Opening the door to university health research: recommendations for increasing accessibility for individuals with intellectual disability.

BACKGROUND: Advances in health equity rely on representation of diverse groups in population health research samples. Despite progress in the diversification of research samples, continued expansion to include systematically excluded groups is needed to address health inequities. One such group that is infrequently represented in population health research are adults with intellectual disability. Individuals with intellectual disability experience pervasive health disparities. Representation in population health research is crucial to determine the root causes of inequity, understand the health of diverse populations, and address health disparities. The purpose of this paper was to develop recommendations for researchers to increase the accessibility of university health research and to support the inclusion of adults with intellectual disability as participants in health research. METHODS: A comprehensive literature review, consultation with the university ethics review board, and review of United States federal regulations was completed to identify barriers to research participation for individuals with intellectual disability. A collaborative stakeholder working group developed recommendations and products to increase the accessibility of university research for participants with intellectual disability. RESULTS: Eleven key barriers to research participation were identified including gaps in researchers' knowledge, lack of trust, accessibility and communication challenges, and systematic exclusion among others. Together the stakeholder working group compiled seven general recommendations for university health researchers to guide inclusion efforts. Recommendations included: 1) address the knowledge gap, 2) build community partnerships, 3) use plain language, 4) simplify consent and assent processes, 5) establish research capacity to consent, 6) offer universal supports and accommodations, and 7) practice accessible dissemination. In addition, four products were created as part of the stakeholder working group to be shared with researchers to support the inclusion of participants with intellectual disability. 1) Supports I Need Checklist, 2) Plain language glossary of health and research terms, 3) Understanding Consent and Assent in Plain Language, 4) Easy-Read Paper Template. CONCLUSION: Community members and individuals with intellectual disability want to be included in research and are eager to engage as research participants. It is the responsibility of the researcher to open the door to university health research. The recommendations discussed in this paper could increase accessibility for a broader range of research participants and, in particular, promote the inclusion of individuals with intellectual disability to advance health equity in population health research.

Increasing Prevalence of Nontuberculous Mycobacteria in Respiratory Specimens from US-Affiliated Pacific Island Jurisdictions1.

Nontuberculous mycobacteria (NTM) respiratory infections represent a growing public health problem in many countries. However, there are limited published epidemiologic studies for the Western Pacific region. We reviewed respiratory specimens submitted to Diagnostic Laboratory Services in Hawaii, USA, for culture of Mycobacterium tuberculosis during August 2007-December 2011 to determine the NTM isolation rate. We observed a statistically significant increase in the rate of specimens with NTM isolated in respiratory culture (adjusted rate ratio per year 1.65, 95% CI 1.54-1.77; p<0.01). In contrast, the number of patients with respiratory cultures positive for M. tuberculosis showed no increase (adjusted rate ratio per year 0.98, 95% CI 0.94-1.01; p = 0.19). A 6-month subset of NTM isolates was identified by using a nucleic acid probe or 16S rRNA sequencing. M. avium complex and M. fortuitum were the most common NTM identified.

A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis.

BACKGROUND: Hydranencephaly is a congenital anomaly leading to replacement of the cerebral hemispheres with a fluid-filled cyst. The goals of this work are to describe a novel autosomal-recessive syndrome that includes hydranencephaly (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH)); to identify its genetic cause(s) and to provide functional insight into pathomechanism. METHODS: We used homozygosity mapping and exome sequencing to identify recessive mutations in a single family with three affected fetuses. Immunohistochemistry, RT-PCR and imaging in cell lines, and zebrafish models, were used to explore the function of the gene and the effect of the mutation. RESULTS: We identified a homozygous nonsense mutation in CEP55 segregating with MARCH. Testing the effect of this allele on patient-derived cells indicated both a reduction of the overall CEP55 message and the production of a message that likely gives rise to a truncated protein. Suppression or ablation of cep55l in zebrafish embryos recapitulated key features of MARCH, most notably renal dysplasia, cerebellar hypoplasia and craniofacial abnormalities. These phenotypes could be rescued by full-length but not truncated human CEP55 message. Finally, we expressed the truncated form of CEP55 in human cells, where we observed a failure of truncated protein to localise to the midbody, leading to abscission failure and multinucleated daughter cells. CONCLUSIONS: CEP55 loss of function mutations likely underlie MARCH, a novel multiple congenital anomaly syndrome. This association expands the involvement of centrosomal proteins in human genetic disorders by highlighting a role in midbody function.

Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.

The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

Variance component estimates for growth traits in beef cattle using selected variants from imputed low-pass sequence data.

A beef cattle population (n = 2,343) was used to assess the impact of variants identified from the imputed low-pass sequence (LPS) on the estimation of variance components and genetic parameters of birth weight (BWT) and post-weaning gain (PWG). Variants were selected based on functional impact and were partitioned into four groups (low, modifier, moderate, high) based on predicted functional impact and re-partitioned based on the consequence of mutation, such as missense and untranslated region variants, into six groups (G1-G6). Each subset was used to construct a genomic relationship matrix (GRM) for univariate animal models. Multiple analyses were conducted to compare the proportion of additive genetic variation explained by the different subsets individually and collectively, and these estimates were benchmarked against all LPS variants in a single GRM and array (e.g., GeneSeek Genomic Profiler 100K) genotypes. When all variants were included in a single GRM, heritability estimates for BWT and PWG were 0.43 ±â€…0.05 and 0.38 ±â€…0.05, respectively. Heritability estimates for BWT ranged from 0.10 to 0.42 dependent on which variant subsets were included. Similarly, estimates for PWG ranged from 0.05 to 0.38. Results showed that variants in the subsets modifier and G1 (untranslated region) yielded the highest heritability estimates and were similar to the inclusion of all variants, while estimates from GRM containing only variants in the categories High, G4 (non-coding transcript exon), and G6 (start and stop loss/gain) were the lowest. All variants combined provided similar heritability estimates to chip genotypes and provided minimal to no additional information when combined with chip data. This suggests that the chip single nucleotide polymorphisms and the variants from LPS predicted to be less consequential are in relatively high linkage disequilibrium with the underlying causal variants as a whole and sufficiently spread throughout the genome to capture larger proportions of additive genetic variation.

Animals from a crossbred beef cattle population were sequenced at low depth (i.e., 0.5×) and different subsets of selected imputed variants were investigated relative to their ability to explain variation in birth weight (BWT) and post-weaning gain (PWG). Variants were classified by both their predicted functional impact and by the consequence of the mutation and partitioned into subsets within these two criteria. When ~ 1 million variants were included in the same genomic relationship matrix, heritability estimates were similar to a 100k chip array. Heritability estimates for BWT ranged from 0.10 to 0.42 dependent on which variant subsets were included. Similarly, estimates for PWG ranged from 0.05 to 0.38. Differences in minor allele frequency were observed among subsets and these differences likely contributed to differences in heritability estimates. Results suggest that linkage disequilibrium between the variants categorized as being less consequential and underlying causal variants is high as indicated by the high percentage of variation explained.

Hawai'i Rural Health Program: Shaping the Next Generation of Rural Doctors.

Like many areas of the United States, Hawai'i and its rural communities are suffering from a significant physician shortage. The University of Hawai'i (UH) John A. Burns School of Medicine (JABSOM) developed the Hawai'i Rural Health Program (HRHP) in 2011 to help provide early and substantial rural training experiences for its medical students in hopes of generating more rural health care providers. Thus far, 20.6% of the students who participated in this program and have since graduated from residency are now practicing in rural communities. Final exam grades of students who participated in the program were not statistically different from those who did not participate, suggesting a similar quality of training between both the rural and traditional cohorts of students. Reflections from students who completed the program demonstrate the large and lasting impact that this immersive experience has on their medical education and desire to help rural communities.

Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity.

Genetic parameter estimates for bull prolificacy and its relationship with scrotal circumference in a commercial beef cattle population.

The commercial beef cattle industry relies heavily on the use of natural service sires. When artificial insemination is deemed difficult to implement, multisire breeding pastures are used to increase reproductive rates in large breeding herds or to safe-guard against bull injury during the breeding season. Although each bull might be given an equal opportunity to produce offspring, evidence suggest that there is substantial variation in the number of calves sired by each bull in a breeding pasture. With the use of DNA-based paternity testing, correctly assigning calves to their respective sires in multisire pastures is possible and presents an opportunity to investigate the degree to which this trait complex is under genetic control. Field data from a large commercial ranch was used to estimate genetic parameters for calf count (CC; 574 records from 443 sires) and yearling scrotal circumference (SC; n = 1961) using univariate and bivariate animal models. Calf counts averaged 12.2 ± 10.7 and SC averaged 35.4 ± 2.30 cm. Bulls had an average of 1.30 records and there were 23.9 ± 11.1 bulls per contemporary group. The model for CC included fixed effects of age during the breeding season (in years) and contemporary group (concatenation of breeding pasture and year). Random effects included additive genetic and permanent environmental effects, and a residual. The model for SC included fixed effects of age (in days) and contemporary group (concatenation of month and year of measurement). Random effects included an additive genetic effect and a residual. Univariate model heritability estimates for CC and SC were 0.178 ± 0.142 and 0.455 ± 0.072, respectively. Similarly, the bivariate model resulted in heritability estimates for CC and SC of 0.184 ± 0.142 and 0.457 ± 0.072, respectively. Repeatability estimates for CC from univariate and bivariate models were 0.315 ± 0.080 and 0.317 ± 0.080, respectively. The estimate of genetic correlation between CC and SC was 0.268 ± 0.274. Heritability estimates suggest that both CC and SC would respond favorably to selection. Moreover, CC is lowly repeatable and although favorably correlated, SC appears to be weakly associated with CC.

Mapping the Trends of Kawasaki Disease in Hawai'i from 1996 to 2018.

Kawasaki disease is a systemic vasculitis of unknown etiology and is the leading cause of acquired heart disease in children in the developed world. Historically, Hawai'i has had the highest incidence of Kawasaki disease in the United States, likely due to the population's unique ancestral composition. To analyze the epidemiology, demographics and spatiotemporal distribution of Kawasaki disease in Hawai'i, a retrospective chart review was conducted utilizing data from Kapi'olani Medical Center for Women and Children encompassing the period of 1996-2018. A total of 858 patients were analyzed with 877 episodes of Kawasaki disease. On average, 37 episodes of Kawasaki disease were diagnosed annually over the 23-year period. The annual incidence was 32 per 100 000 children <5 years of age. Asian children (66.1%) accounted for the majority of cases, followed by Native Hawaiians and Other Pacific Islanders (16.6%). Unlike Japan and the continental United States, there was no characteristic seasonal pattern in the distribution of Kawasaki disease in Hawai'i, which may be attributed to its tropical climate or the recent changes in global weather patterns. Local geographical differences in the incidence of Kawasaki disease demonstrated that the Windward (Eastern) coast of O'ahu had a higher rate, while the Leeward (Western) coast displayed a lower incidence rate. This could be explained by variations in ethnic composition and weather patterns of certain areas. Future studies could provide geographical weather data and statistical analysis to determine what environmental triggers are correlated with Kawasaki disease trends in the State of Hawai'i.