Adult Patients With Undiagnosed Conditions and Their Responses to Clinically Uncertain Results From Exome Sequencing

Background:

People with conditions that are unknown or hard to diagnose may be helped by a genetic technique. It is called exome sequencing. It helps diagnose disease by unlocking all the data in a person s genetic code. But the results from it are often unclear. Uncertain results can pose problems for doctors and patients. Researchers want to learn more about how people respond when they get uncertain results.

Objective:

To study the psychological and behavioral effects of getting uncertain results from exome sequencing.

Eligibility:

Adults who have:

Had a diagnostic odyssey for at least 6 months. An example is having clinical symptoms but no diagnosis.

And had exome sequencing to try to reach a diagnosis.

Design:

Participants will choose a date and time for their interview. They will sign a form to give consent and authorization.

Participants will fill out 2 forms. One is the Intolerance of Uncertainty Short Form Scale. The other is the Perceptions of Uncertainties in Genome Sequencing Scale.

Both scales ask about what it is like to get clinically uncertain results from exome sequencing. They focus on coping and other behavioral responses.

Participants will have a phone interview. It will last for 45-60 minutes. It will be recorded and transcribed.

At the start of the call, the researcher will review the consent form with the participant. Participants will give data such as race, education, income, and how long they have been looking for a diagnosis.

Participants will read their responses to the 2 scales during the interview.

Study Overview

• Status: Completed
• Conditions: Undiagnosed Disease

Detailed Description

Patients pursuing exome sequencing in their quest for diagnosis will most often receive a clinically uncertain result. A clinically uncertain result is a result that has some level of objective uncertainty frequently viewed by clinicians in regard to a patient s diagnosis. A clinically uncertain result can be a result that is negative, with no reportable variants, or that includes one or more variants deemed uncertain with regard to the cause of a patient s illness. Clinically uncertain results present challenges to both providers and patients in the forms of disclosing and processing uncertain health information. This exploratory study aims to seek insight into the psychological and behavioral impact of receiving clinically uncertain results from exome sequencing. Semi-structured phone interviews will be conducted with approximately 30-40 adult patients with undiagnosed conditions who have received clinically uncertain result from exome sequencing. The interviews will focus on the experience of receiving the clinically uncertain result, with emphasis on appraisal of uncertainty, coping, and other affective and behavioral responses. Interviews will be transcribed and subjected to thematic analysis. Understanding how patients with undiagnosed conditions respond to clinically uncertain results from exome sequencing may inform providers practices around informed consent for exome sequencing and the disclosure of clinically uncertain results through a greater consideration of patient concerns and challenges with adaptation. This study may also identify implications for interventions to reduce negative effects of receiving uncertain genomic information.

• Study Type: Observational
• Enrollment (Actual): 26

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins School of Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Data will be received from up to 250 potential participants, in order to do interviews with a sample of approximately 30-40 participants. Participants are adult patients with undiagnosed conditions who have received one of the most common types of clinically uncertain results (negative result or one or more variants of uncertain significance (VUSs) without a known pathogenic result) from exome sequencing. Patients will be recruited from Johns Hopkins Hospital Genetics Clinics and Kennedy Krieger Institute.

Description

• INCLUSION CRITERIA:

• Had endured a diagnostic odyssey of at least 6 months before receiving exome sequencing. A diagnostic odyssey may be defined as:

  • Having a set of clinical symptoms but no diagnosis OR
  • Having a clinical diagnosis of a broad category of disease (i.e. ataxia, muscular dystrophy) but no specific diagnosis OR
  • Having a clinical diagnosis composed of psychosomatic and/or descriptive diagnoses that individually define single symptoms or groups of symptoms (i.e. migraines, IBS, joint pain), but that do not explain the entire phenotype
• and Had exome sequencing in an attempt to attain diagnosis
• and Received post-test counseling for exome sequencing by a genetic counselor

• and Received a clinically uncertain result from exome sequencing. For the purposes of this study, a clinically uncertain result is defined as one of the following options:

  • One or more VUSs
  • A negative test result (no reported variants)
• and Result disclosure for exome sequencing occurred anywhere from 1 week to 7 years prior to being interviewed

EXCLUSION CRITERIA:

• Exome sequencing results provided a genetic diagnosis for the patient that does not fall into one of the above inclusion categories
• Patient was under age 18 at time of clinically uncertain result disclosure
• Patient has a cognitive disability that prevents him/her from comprehensibly answering interview questions
• Patient cannot speak or understand English

Patients who have since received a genetic diagnosis (from some other mechanism besides their exome sequencing test) may still participate in the study if they are able to recount their experiences around receiving this sort of exome sequencing result during the time they were undiagnosed.

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Negative; Adult patients with undiagnosed conditions who have received an uninformative negative result from exome sequence.
VUS; Adult patients with undiagnosed conditions who have received one or more variants ofuncertain significance from exome sequence.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recall and Perception	Extent of the patients recall of their clinically uncertain result, including their understanding of the limitations of a clinically uncertain result due to its uncertain nature. It will also explore how patients appraise the uncertainty related to their clinically uncertain result, as well as their perceptions of the relationship between their clinically uncertain result and the cause of their illness.	Interview
Affective and Behavioral Responses	How patients describe and categorize their emotional reactions to receiving clinically uncertain result from exome sequencing. It will also explore how patients describe their behavior in response to clinically uncertain result disclosures, such as use of coping strategies and decisions to disclose their results to family and friends.	Interview

Collaborators and Investigators

• Sponsor: National Human Genome Research Institute (NHGRI)

Publications and helpful links

General Publications

• Vos J, Otten W, van Asperen C, Jansen A, Menko F, Tibben A. The counsellees' view of an unclassified variant in BRCA1/2: recall, interpretation, and impact on life. Psychooncology. 2008 Aug;17(8):822-30. doi: 10.1002/pon.1311.
• Han PKJ, Umstead KL, Bernhardt BA, Green RC, Joffe S, Koenig B, Krantz I, Waterston LB, Biesecker LG, Biesecker BB. A taxonomy of medical uncertainties in clinical genome sequencing. Genet Med. 2017 Aug;19(8):918-925. doi: 10.1038/gim.2016.212. Epub 2017 Jan 19.
• Skinner D, Raspberry KA, King M. The nuanced negative: Meanings of a negative diagnostic result in clinical exome sequencing. Sociol Health Illn. 2016 Nov;38(8):1303-1317. doi: 10.1111/1467-9566.12460. Epub 2016 Aug 19.

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2018
• Primary Completion (Actual): May 7, 2020
• Study Completion (Actual): May 7, 2020

Study Registration Dates

• First Submitted: July 27, 2018
• First Submitted That Met QC Criteria: July 27, 2018
• First Posted (Actual): July 30, 2018

Study Record Updates

• Last Update Posted (Actual): May 11, 2020
• Last Update Submitted That Met QC Criteria: May 7, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Qualitative; Genetic Testing; Variant of Uncertain Significance; Uncertainty
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Undiagnosed Diseases
• Other Study ID Numbers: 999918124; 18-HG-N124

Drug and device information, study documents

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