Translating Genetic Knowledge Into Clinical Care in Non-Autoimmune Diabetes (TRANSLATE)

TRANSLATE - Translating Genetic Knowledge Into Clinical Care in Non-Autoimmune Diabetes

The aim of TRANSLATE is to implement genetic information directly into patient care to improve diagnosis and treatment of non-autoimmune diabetes. This project is the first large-scale implementation of systematic genetic testing within a common, non-communicable, chronic disease in Denmark, and will spearhead efforts to advance personalized medicine in Denmark.

The project will contribute to establishing technology, workflow, and evidence on how to implement and communicate actionable genetic information to clinicians and patients in a generalized format. These developments are pivotal for personalized medicine to reach broader clinical application.

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes Mellitus, Type 2; Diabetes, Gestational
• Intervention / Treatment: Other: Whole genome sequencing

Detailed Description

The TRANSLATE project is an integrative project with multifaceted goals, that can be broken down into two main columns. The foundation for both columns is the WGS analysis in a clinical diagnostic setting in order to guide patient treatment. Patients are not randomized and the inclusion and exclusion criteria are deliberately broad and minimal, respectively.

The first column is the clinical development project, which seeks to complete a novel diagnostic process. This column will develop new pipelines and uncover barriers and challenges associated with gene-based precision medicine to facilitate sustainable implementation of gene-based precision medicine beyond the TRANSLATE project.

During the project, we wish to focus on potential barriers against a broad application of gene-based precision medicine in a common disease. These may include:

• Challenges pertaining to the selection of variants that are deemed clinically actionable, automation of genetic interpretation/translation, and the feasibility of large-scale precision medicine implementation
• Ethical concerns of patients, clinicians, and other technicians with regard to the application and utility of genetic information
• Validity and limitations of current computational pipelines for variant calling including the calling of structural variants and aggregate genetic tools
• Challenges regarding the interoperability of IT systems and databases nationally in Denmark, specifically how central databases can be linked to clinical end-users
• How implementation of genetic analyses affects clinical decision-making and/or clinical trajectories, both qualitatively and quantitatively

The second column is a register-based research project in which we will utilize data from the patients to advance gene-based precision medicine. In this column we will both address how to establish comprehensive research infrastructure, as well as answer specific research questions. We will address how to combine and harmonize genetic data with other Danish registry sources. We will use the newly established methodologies to focus on the following research areas with respect to patient stratification, clinical trajectories, complication development, and other clinically relevant outcomes:

• Polygenic risk scores
• Machine learning algorithms
• Combined polygenic and monogenic traits
• Non-coding variation
• Structural variation, specifically exon deletions and duplications, which have previously been shown as a cause of monogenic diabetes

• Study Type: Observational
• Enrollment (Anticipated): 6500

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet
  • Herlev, Denmark
    • Herlev Hospital
  • Herlev, Denmark
    • Steno Diabetes Center Copenhagen
  • Hillerød, Denmark
    • Hillerød Hospital
  • Hvidovre, Denmark
    • Hvidovre Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients in the target groups with non-autoimmune/non-T1D attending SDCC or pregnant women with gestational diabetes attending one of the obstetric clinics in the project will be offered a genetic test.

Description

Inclusion Criteria:

• Any case of non-T1D defined as debut >30 years of age, OR debut <30 years of age AND negative autoantibodies
• Any case of diabetes diagnosed in pregnancy (obstetric departments)

Exclusion Criteria:

• Age <18 years
• Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with non-autoimmune diabetes (type 2 diabetes); Any case of non-T1D defined as: Debut >30 years of age OR; Debut <30 years of age AND negative autoantibodies treated at Steno Diabetes Center Copenhagen	Other: Whole genome sequencing; Each participant will have WGS performed in order to report on clinically actionable genetic variation in diabetes.; Other Names: WGS
Patients with gestational diabetes; Any case of diabetes diagnosed in pregnancy treated at the following obstetric clinics in the Capital Region in Denmark: Rigshospitalet, Nordsjællands Hospital, Herlev Hospital, Hvidovre Hospital	Other: Whole genome sequencing; Each participant will have WGS performed in order to report on clinically actionable genetic variation in diabetes.; Other Names: WGS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Selection of clinically actionable genetic variation in diabetes	Using mixed methods such as gene burden investigations, workgroups, interviews, etc. challenges related to the selection of clinically actionable genetic variants and automation of interpretation/translation will be delineated.	Until final patient inclusion (May 2025) + 2 years (May 2027)
Ethical concerns regarding the application and utility of genetic information	The project will address how patients, clinicians, technicians etc. shape their understanding of the utility and challenges associated with gene-based precision medicine using ethnographic methods such as field observations and semi-structured interviews.	Until final patient inclusion (May 2025) + 2 years (May 2027)
Validity and limitations of current computational pipelines	By comparing computational and analytical methods, the project will investigate the validity and limitations of different computational pipelines. This includes handling of single nucleotide variants, as well as structural variation.	Until final patient inclusion (May 2025) + 2 years (May 2027)
Interoperability of IT systems and databases	The project will address the flow of data to and from clinical end-users, through centralized databases, both with respect to how the data flow is perceived by users and potential challenges, and how interoperability can be improved to enhance clinical utility. The project will also address how to harmonize data from different sources.	Until final patient inclusion (May 2025) + 2 years (May 2027)
Impact on clinical decision-making and clinical trajectories	Using mixed methods such as mapping of clinical trajectories through clinical registries and qualitative methods such as interviews, workgroups, etc., the project will investigate how implementation of gene-based precision diabetes impacts clinical decision making.	Until final patient inclusion (May 2025) + 2 years (May 2027)

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Collaborators: Rigshospitalet, Denmark; Hvidovre University Hospital; Herlev Hospital; Steno Diabetes Center Copenhagen; Nordsjaellands Hospital; BGI Europe; Intomics A/S; Danish National Genome Center
• Investigators: Principal Investigator: Torben Hansen, PhD, University of Copenhagen

Publications and helpful links

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2022
• Primary Completion (Anticipated): May 31, 2025
• Study Completion (Anticipated): May 31, 2027

Study Registration Dates

• First Submitted: May 2, 2022
• First Submitted That Met QC Criteria: May 5, 2022
• First Posted (Actual): May 10, 2022

Study Record Updates

• Last Update Posted (Actual): May 17, 2022
• Last Update Submitted That Met QC Criteria: May 10, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Genetics; Personalized medicine; Precision medicine
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational
• Other Study ID Numbers: 9090-00078B

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Data will be reported to Danish National Genome Center after completion.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No