TRIAGE-GS: Towards Reducing Inefficiencies Affecting Genetics Encounters Through Genome Sequencing

The primary outcome measure for Aim 1 is a time-to-event variable. The event of interest is "diagnosis or no active follow-up," as measured for each participant from the date of randomization to the date of disclosure of the diagnosis/plan. Selection of a composite event variable was based on input from patients, families, and clinicians regarding the utility of negative GS results in certain scenarios. For example, a negative GS result might lower the index of suspicion for Mendelian disorders of known genetic basis, such that no further testing or short-term follow-up is recommended, or a clinical diagnosis of exclusion is made with confidence.

The main outcome for Aim 2 will be differences in C-GUIDE total score, comparing the perceived utility of GS (in the GS-first group) with the first genetic test initiated by the geneticist for participants in the standard-of-care group.

The other main outcome for Aim 2 will be differences in GENE-U total score, comparing the perceived utility of GS (in the GS-first group) with the first genetic test initiated by the geneticist for participants in the standard-of-care group.

An incremental cost-effectiveness analysis (CEA) that compares GS-first to standard-of-care per additional positive finding will be undertaken from the perspectives of the healthcare system and society. The economic evaluation will use recommended methods.

This can be stratified by the original referral source (i.e., internal referrals from providers at SickKids/CHEO vs. referrals from external providers).

Including time recorded by the analyst, number/type of variants unnecessarily reported due to incomplete phenotypic information, etc.

Including variants seen by GS that were not reported based on phenotypic information known prior to geneticist assessment, variants identified on reanalysis using new HPO terms entered post-geneticist assessment, or variant types (e.g., repeat expansions) that were missed by GS due to technical limitations, etc.

A secondary analysis under the CEA will examine the incremental cost per unit improvement in C-GUIDE score

The investigators will assess factors that motivated families to participate, as well as factors that presented potential barriers at T0. These questions were developed by the study team for the purposes of this study. This component of the outcome measures will also be offered to individuals who decline to participate in an attempt to better understand barriers and improve the study.

The study team will collect detailed sociodemographic, and equity related variables at T0. Some of this information is already collected in the electronic medical record as part of routine clinic visits. In cases where this information is readily available, the study team will gather it from the chart and not ask families to answer the questions again.

Health literacy is described as the degree to which one can read, understand, exchange, and use health information and resources. The BRIEF: Health Literacy Screening Tool consists of four questions that participants respond to on a 5-point Likert scale, and will be administered at T0. It measures patients' health literacy, where higher scores indicate higher levels of health literacy.

The Everyday Discrimination Scale (Short Version) consists of 6 items intended to capture respondents' experiences with discrimination in their life. It is reliable (α = 0.77). It will be administered at T0 only.

The UNC-GKS consists of 25 items to measure genomic knowledge among people facing decisions about genome-wide sequencing. It was shown to assess genomic knowledge with good internal reliability (Cronbach's α = 0.90), and convergent validity supported by association with health literacy and numeracy (rs = 0.41-0.46). It will be administered at T0, T1, T2 and TN (up to a maximum of T4) to allow comparison throughout families' diagnostic journeys, and assess whether there are differences in knowledge/understanding between the study arms.

The short form of the Spielberger STAI consists of 6 items that measure fluctuations in state anxiety.60 This short form version was found to be reliable (α = 0.32) and valid as compared to the full (20-item) version.60 It will be administered at all time points, starting at T0.

The GCSS is a 6-item instrument to measure an individual's satisfaction with the genetic counselling they received. It is reliable (Cronbach's α = 0.90) and described as face valid. It will be administered at all time points, starting at T1.

The GENEtic Utility (GENE-U) scale consists of 21 items that capture the caregiver's test-specific reactions. It is designed for administration after test completion and results disclosure, and it is intended to be complementary to assessments of clinical utility. Convergent validity has been calculated using the Pearson correlation coefficient between scores on the GENE-U and measures of theoretically related constructs, and scores supported construct validity. It will be administered at all time points, starting at T2.

To capture clinicians' assessment of utility, the investigators will use the Clinician-reported Genetic Testing Utility InDEx (C-GUIDE™). C-GUIDE™ was developed to assess the post-test utility of diagnostic and secondary variants generated by germline genetic tests. Evaluation using case vignettes has demonstrated that C-GUIDE v1.2 is reliable (Krippendorff's α=0.675) and valid. Consulting geneticists or genetic counsellors will be asked to complete C-GUIDE™ ratings on each enrolled index case within two weeks of the first result disclosure (T1), and for each subsequent result disclosure during the study period (TN), to allow for an assessment of clinical utility overtime.

The study team will supplement the C-GUIDE™ ratings by documenting information from the patient's chart about the care plan that was recommended based each result (e.g., follow-up visits, referrals, surveillance plans, investigations, treatments, procedures). The source for this information will be the consult note written by the consulting geneticist following results disclosure.