Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis
ID: NCT06535542
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This pilot study investigates integrating whole genome sequencing and digital twin technology for managing hypercholesterolemia in Abu Dhabi clinics. It aims to establish protocols for larger future studies and incorporate genomic insights into routine medical care.
Read Full Scientific Objectives & Methods
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the Middle East, with hypercholesterolemia being a significant contributor. Genetic mechanisms of hypercholesterolemia in this region are not well understood. Autosomal dominant hypercholesterolemia is a major factor, yet only \~7% of Emiratis with familial hypercholesterolemia (FH) have these mutations. In 2013, Talmud et al. identified common variants through genome-wide association studies (GWAS) that suggest a polygenic cause for hypercholesterolemia in mutation-negative FH patients. A polygenic risk score based on 12 SNPs was validated in White European populations and is used in the UK's NHS diagnostic pipeline. Distinguishing polygenic hypercholesterolemia from FH without genetic testing is challenging. These patients exhibit familial moderate hypercholesterolemia and early coronary heart disease, with elevated LDL-C, normal triglycerides, and no tendon xanthoma. Their cardiovascular risk is similar to monogenic FH with age. Statins, though commonly prescribed for ASCVD prevention, can cause musculoskeletal symptoms leading to poor adherence, discontinuation, elevated cholesterol, and increased cardiovascular risk. Many patients fail to achieve target LDL-C levels due to suboptimal dosing. Certain gene variants increase the risk of statin side effects. This study seeks to integrate whole genome sequencing (WGS) technology in a clinical setting through an innovative digital twin platform. This platform allows clinicians to assess monogenic and polygenic risks in real-time and make informed statin prescribing and management decisions.
Participants in this arm will have their blood sample analyzed by whole-genome sequencing (WGS) and will be given access to Predictiv™ Deoxyribonucleic acid (DNA)-based digital twin platform, a web-based interactive application with WGS results. The platform will include positive monogenic and polygenic Familial Hypercholesterolemia results and pharmacogenomics results on statins and clopidogrel. A report of positive monogenic variants will be included in their medical record. This may also include genes on the American College of Medical Genetics and Genomics (ACMG) secondary findings (SF) version 3.2 list if the participant consents to receive these incidental findings. The report will only include pathogenic, likely pathogenic, and variant of uncertain significance (VUS) results.
Treatment Arms Description
20 participants who are randomized to have whole-genome sequencing performed on their sample and given access to Predictiv™ Digital Twin. These participants will meet with a genetic counselor for results disclosure and training to access the Predictiv™ Digital Twin platform.
20 participants who are randomized to not have whole-genome sequencing performed on their sample. These participants will have standard-of-care familial hypercholesterolemia (FH) evaluation using medical history and family history only. They will not receive genetic results or Predictiv™ Digital Twin results as part of this study.
- Patients with 2 or more LDL-C levels greater than 190 mg/dL or 5.0 mmol/L in the past 12 months
- Undiagnosed patients meeting Possible, Probable or Definitive FH criteria according to Dutch Lipid Clinic Network (DLCN) criteria (Eur Heart J. 2011 Jul;32(14):1769-818. doi: 10.1093/eurheartj/ehr158. Epub 2011 Jun 28.)
- Patients who have not been on anti-lipidemic medication in the past 3 months
- Ages 18-55
- Emirati national
- All patients must be fluent in English or Arabic
- \- Patients who do not meet the above criteria
- Patients with a previous diagnosis of FH
- Patients with a progressive debilitating illness
- Patient with untreated hypothyroidism, history of proteinuria, obstructive liver disease, chronic renal failure, human immunodeficiency virus infection, or on immunosuppressant or steroid or psychiatric medications
- Patients with untreated clinical anxiety or depression (as measured by a Hospital Anxiety and Depression Scale (HADS) score of ≥ 16 on the depression subscale)
- Patients who are pregnant
Primary Outcome Measures
- Diagnostic capabilities — Time Frame: From consent date until first documented report, up to 6 months
Diagnostic yield of standard-of-care (based on medical and family history) versus whole genome sequencing (WGS) for identifying monogenic and polygenic familial hypercholesterolemia.
View Secondary Outcome Measures (6)
- Prognostic capabilities of standard-of-care — Time Frame: Baseline to End of Study, up to 12 months
Prognostic capabilities of standard-of-care (based on medical and family history) versus whole genome sequencing for predicting outcomes and management in monogenic and polygenic familial hypercholesterolemia.
- Resources Implementation for WGS in a clinical setting — Time Frame: Baseline to End of Study, up to 12 months
Assessed by documenting resources necessary for each phase, including execution of WGS, reporting of results, and overall evaluation,
- Participant characteristics — Time Frame: Baseline
Age, sociodemographic, personal and family history
- Change in Perceived Utility — Time Frame: Baseline, post-disclosure of results (approximately 2-3 months after enrollment), 6 months post-enrollment
Assessed using novel participant surveys via questions including: attitudes towards DNA testing and results, understanding of results, change in expectations, confidence, concerns.
- Changes in Health Care Utilization — Time Frame: Baseline to End of Study, up to 12 months
Assessed by reviewing medical records comparing number of services and procedures received related to the diagnosis.
- Clinician Attitudes About WGS — Time Frame: Baseline
A self-built survey was created to assess physicians' perspective and attitude toward WGS
This trial is recruiting at 1 study facilities worldwide. Click below to see if there is a clinic or hospital in your area:
Show All 1 Facilities & Contact Sites
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View Official Medical/Scientific Title
A Randomized Trial of Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis