Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering.

Developmental stuttering is a speech disorder characterized by disruption in the forward movement of speech. This disruption includes part-word and single-syllable repetitions, prolongations, and involuntary tension that blocks syllables and words, and the disorder has a life-time prevalence of 6-12%. Within Vanderbilt's electronic health record (EHR)-linked biorepository (BioVU), only 142 individuals out of 92,762 participants (0.15%) are identified with diagnostic ICD9/10 codes, suggesting a large portion of people who stutter do not have a record of diagnosis within the EHR. To identify individuals affected by stuttering within our EHR, we built a PheCode-driven Gini impurity-based classification and regression tree model, PheML, by using comorbidities enriched in individuals affected by stuttering as predicting features and imputing stuttering status as the outcome variable. Applying PheML in BioVU identified 9,239 genotyped affected individuals (a clinical prevalence of ∼10%) for downstream genetic analysis. Ancestry-stratified GWAS of PheML-imputed affected individuals and matched control individuals identified rs12613255, a variant near CYRIA on chromosome 2 (B = 0.323; p value = 1.31 × 10-8) in European-ancestry analysis and rs7837758 (B = 0.518; p value = 5.07 × 10-8), an intronic variant found within the ZMAT4 gene on chromosome 8, in African-ancestry analysis. Polygenic-risk prediction and concordance analysis in an independent clinically ascertained sample of developmental stuttering cases validate our GWAS findings in PheML-imputed affected and control individuals and demonstrate the clinical relevance of our population-based analysis for stuttering risk.

Diversity of Research Participant Gender, Race, and Ethnicity in Communication Sciences and Disorders: A Systematic Review and Quantitative Synthesis of American Speech-Language-Hearing Association Publications in 2020.

Purpose: One manifestation of systemic inequities in communication sciences and disorders (CSD) is the chronic underreporting and underrepresentation of sex, gender, race, and ethnicity in research. The present study characterized recent demographic reporting practices and representation of participants across CSD research. Methods: We systematically reviewed and extracted key reporting and participant data from empirical studies conducted in the United States (US) with human participants published in the year 2020 in journals by the American Speech-Language-Hearing Association (ASHA; k = 407 articles comprising a total n = 80,058 research participants, search completed November 2021). Sex, gender, race, and ethnicity were operationalized per National Institutes of Health guidelines (National Institutes of Health, 2015a, 2015b). Results: Sex or gender was reported in 85.5% of included studies; race was reported in 33.7%; and ethnicity was reported in 13.8%. Sex and gender were clearly differentiated in 3.4% of relevant studies. Where reported, median proportions for race and ethnicity were significantly different from the US population, with underrepresentation noted for all non-White racial groups and Hispanic participants. Moreover, 64.7% of studies that reported sex or gender and 67.2% of studies that reported race or ethnicity did not consider these respective variables in analyses or discussion. Conclusion: At present, research published in ASHA journals frequently fails to report key demographic data summarizing the characteristics of participants. Moreover, apparent gaps in representation of minoritized racial and ethnic groups threaten the external validity of CSD research and broader health care equity endeavors in the US. Although our study is limited to a single year and publisher, our results point to several steps for readers that may bring greater accountability, consistency, and diversity to the discipline.

End-of-life cell cycle arrest contributes to stochasticity of yeast replicative aging.

There is growing evidence that stochastic events play an important role in determining individual longevity. Studies in model organisms have demonstrated that genetically identical populations maintained under apparently equivalent environmental conditions display individual variation in life span that can be modeled by the Gompertz-Makeham law of mortality. Here, we report that within genetically identical haploid and diploid wild-type populations, shorter-lived cells tend to arrest in a budded state, while cells that arrest in an unbudded state are significantly longer-lived. This relationship is particularly notable in diploid BY4743 cells, where mother cells that arrest in a budded state have a shorter mean life span (25.6 vs. 35.6) and larger coefficient of variance with respect to individual life span (0.42 vs. 0.32) than cells that arrest in an unbudded state. Mutations that cause genomic instability tend to shorten life span and increase the proportion of the population that arrest in a budded state. These observations suggest that randomly occurring damage may contribute to stochasticity during replicative aging by causing a subset of the population to terminally arrest prematurely in the S or G2 phase of the cell cycle.

A study of respiratory sinus arrhythmia and stuttering persistence.

INTRODUCTION: The present study investigated potential differences in respiratory sinus arrhythmia between preschool-age children with persisting stuttering, children who recovered from stuttering, and children who do not stutter. METHODS: Participants were 10 children with persisting stuttering (persisting group), 20 children who recovered from stuttering (recovered group), and 36 children who do not stutter (non-stuttering group). Participants viewed a neutral video clip to establish a pre-arousal baseline and then viewed two emotionally-arousing video clips (positive and negative, counterbalanced). Age-appropriate speaking tasks followed each of the video clips (post-baseline, post-positive, and post-negative). Respiratory sinus arrhythmia (RSA), an index of parasympathetic nervous system activity, was measured during the video clips and subsequent speaking tasks. RESULTS: First, the persisting group, recovered group, and non-stuttering group did not significantly differ in baseline RSA. Second, during the emotionally-arousing video clips, there was a significant group x condition interaction, with the recovered group exhibiting significantly lower RSA in the positive than negative condition, and the non-stuttering group exhibiting significantly higher RSA in the positive than negative condition. Third, in the narrative tasks, there was a significant group x condition interaction, with a greater difference in RSA between the post-baseline speaking task and the post-positive and post-negative speaking tasks for the persisting compared to the non-stuttering group. Lastly, a follow-up analysis indicated that the recovered and nonstuttering groups, compared to the persisting group, exhibited significantly greater RSA during the baseline (neutral) condition compared to the post-neutral narrative task. CONCLUSIONS: Findings provide a physiological perspective of emotion within children who stutter and persist and children who stutter and recover. Future investigations with larger sample sizes and diverse methodologies are necessary to provide novel insights on the specific emotion-related processes that are potentially involved with persistence of stuttering in young children.

Population-based genetic effects for developmental stuttering.

Despite a lifetime prevalence of at least 5%, developmental stuttering, characterized by prolongations, blocks, and repetitions of speech sounds, remains a largely idiopathic speech disorder. Family, twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; however, its complex mode of inheritance combined with thus-far underpowered genetic studies contribute to the challenge of identifying and reproducing genes implicated in developmental stuttering susceptibility. We conducted a trans-ancestry genome-wide association study (GWAS) and meta-analysis of developmental stuttering in two primary datasets: The International Stuttering Project comprising 1,345 clinically ascertained cases from multiple global sites and 6,759 matched population controls from the biobank at Vanderbilt University Medical Center (VUMC), and 785 self-reported stuttering cases and 7,572 controls ascertained from The National Longitudinal Study of Adolescent to Adult Health (Add Health). Meta-analysis of these genome-wide association studies identified a genome-wide significant (GWS) signal for clinically reported developmental stuttering in the general population: a protective variant in the intronic or genic upstream region of SSUH2 (rs113284510, protective allele frequency = 7.49%, Z = -5.576, p = 2.46 × 10-8) that acts as an expression quantitative trait locus (eQTL) in esophagus-muscularis tissue by reducing its gene expression. In addition, we identified 15 loci reaching suggestive significance (p < 5 × 10-6). This foundational population-based genetic study of a common speech disorder reports the findings of a clinically ascertained study of developmental stuttering and highlights the need for further research.

Identifying developmental stuttering and associated comorbidities in electronic health records and creating a phenome risk classifier.

PURPOSE: This study aimed to identify cases of developmental stuttering and associated comorbidities in de-identified electronic health records (EHRs) at Vanderbilt University Medical Center, and, in turn, build and test a stuttering prediction model. METHODS: A multi-step process including a keyword search of medical notes, a text-mining algorithm, and manual review was employed to identify stuttering cases in the EHR. Confirmed cases were compared to matched controls in a phenotype code (phecode) enrichment analysis to reveal conditions associated with stuttering (i.e., comorbidities). These associated phenotypes were used as proxy variables to phenotypically predict stuttering in subjects within the EHR that were not otherwise identifiable using the multi-step identification process described above. RESULTS: The multi-step process resulted in the manually reviewed identification of 1,143 stuttering cases in the EHR. Highly enriched phecodes included codes related to childhood onset fluency disorder, adult-onset fluency disorder, hearing loss, sleep disorders, atopy, a multitude of codes for infections, neurological deficits, and body weight. These phecodes were used as variables to create a phenome risk classifier (PheRC) prediction model to identify additional high likelihood stuttering cases. The PheRC prediction model resulted in a positive predictive value of 83 %. CONCLUSIONS: This study demonstrates the feasibility of using EHRs in the study of stuttering and found phenotypic associations. The creation of the PheRC has the potential to enable future studies of stuttering using existing EHR data, including investigations into the genetic etiology.

Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae.

Chronological aging of budding yeast cells results in a reduction in subsequent replicative life span through unknown mechanisms. Here we show that dietary restriction during chronological aging delays the reduction in subsequent replicative life span up to at least 23days of chronological age. We further show that among the viable portion of the control population aged 26days, individual cells with the lowest mitochondrial membrane potential have the longest subsequent replicative lifespan. These observations demonstrate that dietary restriction modulates a common molecular mechanism linking chronological and replicative aging in yeast and indicate a critical role for mitochondrial function in this process.

Molecular mechanisms underlying genotype-dependent responses to dietary restriction.

Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.

pH neutralization protects against reduction in replicative lifespan following chronological aging in yeast.

Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.