responsiveness (|standardized response mean| = 0.6-0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups. Diffusion MRI is sensitive to disease progression at very early-stage SCA1 and SCA3 and may provide a >5-fold reduction in sample sizes relative to SARA as endpoint for 6-month-long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Implementing pharmacogenetic testing to optimize proton-pump inhibitors use among Indian population based on CPIC-CYP2C19-PPI dosing guidelines: The need of the hour.

Proton-pump inhibitors (PPIs) are widely prescribed to decrease stomach acid and treat various acid-related Gastrointestinal tract (GIT) diseases. However, genetic variations, particularly in the CYP2C19 gene, affect PPIs metabolism and efficacy. Variants in CYP2C19 can result in different rates of PPI metabolism, influencing their effectiveness. Personalized medicine strategies, such as genotyping for CYP2C19, have the potential to enhance the effectiveness of PPI therapy and patient safety. This review aims to describe the relevance of CYP2C19 genetic profiling in the indian population, including normal function (e.g. CYP2C19*1, *11, *13, *15, *18, *28, and 38), decreased function (e.g., CYP2C19*9, *10, *16, *19, *25, and 26), loss of function (e.g., CYP2C19*2, *3, *4, *5, *6, *7, *8, *22, *24, *35, *36, and *37), and increased function (e.g., CYP2C19*17) variants. This review also examines the clinical pharmacogenomics implementation consortium (CPIC)-CYP2C19-PPI guidelines to highlight the importance of pharmacogenomics (PGx)-informed personalized PPI therapy for gastroesophageal reflux disease and peptic ulcer disease treatment. On average, each person in India possesses eight pharmacogenetic (PGx) variants that can be clinically significant, underscoring the need for preemptive testing. Implementing CYP2C19 genetic testing in India requires expanding laboratory capacity, increasing accessibility in primary care, increasing public awareness, collaboration between pharmacovigilance and PGx programs, investing in advanced sequencing technologies, data management systems, and integration with electronic health records and clinical decision support systems. Addressing challenges such as genetic diversity, socioeconomic factors, health-care access issues, and shortage of trained professionals is essential for implementation. Due to the lack of definitive country-specific policies and PGx guidelines from Indian drug regulatory agencies, guidelines from international consortia such as the Clinical Pharmacogenetics Implementation Consortium and drug labeling offer crucial foundational evidence. This evidence can be used to enhance patient outcomes and ensure the safe and effective use of PPIs in India.

Advanced practice nurse pharmacogenomics capacity and utilization.

Guided by Clinical Pharmacogenomic Implementation Consortium (CPIC) guidelines for >140 medications, pharmacogenomic tests inform medication selection and dosing to optimize efficacy while minimizing toxicities. This study assessed pharmacogenomic self-reported curricular content, knowledge, skills, attitudes, and usage in advanced practice registered nurses (APRNs) with prescriptive privileges. An online survey was administered assessing pharmacogenomic curricular content, knowledge, skills, attitudes, and usage. Data from 266 APRNs were analyzed. Most graduated with their highest nursing degree ∼10 years ago and reported pharmacogenomic curricular content ( n = 124, 48%). Pharmacogenomic curricular content was associated with pharmacogenomic familiarity ( p = .045) but not with knowledge confidence ( p = .615). Pharmacogenomic usage, defined as ordering a pharmacogenomic test within the past year, was low ( n = 76, 29%) and most ( n = 210, 84%) reported never using CPIC Guidelines. Advanced practice registered nurses ( n = 162) who did not anticipate ordering a pharmacogenomic test in the next year ( n = 77, 48%) indicated that they did not know what test to order. Deficits were identified in APRN pharmacogenomic knowledge and skills despite academic training. Most reported not ordering pharmacogenomic tests, did not know what test to order, and did not use CPIC guidelines. Pharmacogenomics is a quality and safety issue. Academic training did not result in practice integration and most reported capacity deficits. Recommendation for overcoming academic deficits include: (1) assessment of pharmacogenomics curricular content and faculty teaching capacity; (2) training addressing identified deficiencies; and (3) Commission of Collegiate Nursing Education policies that include pharmacogenomics in advanced pharmacology. Practicing APRN plans include on-the-job training and/or mandatory training at the time of relicensure.

Liver disease and transplantation in telomere biology disorders: An international multicenter cohort.

Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. Group A ("Advanced") included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M ("Mild") included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

Low Vitamin D Levels in Patients with Symptoms of Gastroparesis: Relationships with Nausea and Vomiting, Gastric Emptying and Gastric Myoelectrical Activity

Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied.AimsTo determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp.Methods25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and dysrhythmic ranges, was recorded using electrogastrography.ResultsOverall, vitamin D levels were low (< 30 ng/ml) in 288 of 513 (56.1%) patients with symptoms of Gp (206 of 376 (54.8%) patients with delayed gastric emptying (Gp) and 82 of 137 (59.9%) patients with symptoms of Gp and normal gastric emptying). Low vitamin D levels were associated with increased nausea and vomiting (P < 0.0001), but not with fullness or bloating subscores. Low vitamin D levels in patients with Gp were associated with greater meal retention at four hours (36% retention) compared with Gp patients with normal vitamin D levels (31% retention; P = 0.05). Low vitamin D in patients with normal gastric emptying was associated with decreased normal 3 cpm GMA before (P = 0.001) and increased tachygastria after WLST (P = 0.01).ConclusionsLow vitamin D levels are present in half the patients with symptoms of gastroparesis and are associated with nausea and vomiting and gastric neuromuscular dysfunction.

Pilot study to evaluate automated laboratory data transfer into Medidata Rave for NCI-supported pediatric cooperative group trials in the Pediatric Early Phase Clinical Trials Network (PEP-CTN) and Pediatric Brain Tumor Consortium (PBTC).

e23017 Background: Electronic data capture (EDC) has the potential to improve data accuracy and efficiency. As an initial step toward improvement in the accuracy and completeness of data acquisition for clinical trials, PEP-CTN and PBTC conducted a pilot project to assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records to the NCI Medidata Rave EDC that is housed within each consortium’s Uniform Resource Locator (URL). The pilot aimed to assess feasibility of automated laboratory data extraction and transfer and to evaluate discrepancies between laboratory data obtained retrospectively through automated extraction and data manually ascertained during the original conduct of the study. Methods: Data from patients treated on 7 completed PEP-CTN or PBTC trials at 7 sites were included. Each consortium created a Rave EDC study to receive data. Sites used the ExtractEHR R package or local methods to map and extract laboratory data for designated patients. Post-extraction data were uploaded via a file transfer protocol (FTP) periodically polled by the Rave Batch Uploader (BU) that uploaded data into Rave EDC. After successful upload, extracted data (EHR) were compared to laboratory data that had been manually reported when patients were enrolled on the trials (MANUAL) and discrepancies were identified. Discrepancy types were categorized and 2 sites reviewed discrepancies at their sites to identify reasons. Results: Preparation and support for automated extraction and upload required significant central operations and local site effort. All sites successfully extracted specified laboratory data and had at least one complete upload via BU to Rave EDC. There were more laboratory data in the EHR datasets than MANUAL datasets across most sites. These results were due to multiple EHR results on a given day or from additional days in the study window than specified in MANUAL. Sites verified that laboratory data in MANUAL and not EHR were stored in un-extractable formats (e.g. PDFs) or outside laboratories. Most discrepant results in both EHR and MANUAL were mismatched values or units. Conclusions: This pilot demonstrated the feasibility of implementing automated laboratory data extraction and transfer in the cooperative group setting. Automated data transfer requires significant central operational support as well as detailed protocols, data specifications, and case report forms and engagement of site technical teams to be successful, but also permits collection of more comprehensive data with reduced manual data entry. Clinical trial information: NCT05020951 .

Utilizing Pharmacogenomic Data for a Safer Use of Statins among the Emirati Population.

Statins are the most prescribed lipid-lowering drugs worldwide. The associated adverse events, especially muscle symptoms, have been frequently reported despite their perceived safety. Three pharmacogenes, the solute carrier organic anion transporter family member 1B1 (SLCO1B1), ATP-binding cassette subfamily G member 2 (ABCG2), and cytochrome P450 2C9 (CYP2C9) are suggested as safety biomarkers for statins. The Clinical Pharmacogenomic Implementation Consortium (CPIC) issued clinical guidelines for statin use based on these three genes. The present study aimed to examine variants in these pharmacogenes to predict the safety of statin use among the Emirati population. Analyzing 242 whole exome sequencing data at the three genes enabled the determination of the frequencies of the single nucleotide polymorphisms (SNPs), annotating the haplotypes and the predicted functions of their proteins. In our cohort, 29.8% and 5.4% had SLCO1B1 decreased and poor function, respectively. The high frequency warns of the possibility of significant side effects of some statins and the importance of pharmacogenomic testing. We found a low frequency (6%) of the ABCG2:rs2231142 variant, which indicates the low probability of Emirati patients being recommended against higher rosuvastatin doses compared with other populations with higher frequencies of this variant. In contrast, we found high frequencies of the functionally impaired CYP2C9 alleles, which makes fluvastatin a less favorable choice. Among the sparse studies available, the present one demonstrates all SLCO1B1 and CYP2C9 function-impairing alleles among Emiratis. We highlighted how population-specific pharmacogenomic data can predict safer choices of statins, especially in understudied populations.

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world

Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p=0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p<0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p<0.001). Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

555 Design Lab Methodology Supports Innovation in Clinical Trials

OBJECTIVES/GOALS: Since 2017, we have used the Design Lab methodology to support investigators taking innovative approaches to clinical effectiveness trial design. To date we have held 12 Design Labs and this year we are creating a handbook that will support dissemination of this approach across the Clinical and Translational Science Award consortium. METHODS/STUDY POPULATION: The Clinical Trial Design Lab brings together a multi-stakeholder group to consider innovative and impactful clinical trial designs. An investigative team is selected from a competitive pool of applicants, after which expert-led consultations support the investigator team to think about evidence generation in the context of the full treatment development pathway. Teams map the stakeholders at each step of this pathway (e.g. clinicians, patients, researchers, funders, industry experts, policy experts, regulatory experts, payers) and consider innovative design solutions. These consultations prepare investigators for an event that involves all stakeholders in a structured and facilitated discussion about trial designs that generate the best evidence and increase potential for health impact. RESULTS/ANTICIPATED RESULTS: The result of our work will be a set of Design Lab principles, a handbook with templates that support stakeholder mapping and structured discussions, and educational resources to accompany the handbook. The work is supported by a literature review that characterizes the multi-component processes included in the Design Lab, situates them within the larger context of team science interventions, and lays groundwork for the development of process metrics and impact evaluation criteria to assess the Design Lab method. In this poster presentation, we will share our multi-component broadly engaged team science approach, provide a brief outline of the principles and educational resources, and include an early version of the evaluation criteria. DISCUSSION/SIGNIFICANCE: Broadly engaged team science supports innovative thinking about study design and is especially important in the development of clinical trials. We have grown the Design Lab program of work over the past seven years and are now able to characterize our team science methodology and support others to use this approach to innovate for health impact.

Large-scale next generation sequencing based analysis of SLCO1B1 pharmacogenetics variants in the Saudi population

BackgroundSLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East.MethodsThe dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC).ResultsWe identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations.ConclusionsThe data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.

Implementation and Evaluation of a National Well-Being Curriculum for KL2 Scholars.

Introduction: The study aimed to pilot test a well-being curriculum for KL2 scholars to be used across the Clinical and Translational Science Award consortium. Methods: Between November 2022, and May 2023, 36 KL2 scholars from 25 hubs participated in the program. The General Well-Being Index for U.S. Workers and the Patient Reported Outcomes Measurement Information System (PROMIS-29) were completed by scholars before and after the program. Results: Postparticipation, there was a trend of improvement in the domains of well-being, sleep, anxiety, and fatigue. Conclusion: Implementing a virtual synchronous well-being curriculum allowed the scholars to connect across the consortium and improve their well-being.

Optimizing pharmacogenomic decision-making by data science

Healthcare systems have made rapid progress towards combining data science with precision medicine, particularly in pharmacogenomics. With the lack of predictability in medication effectiveness from patient to patient, acquiring the specifics of their genotype would be highly advantageous for patient treatment. Genotype-guided dosing adjustment improves clinical decision-making and helps optimize doses to deliver medications with greater efficacy and within safe margins. Current databases demand extensive effort to locate relevant genetic dosing information. To address this problem, Patient Optimization Pharmacogenomics (POPGx) was constructed. The objective of this paper is to describe the development of POPGx, a tool to simplify the approach for healthcare providers to determine pharmacogenomic dosing recommendations for patients taking multiple medications. Additionally, this tool educates patients on how their allele variations may impact gene function in case they need further healthcare consultations. POPGx was created on Konstanz Information Miner (KNIME). KNIME is a modular environment that allows users to conduct code-free data analysis. The POPGx workflow can access Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines and subsequently be able to present relevant dosing and counseling information. A KNIME representational state transfer (REST) application program interface (API) node was established to retrieve information from CPIC and drugs that are exclusively metabolized through CYP450, and these drugs were processed simultaneously to demonstrate competency of the workflow. The POPGx program provides a time-efficient method for users to retrieve relevant, patient-specific medication selection and dosing recommendations. Users input metabolizer gene, genetic allele data, and medication list to retrieve clear dosing information. The program is automated to display current guideline recommendations from CPIC. The integration of this program into healthcare systems has the potential to revolutionize patient care by giving healthcare practitioners an easy way to prescribe medications with greater efficacy and safety by utilizing the latest advancements in the field of pharmacogenomics.

Pharmacogenomic allele coverage of genome-wide genotyping arrays: a comparative analysis.

The use of genome-wide genotyping arrays in pharmacogenomics (PGx) research and clinical implementation applications is increasing but it is unclear which arrays are best suited for these applications. Here, we conduct a comparative coverage analysis of PGx alleles included on genome-wide genotyping arrays, with an emphasis on alleles in genes with PGx-based prescribing guidelines. Genomic manifest files for seven arrays including the Axiom Precision Medicine Diversity Array (PMDA), Axiom PMDA Plus, Axiom PangenomiX, Axiom PangenomiX Plus, Infinium Global Screening Array, Infinium Global Diversity Array (GDA) and Infinium GDA with enhanced PGx (GDA-PGx) Array, were evaluated for coverage of 523 star alleles across 19 pharmacogenes included in prescribing guidelines developed by the Clinical Pharmacogenetic Implementation Consortium and Dutch Pharmacogenomics Working Group. Specific attention was given to coverage of the Association of Molecular Pathology's Tier 1 and Tier 2 allele sets for CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, NUDT15, TPMT and VKORC1 . Coverage of the examined PGx alleles was highest for the Infinium GDA-PGx (88%), Axiom PangenomiX Plus (77%), Axiom PangenomiX (72%) and Axiom PMDA Plus (70%). Three arrays (Infinium GDA-PGx, Axiom PangenomiX Plus and Axiom PMDA Plus) fully covered the Tier 1 alleles and the Axiom PangenomiX array provided full coverage of Tier 2 alleles. In conclusion, PGx allele coverage varied by gene and array. A superior array for all PGx applications was not identified. Future comparative analyses of genotype data produced by these arrays are needed to determine the robustness of the reported coverage estimates.

Capabilities and Limitations of Student-Led Free Vision Screening Programs in the United States.

The Consortium of Student-Led Eye Clinics (CSLEC), founded in 2021, administered a comprehensive survey to document the types of services, most common diagnoses, and follow-up care protocols offered by student-led free vision screening programs (SLFVSP) in the United States. An 81-question institutional review board (IRB)-approved survey was administered to student-led vision screening eye clinics from October 1, 2022 to February 24, 2023. Sixteen SLFVSPs were included in the final analysis, of which 81% (n = 13) conducted variations of fundoscopic examinations and 75% (n = 12) measured intraocular pressure. Cataracts and diabetic retinopathy were reported as the most frequent diagnoses by the majority of SLFVSPs (n = 9, 56%); non-mobile SLFVSPs more commonly reported cataract as a frequent diagnosis (P < 0.05). Most patients screened at participating programs were uninsured or met federal poverty guidelines. Prescription glasses were offered by 56% of the programs (n = 9). SLFVSPs that directly scheduled follow-up appointments reported higher attendance rates (66.5%) than those that only sent referrals (20%). Transportation was the most cited barrier for follow-up appointment attendance. SLFVSPs, one community vision screening initiative subtype, vary significantly in scope and capabilities of identifying vision threatening disease. The follow-up infrastructure is not uniformly robust and represents a key target for improving care delivery to at-risk populations. The CSLEC aims to develop a consensus-based standardization for the scope of screening services, offer guidelines for diagnostic criteria, promote real-time data stewardship, and identify means to improve follow-up care mechanisms in member communities.

Translation in action: Influence, collaboration, and evolution of COVID-19 research with Clinical and Translational Science Awards consortium support.

The National Institutes of Health (NIH)'s Clinical and Translational Science Awards (CTSA) consortium aims to accelerate translational processes that move discoveries from bench to bedside. The coronavirus disease 2019 (COVID-19) pandemic presented unmatched challenges and applications for CTSA hubs nationwide. Our study used bibliometrics to assess features of COVID-19 publications supported by the national CTSA program to characterize the consortium's response to the pandemic. Our goal was to understand relative scientific influence, collaboration across hubs, and trends in research emphasis over time. We identified publications from NIH's curated iSearch COVID-19 Publication Portfolio from February 2020 to February 2023; 3234 peer-reviewed articles relevant to COVID-19 cited a CTSA grant. All 66 CTSA hubs were represented, with large-size and longstanding hubs contributing more publications. Most publications cited UL1 grants, 457 cited KL2/TL1 training grants, and 164 cited multiple hub grants. Compared to a random sample of non-CTSA-supported COVID-19 publications, the CTSA portfolio exhibited greater clinical relevance, more human research, and higher altmetric and citation influence. Results were similar for multi-hub publications involving networked initiatives like multi-site clinical trials or the National COVID-19 Cohort Collaborative. Shifts from molecular/cellular-oriented research toward human-oriented research over time were evident, demonstrating translation in action. Results illuminate how the CTSA consortium confronted the pandemic through high-quality projects oriented toward human research, working across hubs on high-value collaborations, advancing along the translational spectrum over time. Findings validate CTSA hubs as critical support structures during health emergencies.

The Time for Specialty Care Collaboration is Now: How the Consortium of Student-Led Eye Clinics Makes the Case

The Consortium of Student Led Eye Clinics (CSLEC) was founded in 2021 as a part of the Editorial Fellowship offered by the Journal of Student Run Free Clinics (JSRC), to increase collaboration between vision screening programs in the United States. So far, the CSLEC has recruited over a dozen programs, initiating a mentorship process to pair new organizations with long-established clinics. The CSLEC has also worked to generate bi-monthly workshops highlighting different operational strategies and insights from member institutions. With a multi-institution research team, a comprehensive survey has been an ongoing priority to assess baseline characteristics of vision screening programs, including from non-CSLEC member institutions. Ultimately, to further optimize and standardize operations across vision screening programs, the CSLEC seeks to incorporate the expertise of all member institutions to integrate consensus-based decision making to serve as a legitimate source of access to eye care, ultimately to identify and treat vision-threatening illness in populations without stable access.

Hemophilia A Research Program (HARP): A Novel Study Design for a Multicenter and Decentralized Prospective Observational Longitudinal Cohort Study in Hemophilia A

Background: Hemophilia A is a rare X-linked bleeding disorder caused by factor VIII (FVIII) deficiency. There is a compelling need in hemophilia to better understand the causes of bleeding in females and the factors underlying FVIII inhibitor development. To meet this need we are establishing a new NHLBI funded Hemophilia A Analytical Cohort Research Program (HARP) as part of a public-private partnership to support an Intergenerational Precision Medicine Program for the study of factor VIII (FVIII) immunogenicity in severe hemophilia A (Harpf8.org). The HARP objectives are: 1) Longitudinal assessment of bleeding in females with a severe hemophilia A genotype beginning in pregnancy; 2) Longitudinal assessment of anti-FVIII antibody formation in severe hemophilia A from birth through at least the first 2 years of life; 3) Studies of causes of bleeding in females with a severe hemophilia A genotype; 4) Studies of the immune response to FVIII in severe hemophilia A; 5) Development of a well-curated annotated data set of genetic, hemophilia, immune, environmental, psychosocial, and quality of life metrics; 6) Development of a multi-omics and immunologic biospecimen resource; and 7) Development of the hemophilia analytical Portal (F8portal.org). Study design: The HARP is a multicenter and decentralized prospective observational longitudinal cohort study beginning in pregnancy. It will follow 50 mother-baby pairs where the babies have severe hemophilia A and the mothers have a severe hemophilia A genotype. The private Clinical Consortium (CC) will oversee the study throughout the U.S., including sites that care for the mothers (up to 200 sites) and sites that care for the child (up to 70 sites). The CC will also conduct decentralized aspects of the study including collection of patient reported outcomes and local sample collection. The primary maternal endpoint is primary postpartum hemorrhage; the primary pediatric endpoint is rate of development of humoral immune response to FVIII and proportion that progress to clinical inhibitors. Mother and child secondary endpoints reflect the diverse research the HARP resource will support. Inclusion criteria for the pregnant person are: Pregnant and prior to 37 weeks gestation, known or at-risk to have a severe hemophilia A genotype, pregnant with a fetus at-risk for severe hemophilia A, ability to give informed consent, and &amp;gt; 18 years old. Inclusion criteria for the child are: severe hemophilia A, born to a person in the study. Exclusion/discontinuation criteria are: Presence of another significant bleeding disorder in mother or child; mother age &amp;lt;18 years; no fetus is at-risk to inherit severe hemophilia A; the child does not have severe hemophilia A; the child has a severe immune disorder; the mother or child participates in another study with blood collection volumes that exceed safety limits; mother's or child's healthcare will be outside the U.S.; the mother is a prisoner; any other reason that in the opinion of the investigator a subject is unsuitable for the study Summary: The HARP innovates in multiple areas of clinical study design to conduct a national prospective longitudinal intergenerational study in a rare disorder beginning in pregnancy. The structure includes a new multidisciplinary CC, systematic inclusion of Lived Experience Experts, strategies for broad community engagement, recruitment, and retention, and decentralized operations. This cohort will enable deep characterization, including genomics and other -omics, on pregnancy-associated bleeding and drivers of FVIII inhibitors in hemophilia A. The HARP Shareable Resource will be comprised of well annotated data and biological samples accessible to researchers through a portal, F8portal.org, and a linked biorepository.

428. Risk Stratification and Clinical Outcomes in a Mixed Vaccination Cohort of COVID-19 Patients Admitted in a Tertiary Hospital Using ISARIC 4C Scores

Abstract Background The risk of clinical deterioration and death with the use of prognostic tools remain necessary for strategic planning among COVID-19 patients. The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) developed and validated Coronavirus Clinical Characterization Consortium (4C) scores to predict clinical deterioration and mortality. ISARIC 4C scores uses readily available clinical parameters. With the increasing uptake of COVID-19 vaccine, there is a need to evaluate these tools. The study examined a cohort of fully vaccinated (FV), partially vaccinated (PV) and unvaccinated (UV) COVID-19 patients and determined their clinical outcomes and stratified risks using ISARIC 4C scores. Methods We reviewed medical records of confirmed COVID-19 patients admitted to a single tertiary hospital between May 2021 and April 2022. Vaccination status were classified as FV, PV and UV. The primary outcome was in-hospital mortality. Baseline data were collected and predictors recorded upon admission were used to calculate the 4C scores. Multiple logistic regression analysis was used to determine the association of vaccination status and 4C Deterioration and Mortality scores with in-hospital mortality. STATA 14 was used for data analysis and p&amp;lt; 0.05 was considered statistically significant. Results A total of 301 confirmed COVID-19 patients were included and 46.5% were fully vaccinated. FV patients had significantly lower CRP (p&amp;lt; 0.0001), had higher mean oxygen saturation (p&amp;lt; 0.0001), had lower mean mortality score (p=0.004), had lower mean % risk for deterioration (p&amp;lt; 0.0001) and had significantly lower 30-day mortality (&amp;lt; 0.0001) compared to those UV and PV. Patient who died had significantly higher mean age (p=0.001), lower mean lymphocyte ratio (p=0.0004), had significantly higher mean deterioration and mortality score (p&amp;lt; 0.0001). Being fully vaccinated was associated with lower risk for mortality (OR=0.4, 95%CI=0.2 to 0.7). Conclusion Fully vaccinated patients were at lower risk for deterioration and mortality. High ISARIC 4C scores were also significantly associated with higher risk for mortality. Risk stratification tools should be utilized in COVID-19 management as they provide a helpful means to identify patients at risk for worse outcomes. Disclosures All Authors: No reported disclosures

Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome.

Amitriptyline (AT) is recommended as first-line prophylactic therapy in patients with cyclic vomiting syndrome (CVS). However, significant side effects limit its use and dosing is based on trial and error. Though the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, this is not followed in clinical practice. This pilot study determined CYP2C19 and CYP2D6 genotypes and ascertained its association with adverse drug reactions (ADRs), clinical response, and serum concentration of AT and nortriptyline in a well-characterized cohort of adults with CVS. Of 46 subjects with CVS, age 33 ± 12 years, 61% female, 85% Caucasian, a third (33%) had normal CYP2C19 metabolizer status, while 4% were poor, and 43% were ultrarapid metabolizers. Most (61%) had normal CYP2D6 genotype while 9% were poor and 2% were ultra-rapid metabolizers. There was no statistically significantassociation between genotype and ADRs, clinical response or serum drug concentration. There was a trend towards significance between genotype and clinical response, with 64% of responders having normal CYP2D6 metabolism versus 36% of nonresponders (p = 0.06). ADRs were encountered in 46% of patients with 28% discontinuing the medication as a result. A subset of patients with CVS have dysfunctional alleles of CYP2C19 and CYP2D6. Larger prospective studies to evaluate the clinical impact of pharmacogenomic testing in CVS are needed. This has the potential to optimize clinical management, predict ADRs and allow for personalized therapy.