Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis

Abu Dhabi Health Services Company40 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

TRIPLE

Interventions

Whole Genome SequencingGENETIC

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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 Exclusion Criteria: * \- 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

Outcomes

Primary Outcomes

Diagnostic capabilities

Diagnostic yield of standard-of-care (based on medical and family history) versus whole genome sequencing (WGS) for identifying monogenic and polygenic familial hypercholesterolemia.

Time frame: From consent date until first documented report, up to 6 months

Secondary Outcomes

Prognostic capabilities of standard-of-care

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.

Time frame: Baseline to End of Study, up to 12 months

Resources Implementation for WGS in a clinical setting

Assessed by documenting resources necessary for each phase, including execution of WGS, reporting of results, and overall evaluation,

Time frame: Baseline to End of Study, up to 12 months

Participant characteristics

Age, sociodemographic, personal and family history

Time frame: Baseline

Change in Perceived Utility

Assessed using novel participant surveys via questions including: attitudes towards DNA testing and results, understanding of results, change in expectations, confidence, concerns.

Time frame: Baseline, post-disclosure of results (approximately 2-3 months after enrollment), 6 months post-enrollment

Changes in Health Care Utilization

Assessed by reviewing medical records comparing number of services and procedures received related to the diagnosis.

Time frame: Baseline to End of Study, up to 12 months

Clinician Attitudes About WGS

A self-built survey was created to assess physicians' perspective and attitude toward WGS

Time frame: Baseline

Integrating Whole Genome Sequencing and Digital Twins Into the Management of Hypercholesterolemia in Emiratis

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts