Digital family health history tools have been developed but few have been tested with non-English speakers and evaluated for acceptability and usability. This study describes the cultural and linguistic adaptation and evaluation of a family health history tool (VICKY: VIrtual Counselor for Knowing Your Family History) for Spanish speakers. In-depth interviews were conducted with 56 Spanish-speaking participants; a subset of 30 also participated in a qualitative component to evaluate the acceptability and usability of Spanish VICKY. Overall, agreement in family history assessment was moderate between VICKY and a genetic counselor (weighted kappa range: 0.4695 for stroke—0.6615 for heart disease), although this varied across disease subtypes. Participants felt comfortable using VICKY and noted that VICKY was very likeable and possessed human-like characteristics. They reported that VICKY was very easy to navigate, felt that the instructions were very clear, and thought that the time it took to use the tool was just right. Spanish VICKY may be useful as a tool to collect family health history and was viewed as acceptable and usable. The study results shed light on some cultural differences that may influence interactions with family history tools and inform future research aimed at designing and testing culturally and linguistically diverse digital systems.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder that results in skin fibrosis, autoantibody production, and internal organ dysfunction. We previously identified 4 “intrinsic” subsets of SSc based upon skin gene expression that are found across organ systems. Gene expression regulators that underlie the SSc-intrinsic subsets, or are associated with clinical covariates, have not been systematically characterized. Here, we present a computational framework to calculate the activity scores of gene expression regulators and identify their associations with SSc clinical outcomes. We found that regulator activity scores can reproduce the intrinsic molecular subsets, with distinct sets of regulators identified for inflammatory, fibroproliferative, limited, and normal-like samples. Regulators most highly correlated with modified Rodnan skin score (MRSS) also varied by intrinsic subset. We identified subgroups of patients with fibroproliferative and inflammatory SSc with more severe pathophenotypes, such as higher MRSS and increased likelihood of interstitial lung disease (ILD). Using an independent cohort, we show that the group with more severe ILD was more likely to show forced vital capacity decline over a period of 36–54 months. Our results demonstrate an association among the activation of regulators, gene expression subsets, and clinical variables that can identify patients with SSc with more severe disease.

Key Points: Single-molecule real-time sequencing with the PacMUC1 script resolved exact MUC1 variable tandem repeat structure and full allelic variation. In 300 individuals, the protocol identified 215 distinct MUC1 tandem repeat alleles with 80 repeat units and nine frameshift mutation types. Probe extension assay identified 90% of families with frameshift mutations, detection of frameshifted mucin-1 aided genetically unresolved cases. Background: ADTKD- MUC1 is caused by frameshift mutations in the MUC1 gene, producing a frameshifted neoprotein (MUC1fs) toxic to kidney cells. The gene's variable number of tandem repeats (VNTR), with approximately 80% guanine/cytosine content, has made it largely inaccessible to standard short-read sequencing, leaving the reference sequence and natural variation poorly defined and complicating mutation detection. Methods: Using single-molecule real-time (SMRT) sequencing, we characterized MUC1 VNTR in 300 individuals, including 279 from 143 families suspected of having ADTKD- MUC1 , assessing VNTR length, repeat structure, and frameshift mutations. Results were compared with the Clinical Laboratory Improvement Amendments–approved probe-extension assay, detecting the prevalent 59dupC mutation, and with MUC1fs immunohistochemistry, which detects the pathogenic protein independent of the underlying genomic change. Results: We identified 215 unique VNTR alleles composed of 80 distinct repeat units, 46 (58%) of which were novel, and nine distinct frameshift mutations present on 52 mutated alleles. Overall, MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD- MUC1 , comprising 135 affected individuals (48%). The SMRT assay outperformed the probe-extension assay by identifying frameshift mutations in two families with previously inconclusive results and in eight additional families whose mutations were undetectable by the probe-extension design. When successful, SMRT assay showed 100% concordance with probe-extension assay at the family level and 98% at the individual level, with discordance attributable to allelic dropout inherent to both long-range PCR amplification and long-read sequencing. Analysis of the mutational spectrum confirmed 59dupC as the most prevalent mutation, affecting approximately 90% of families, while the other eight mutation types occurred at most twice. Conclusions: The SMRT assay outperformed the Clinical Laboratory Improvement Amendments-approved probe-extension assay by detecting essentially all VNTR-associated frameshift mutations. The probe-extension assay identified approximately 90% of affected families. MUC1fs immunohistochemistry added diagnostic value in genetically unresolved cases by detecting the pathogenic protein independent of the underlying mutation.