Publications by authors named "Jinkuk Hong"

50 Publications

Health profiles of adults with autism spectrum disorder: Differences between women and men.

Autism Res 2021 Jul 2. Epub 2021 Jul 2.

Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.

The purpose of the present study was to investigate the hypothesis that women with autism have poorer health compared with men with autism, and compared with women without autism. Utilizing electronic health records drawn from a single health care system serving over 2 million individuals, 2119 adults with diagnosed autism spectrum disorders were compared with age- and sex-matched controls. When considering health care utilization, we found evidence of multiplicative risk for conditions within some domains (i.e., nutrition conditions, neurologic disease, psychiatric conditions, and sleep disorders) such that women with autism spectrum disorder (ASD) experienced double jeopardy-meaning they had greater rates of health care utilization within a domain than what would separately be expected by virtue of being a woman and having ASD. For other domains (i.e., endocrine disorders, gastrointestinal disorders), the risk was additive such that being a female and having ASD were both associated with higher health care utilization, but there were no significant interaction effects. It was only with respect to one domain (cardiovascular) that rates of health care utilization were reflective of neither ASD diagnosis nor sex. Overall, our findings suggest that women with ASD are a vulnerable subgroup with high levels of health care utilization. LAY SUMMARY: This study asked whether women with autism have poorer health compared with men with autism, and compared with women without autism. To answer this question, we used data from electronic health records. We found that women with autism spectrum disorder (ASD) were at the greatest risk for health problems such as nutrition conditions, neurologic disease, psychiatric conditions, and sleep disorders. More research on health of women with ASD is needed.
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http://dx.doi.org/10.1002/aur.2563DOI Listing
July 2021

Verbal Ability, Behavior Problems, and Mother-Child Relationship Quality in Autism Spectrum Disorder.

J Autism Dev Disord 2021 Jun 15. Epub 2021 Jun 15.

Waisman Center, University of Wisconsin-Madison, Madison, USA.

This study examined differences in mother-child relationship quality and parent-rated child behavior problems based on child verbal status (i.e., minimally verbal versus verbal) in mothers and their adolescent and adult children with autism spectrum disorder (n = 219 dyads; child M = 25.38 years, SD = 10.22). Relationship quality was assessed via parent-reported maternal burden and mother-child closeness, and coded speech samples ascertaining maternal critical and positive remarks regarding the child. Groups did not differ in relationship quality. The verbal group was more likely to display disruptive and socially inappropriate behaviors, but otherwise the groups did not differ in behavior problems. Verbal status moderated the relationship between behavior problems and negative (maternal burden, critical remarks) but not positive (mother-child closeness, positive remarks) aspects of relationship quality.
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http://dx.doi.org/10.1007/s10803-021-05133-2DOI Listing
June 2021

Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community-Based Cohort.

Mov Disord 2021 Jun 12. Epub 2021 Jun 12.

Department of Neurological Sciences, Rush University, Chicago, Illinois, USA.

Background: Premutation-sized (55-200) CGG repeat expansions in the FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS). Most studies of premutation carriers utilized reverse ascertainment to identify patients, leading to a selection bias for larger repeats. As shorter CGG premutation repeats are common in the population, understanding their impact on health outcomes has a potentially large public health footprint.

Objective: The study's objective was to compare an unselected group of premutation carriers (n = 35, 55-101 CGG repeats) with matched controls (n = 61, 29-39 CGG repeats) with respect to FXTAS-type signs using structured neurological assessments.

Methods: Three neurologists independently rated signs, using an adapted version of the FXTAS Rating Scale (Leehey MA, Berry-Kravis E, Goetz CG, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008). This was a double-blind study, as genetic status (premutation vs. control) was known neither by the participants nor by any of the neurologists. Analyses controlled potentially confounding comorbid conditions in the electronic health record (eg, osteoarthritis and stroke) and probed the association of age with signs.

Results: Although there was no overall difference between carriers and controls, among individuals without any potentially confounding comorbid diagnoses, there was a statistically significant age-associated elevation in FXTAS-type signs in premutation carriers compared to controls.

Conclusions: Among those who do not have other comorbid diagnoses, women who have CGG repeats at the lower end of the premutation range may be at greater risk for ataxia and parkinsonism than their age peers, although their overall risk of developing such clinical features is low. This study should provide reassurance to those who share characteristics with the present cohort. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28683DOI Listing
June 2021

Stress and genetics influence hair cortisol in FMR1 premutation carrier mothers of children with fragile X syndrome.

Psychoneuroendocrinology 2021 Jul 13;129:105266. Epub 2021 May 13.

Waisman Center, University of Wisconsin-Madison, United States.

To investigate genetic and environmental influences on cortisol levels, mothers of children with fragile X syndrome (FXS) were studied four times over a 7.5-year period. All participants (n = 84) were carriers of the FMR1 "premutation", a genetic condition associated with impaired HPA axis functioning. Genetic variation was indicated by expansions in the number of CGG (cytosine-guanine-guanine) repeats in the FMR1 gene (67-138 repeats in the present sample). The environmental factor was cumulative exposure to adverse life events during the study period. Cortisol was measured at the beginning of the study via saliva samples and at the end of the study via hair samples; hormone values from these two specimen types were significantly correlated. The interactions between CGG repeat number and adverse life events significantly predicted hair cortisol concentration, including after accounting for the initial salivary cortisol level. For those with fewer CGG repeats, stress exposure was associated with elevated cortisol, the expected response to stress, although women with a higher number of CGGs had a reduced cortisol response to adverse events, which might be related to HPA dysfunction. These results indicate that both exogenous and endogenous factors affect HPA functioning in this population of women.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217368PMC
July 2021

Artificial intelligence-assisted phenotype discovery of fragile X syndrome in a population-based sample.

Genet Med 2021 Jul 26;23(7):1273-1280. Epub 2021 Mar 26.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

Purpose: Fragile X syndrome (FXS), the most prevalent inherited cause of intellectual disability, remains underdiagnosed in the general population. Clinical studies have shown that individuals with FXS have a complex health profile leading to unique clinical needs. However, the full impact of this X-linked disorder on the health of affected individuals is unclear and the prevalence of co-occurring conditions is unknown.

Methods: We mined the longitudinal electronic health records from more than one million individuals to investigate the health characteristics of patients who have been clinically diagnosed with FXS. Additionally, using machine-learning approaches, we created predictive models to identify individuals with FXS in the general population.

Results: Our discovery-oriented approach identified the associations of FXS with a wide range of medical conditions including circulatory, endocrine, digestive, and genitourinary, in addition to mental and neurological disorders. We successfully created predictive models to identify cases five years prior to clinical diagnosis of FXS without relying on any genetic or familial data.

Conclusion: Although FXS is often thought of primarily as a neurological disorder, it is in fact a multisystem syndrome involving many co-occurring conditions, some primary and some secondary, and they are associated with a considerable burden on patients and their families.
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http://dx.doi.org/10.1038/s41436-021-01144-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257481PMC
July 2021

Brief Report: Socioeconomic Factors Associated with Minimally Verbal Status in Individuals with ASD.

J Autism Dev Disord 2021 Jun;51(6):2139-2145

Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave., Madison, WI, 53705, USA.

About 30% of adults with autism are minimally verbal. Past research suggested that after age five, few gain verbal fluency, but studies have rarely investigated whether family environmental factors contribute to the acquisition of verbal fluency. The present study utilized data from the Autism Diagnostic Interview-Revised to compare changes in verbal fluency for 404 individuals with autism from childhood to adolescence and adulthood. Socioeconomic factors were examined across fluency groups (i.e., those who did/did not achieve verbal fluency). Findings indicated that fully 60% of those who were minimally verbal in early childhood acquired verbal fluency in adolescence and adulthood. Parent socioeconomic status differed across fluency groups, suggesting the importance of environmental factors for individual development.
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http://dx.doi.org/10.1007/s10803-020-04646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943642PMC
June 2021

Longitudinal changes in well-being of parents of individuals with developmental or mental health problems.

Soc Sci Med 2020 11 21;264:113309. Epub 2020 Aug 21.

Department of Human Development and Family Studies, Pennsylvania State University, 335 Health and Human Development Building, University Park, PA, 16802, USA.

Rationale: A large body of work demonstrates the impact of caregiving burden on the well-being of parents of individuals with developmental conditions or mental health problems. However, a relative dearth of research examines this impact longitudinally into parents' older age.

Objective: The current study examines (1) longitudinal changes in the effect of having a child with a developmental or mental health problem on parental negative affect, psychological well-being, and somatic symptoms, (2) age and gender moderations on these effects, and (3) the unique impact of factors related to the child's condition.

Method: This study employs hierarchical linear regression models to examine longitudinal survey data from midlife adults (N = 1,101) from two waves of the National Study of Midlife in the United States (MIDUS).

Results: Models revealed some evidence for age attenuation of the impact of caregiving stress. Parents of children with developmental problems still had higher negative affect, poorer psychological well-being, and more somatic symptoms on average than parents in a comparison sample, whereas parents of children with mental health problems only showed evidence of higher negative affect compared to this sample. Within-group analyses also revealed differences between each parenting group into later adulthood.

Conclusions: Parents of individuals with developmental or mental health problems may be at risk for poorer well-being late in life. Yet, age and gender differences as well as diagnostic group differences nuance these findings.
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http://dx.doi.org/10.1016/j.socscimed.2020.113309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441882PMC
November 2020

Low Zone CGG Repeats: Phenotypic Associations in the Context of Parenting Stress.

Front Pediatr 2020 14;8:223. Epub 2020 May 14.

Waisman Center, University of Wisconsin-Madison, Madison, WI, United States.

The gene on the X chromosome has varying numbers of CGG repeats. The modal number is 30, and expansion to >200 results in fragile X syndrome, but the copy number extends down to 6. Past research suggests that individuals whose CGGs are in the "low zone" (LZ; defined here as ≤ 25 CGGs) may be more environmentally-reactive than those with normal range repeats (26-40 CGGs)-a gene x environment interaction. Using a population-based DNA biobank, in our primary analysis we compared 96 mothers with LZ CGG repeats on both alleles to 280 mothers who had CGG repeats in the normal range. Secondarily, we conducted parallel analyses on fathers. We investigated how parents in these two CGG repeat categories differentially responded to stress, defined as parenting a child with disabilities. Significant gene x environment interactions indicated that LZ mothers who had children with disabilities had greater limitations (in executive functioning, depression, anxiety, daily health symptoms, and balance) than LZ mothers whose children did not have disabilities. In contrast, mothers with normal-range CGG repeats did not differ based on stress exposure. For fathers, a similar pattern was evident for one phenotype only (hand tremors). Although on average LZ CGGs are not associated with compromised functioning, the average masks differential response to the environment.
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http://dx.doi.org/10.3389/fped.2020.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240007PMC
May 2020

Trajectories of Change in the Behavioral and Health Phenotype of Adolescents and Adults with Fragile X Syndrome and Intellectual Disability: Longitudinal Trends Over a Decade.

J Autism Dev Disord 2020 Aug;50(8):2779-2792

University of Wisconsin-Madison Waisman Center, 1500 Highland Avenue, Room 531A, Madison, WI, 53705, USA.

This study examined trajectories of daily living skills, behavior problems, body mass index (BMI), and health conditions spanning nearly a decade in adolescents and adults with fragile X syndrome (N = 134; age range at study end = 19-49 years), examining influences of sex and autism spectrum disorder (ASD) symptoms. Hierarchical linear modeling revealed early increases in daily living skills, with decreases at older ages. Behavior problems became less severe over time, with some increases at older ages. Individuals gained weight and had increasing health problems over time. Fewer ASD symptoms were associated with greater daily living skills and fewer behavior problems at study start. This study offers some of the first prospective quantitative analyses of behavioral and health life course trajectories in FXS.
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http://dx.doi.org/10.1007/s10803-020-04367-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377950PMC
August 2020

Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome.

Brain Cogn 2020 03 27;139:105511. Epub 2019 Dec 27.

Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave, Madison, WI 53705, USA. Electronic address:

Individuals who carry a premutation (PM) allele on the FMR1 gene may experience executive limitations associated with their genetic status, including inhibition deficits. However, poor understanding of individualized risk factors has limited clinical management of this group, particularly in mothers who carry the PM allele who have children with fragile X syndrome (FXS). The present study examined CGG repeat length and age as factors that may account for variable expressivity of inhibition deficits. Participants were 134 carriers of the PM allele who were mothers of children with FXS. Inhibition skills were measured using both self-report and direct behavioral assessments. Increased vulnerability for inhibition deficits was observed at mid-range CGG lengths of approximately 80-100 repeats, with some evidence of a second zone of vulnerability occurring at approximately 130-140 CGG repeats. Risk associated with the genotype also became more pronounced with older age. This study identifies personalized risk factors that may be used to tailor the clinical management of executive deficits in carriers of the PM allele. Inhibition deficits may contribute to poor outcomes in carriers of the PM allele and their families, particularly in midlife and early old age, and clinical monitoring may be warranted.
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http://dx.doi.org/10.1016/j.bandc.2019.105511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954879PMC
March 2020

Positive Emotional Support in Premutation Carrier Mothers of Adolescents and Adults With Fragile X Syndrome: Gene by Environment Interactions.

Am J Intellect Dev Disabil 2019 09;124(5):411-426

Sigan L. Hartley, Waisman Center and School of Human Ecology, University of Wisconsin-Madison; Leann S. DaWalt, Jinkuk Hong, Jan S. Greenberg, and Marsha R. Mailick, Waisman Center, University of Wisconsin-Madison.

We examined the benefit of emotional support on daily health in premutation carrier mothers of adolescents and adults with fragile X syndrome ( = 114), and whether this benefit was moderated by the mother's genetic status ( CGG repeat length). In an 8-day daily diary, maternal daily health was assessed subjectively through self-reported number of physical health symptoms and physiologically via cortisol awakening response. Multilevel lagged-day models indicated that premutation carrier mothers with midrange CGG repeats derived less health benefit from a day with high positive emotional support than those with lower or higher numbers of repeats within the premutation range. The data support the influence of both genetic and environmental influences on the health of this population.
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http://dx.doi.org/10.1352/1944-7558-124.5.411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948144PMC
September 2019

Data-driven phenotype discovery of premutation carriers in a population-based sample.

Sci Adv 2019 08 21;5(8):eaaw7195. Epub 2019 Aug 21.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

The impact of the premutation on human health is the subject of considerable controversy. A fundamental unanswered question is whether carrying the premutation allele is directly correlated with clinical phenotypes. A challenging problem in past genotype-phenotype studies of the premutation is ascertainment bias, which could lead to invalid research conclusions and negatively affect clinical practice. Here, we created the first population-based -informed biobank to find the pattern of health characteristics in premutation carriers. Our extensive phenotyping shows that premutation carriers experience a clinical profile that is significantly different from controls and is evident throughout adulthood. Comprehensive understanding of the clinical risk associated with this genetic variant is critical for premutation carriers, their families, and clinicians and has important implications for public health.
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http://dx.doi.org/10.1126/sciadv.aaw7195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703870PMC
August 2019

Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness.

PLoS Genet 2019 04 4;15(4):e1007973. Epub 2019 Apr 4.

Department of Statistics, University of Wisconsin-Madison, Madison, WI, United States of America.

Facial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 4,383 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci, highlighted a handful of candidate genes, and demonstrated enrichment for heritability in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis.
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http://dx.doi.org/10.1371/journal.pgen.1007973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448826PMC
April 2019

Validating psychosocial pathways of risk between neuroticism and late life depression using a polygenic score approach.

J Abnorm Psychol 2019 Apr 4;128(3):200-211. Epub 2019 Mar 4.

Waisman Center, University of Wisconsin-Madison.

Neuroticism is a stable and heritable personality trait that is strongly linked to depression. Yet, little is known about its association with late life depression, as well as how neuroticism eventuates into depression. This study used data from the Wisconsin Longitudinal Study (WLS; N = 4,877) to examine the direct and indirect effects of neuroticism on late life depression at 3 points in the life course-ages 53, 64, and 71-via stressful life events (i.e., independent and dependent) and social supports measured across adulthood and into later life. Neuroticism was assayed using multiple methods, including self-report measures (phenotypic model) and a polygenic score (polygenic model) informed by a meta-analytic genome-wide association study. Results indicated that the phenotypic model of neuroticism and late life depression was partially mediated via dependent stressful life events experienced after the age of 53 and by age 64 social support. This association was replicated in the polygenic model of neuroticism, providing key evidence that the findings are robust. No indirect effects emerged with respect to age 53 social support, age 71 social support, adult dependent stressful life events (experienced between age 19 and 52), and adult and late life independent stressful life events in either the phenotypic or polygenic models as they pertained to late life depression. Results are consistent with previous findings that individuals with high neuroticism may be vulnerable to late life depression through psychosocial risk factors that are, in part, attributable to their own personality. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462143PMC
April 2019

Mortality in individuals with autism spectrum disorder: Predictors over a 20-year period.

Autism 2019 10 28;23(7):1732-1739. Epub 2019 Feb 28.

University of Wisconsin-Madison, USA.

Research has shown that individuals with autism spectrum disorder have higher rates of health problems throughout childhood, adolescence, and adulthood, and that this may result in elevated risk of early mortality. This study reported the rate, timing, and causes of death in a large community-based cohort of adolescents and adults with autism spectrum disorder ( = 406) over a 20-year period (1998-2018) and identified predictors of mortality. Over this period, 6.4% of individuals died at an average age of 39 years. Causes of death included chronic conditions (such as cancer and heart disease), accidents (such as choking on food and accidental poisoning), and health complications due to medication side effects. Even after controlling for age and health status, significant predictors of mortality were early childhood levels of impairments in social reciprocity and high levels of functional impairments at the start of the study period. The results suggest the importance of social engagement and functional self-sufficiency across the life course, as well as adequate access to health care for individuals with autism spectrum disorder.
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http://dx.doi.org/10.1177/1362361319827412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713622PMC
October 2019

Health Profiles of Mosaic Versus Non-mosaic Premutation Carrier Mothers of Children With Fragile X Syndrome.

Front Genet 2018 16;9:173. Epub 2018 May 16.

Department of Pediatrics, Rush University Medical Center, Chicago, IL, United States.

The premutation is of increasing interest to the FXS community, as questions about a primary premutation phenotype warrant research attention. 100 premutation carrier mothers (mean age = 58; 67-138 CGG repeats) of adults with fragile X syndrome were studied with respect to their physical and mental health, motor, and neurocognitive characteristics. We explored the correlates of CGG repeat mosaicism in women with expanded alleles. Mothers provided buccal swabs from which DNA was extracted and the CGG genotyping was performed (Amplidex Kit, Asuragen). Mothers were categorized into three groups: Group 1: premutation non-mosaic ( = 45); Group 2: premutation mosaic ( = 41), and Group 3: premutation/full mutation mosaic ( = 14). Group 2 mothers had at least two populations of cells with different allele sizes in the premutation range besides their major expanded allele. Group 3 mothers had a very small population of cells in the full mutation range (>200 CGGs) in addition to one or multiple populations of cells with different allele sizes in the premutation range. Machine learning (random forest) was used to identify symptoms and conditions that correctly classified mothers with respect to mosaicism; follow-up comparisons were made to characterize the three groups. In categorizing mosaicism, the random forest yielded significantly better classification than random classification, with overall area under the receiver operating characteristic curve (AUROC) of 0.737. Among the most important symptoms and conditions that contributed to the classification were anxiety, menopause symptoms, executive functioning limitations, and difficulty walking several blocks, with the women who had full mutation mosaicism (Group 3) unexpectedly having better health. Although only 14 premutation carrier mothers in the present sample also had a small population of full mutation cells, their profile of comparatively better health, mental health, and executive functioning was unexpected. This preliminary finding should prompt additional research on larger numbers of participants with more extensive phenotyping to confirm the clinical correlates of low-level full mutation mosaicism in premutation carriers and to probe possible mechanisms.
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http://dx.doi.org/10.3389/fgene.2018.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964198PMC
May 2018

Factors associated with sustained community employment among adults with autism and co-occurring intellectual disability.

Autism 2018 10 9;22(7):794-803. Epub 2017 Jul 9.

1 University of Wisconsin-Madison, USA.

Sustaining community employment is a challenge for adults with autism spectrum disorders, especially for those who have co-occurring intellectual disability, but factors contributing to this employment outcome have not been fully evaluated. This study utilized longitudinal data to explore the impact of contextual influences, family factors, and individual characteristics on sustained employment over approximately 18 months ( N = 105). Very few adults with autism spectrum disorder and intellectual disability achieved sustained employment (14.3%). The results indicated that more independent daily living skills, a higher family income, a larger maternal social network, an inclusive school environment in early childhood, and currently living in an area with a larger population size were associated with significantly greater odds of sustaining employment. Follow-up analyses suggested that managing personal care is particularly important for employment.
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http://dx.doi.org/10.1177/1362361317703760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825405PMC
October 2018

Is Low FMR1 CGG Repeat Length in Males Correlated with Family History of BRCA-Associated Cancers? An Exploratory Analysis of Medical Records.

J Genet Couns 2017 Dec 30;26(6):1401-1410. Epub 2017 Jun 30.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

The FMR1 gene has been studied extensively with regard to expansions and premutations, but much less research has focused on potential effects of low CGG repeat length. Previous studies have demonstrated that BRCA1/2 positive women are more likely to have an FMR1 genotype with one low CGG allele, and that women with both FMR1 alleles in the low CGG repeat range are more likely to have had breast cancer compared to women with normal numbers of CGG repeats. However, there has been no research as to whether low CGG repeat length impacts cancer risks in men. Therefore, this study aimed to examine cancer incidence and related risk factors in men with low CGG repeat length in the FMR1 gene. We utilized subject data from the Marshfield Personalized Medicine Research Project to compare cancer-related diagnoses between 878 males with low CGG repeat length (< 24 repeats) and 368 male controls with CGG repeats in the normal range (24 to 40 repeats). We utilized ICD-9 codes to examine various cancer diagnoses, family histories of cancer, other non-malignant neoplasms, cancer surveillance, and genetic susceptibility. Men with low CGG repeats were identified to have significantly higher rates of family history of any cancer type (p = 0.011), family history of any BRCA-associated cancer (p = 0.002), and specifically, family history of prostate cancer (p = 0.007). The mean number of BRCA-associated cancer diagnoses (breast, prostate, pancreatic, and melanoma) per individual in the low CGG group was slightly higher than that of the control group, with this difference trending toward significance (p = 0.091). Additionally, men with low CGG repeats had significantly higher rates of connective/soft tissue neoplasms (p = 0.026). Additional research is needed to replicate the observations reported in this preliminary exploratory study, particularly including verification of ICD-9 codes and family history by a genetic counselor.
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http://dx.doi.org/10.1007/s10897-017-0116-5DOI Listing
December 2017

Validating the social responsiveness scale for adults with autism.

Autism Res 2017 Oct 22;10(10):1663-1671. Epub 2017 Jun 22.

Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, 53705.

The Social Responsiveness Scale [SRS; Constantino & Gruber, 2005] is a widely-used measure of autism symptoms, but its application for the study of adults with autism spectrum disorders has not been fully evaluated. Using a factor structure consistent with The Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-V) criteria for autism spectrum disorder [Frazier et al., 2014], the primary purpose of the current study was to establish the validity of the SRS with a sample of adults with autism spectrum disorder (N = 237). Correlational analyses indicated that SRS factors were highly associated with autism symptoms and behavioral measures, indicating concurrent and predictive validity. Multiple regression results demonstrated that SRS factors were differentially related to measures specific to social or behavioral domains, indicating convergent and discriminant validity. Implications for future research are discussed. Autism Res 2017, 10: 1663-1671. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.1813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648615PMC
October 2017

FMR1 genotype interacts with parenting stress to shape health and functional abilities in older age.

Am J Med Genet B Neuropsychiatr Genet 2017 Jun 13;174(4):399-412. Epub 2017 Apr 13.

Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin.

This study investigated the association of genotype (CGG repeats in FMR1) and the health and well-being of 5,628 aging adults (mean age = 71) in a population-based study. Two groups were contrasted: aging parents who had adult children with developmental or mental health disabilities (n = 785; the high-stress parenting group) and aging parents of healthy children who did not have disabilities (n = 4843; the low-stress parenting group). There were significant curvilinear interaction effects between parenting stress group and CGG repeats for body mass index and indicators of health and functional limitations, and the results were suggestive of interactions for limitations in cognitive functioning. Parents who had adult children with disabilities and whose genotype was two standard deviations above or below the mean numbers of CGGs had poorer health and functional outcomes at age 71 than parents with average numbers of CGGs. In contrast, parents who had healthy adult children and who had similarly high or low numbers of CGG repeats had better health and functional outcomes than parents with average numbers of CGGs. This pattern of gene by environment interactions was consistent with differential susceptibility or the flip-flop phenomenon. This study illustrates how research that begins with a rare genetic condition (such as fragile X syndrome) can lead to insights about the general population and contributes to understanding of how genetic differences shape the way people respond to environments. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435525PMC
June 2017

Executive Functioning Mediates the Effect of Behavioral Problems on Depression in Mothers of Children With Developmental Disabilities.

Am J Intellect Dev Disabil 2017 01;122(1):11-24

Wai Chan, Leann E. Smith, Jan S. Greenberg, Jinkuk Hong, and Marsha R. Mailick, University of Wisconsin, Madison, Waisman Center.

The present investigation explored long-term relationships of behavioral symptoms of adolescents and adults with developmental disabilities with the mental health of their mothers. Fragile X premutation carrier mothers of an adolescent or adult child with fragile X syndrome (n = 95), and mothers of a grown child with autism (n = 213) were included. Behavioral symptoms at Time 1 were hypothesized to predict maternal depressive symptoms at Time 3 via maternal executive dysfunction at Time 2. Results provided support for the mediating pathway of executive dysfunction. Additionally, the association of behavioral symptoms with executive dysfunction differed across the two groups, suggesting that premutation carriers may be more susceptible to caregiving stress due to their genotype.
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http://dx.doi.org/10.1352/1944-7558-122.1.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303617PMC
January 2017

Characterizing Objective Quality of Life and Normative Outcomes in Adults with Autism Spectrum Disorder: An Exploratory Latent Class Analysis.

J Autism Dev Disord 2016 Aug;46(8):2707-2719

Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave., Madison, WI, 53705, USA.

This study aims to extend the definition of quality of life (QoL) for adults with autism spectrum disorder (ASD, n = 180, ages 23-60) by: (1) characterizing the heterogeneity of normative outcomes (employment, independent living, social engagement) and objective QoL (physical health, neighborhood quality, family contact, mental health issues); and (2) identifying predictors of positive normative outcomes and good objective QoL. Findings of an exploratory latent class analysis identified three groups of adults with ASD-Greater Dependence, Good Physical and Mental Health, and Greater Independence. Findings indicate that better daily living skills, better executive function, and more maternal warmth are associated with assignment to better outcome groups. Findings have implications for interventions designed to enhance achievement of normative outcomes and objective QoL.
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http://dx.doi.org/10.1007/s10803-016-2816-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039043PMC
August 2016

Change in the Behavioral Phenotype of Adolescents and Adults with FXS: Role of the Family Environment.

J Autism Dev Disord 2016 May;46(5):1824-33

Waisman Center, University of Wisconsin, 1500 Highland Avenue, Madison, WI, 53705, USA.

The present study examined trajectories of adaptive behavior, behavior problems, psychological symptoms, and autism symptoms in adolescents and adults with fragile X syndrome (n = 147) over a three-year period. Adaptive behavior significantly increased over time, particularly for adolescents, and the severity of behavior problems decreased over time. Family environmental factors predicted phenotypic variables net of gender, intellectual disability status, and medication use. Maternal warmth was associated with higher levels of adaptive behavior, lower levels of autism symptoms, and decreases in behavior problems over time. Maternal depressive symptoms and criticism were associated with higher levels of psychological symptoms. Implications for interventions are discussed.
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http://dx.doi.org/10.1007/s10803-016-2714-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826830PMC
May 2016

Factors Associated with Subjective Quality of Life of Adults with Autism Spectrum Disorder: Self-Report Versus Maternal Reports.

J Autism Dev Disord 2016 Apr;46(4):1368-78

Waisman Center, University of Wisconsin-Madison, 1500 Highland Ave., Madison, WI, 53705, USA.

We examined factors related to subjective quality of life (QoL) of adults with autism spectrum disorder (ASD) aged 25-55 (n = 60), using the World Health Organization Quality of Life measure (WHOQOL-BREF). We used three different assessment methods: adult self-report, maternal proxy-report, and maternal report. Reliability analysis showed that adults with ASD rated their own QoL reliably. QoL scores derived from adult self-reports were more closely related to those from maternal proxy-report than from maternal report. Subjective factors such as perceived stress and having been bullied frequently were associated with QoL based on adult self-reports. In contrast, level of independence in daily activities and physical health were significant predictors of maternal reports of their son or daughter's QoL.
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http://dx.doi.org/10.1007/s10803-015-2678-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788526PMC
April 2016

Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions.

Am J Med Genet B Neuropsychiatr Genet 2014 Dec 25;165B(8):705-11. Epub 2014 Oct 25.

Waisman Center, University of Wisconsin-Madison, Wisconsin.

In a sample of post-menopausal premutation carrier mothers of children with the full mutation of fragile X syndrome (n = 88), this study examined the co-occurrence of the reproductive and psychiatric phenotypes associated with FMR1 premutations. Mean age at menopause was 43.1 years, and 35.2% of premutation carriers reported cessation of menses prior to age 40 (premature ovarian failure), but only 18% of carriers had been medically diagnosed by a physician as having Fragile X-associated Primary Ovarian Insufficiency. There was a significant curvilinear association between CGG repeat length and age at menopause, with women who had mid-range repeats having the earliest menopause, similar to the pattern that has been found for the psychiatric phenotype of the FMR1 premutation.
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http://dx.doi.org/10.1002/ajmg.b.32277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410868PMC
December 2014

Daily Work Stress and Awakening Cortisol in Mothers of Individuals with Autism Spectrum Disorders or Fragile X Syndrome.

Fam Relat 2014 Feb;63(1):135-147

University of Wisconsin-Madison ***

The effect of daily work stress on the next morning's awakening cortisol level was determined in a sample of 124 mothers (M age = 49.89, SD= 6.33) of adolescents and adults with developmental disabilities and compared to 115 mothers (M age = 46.19, SD = 7.08) of individuals without disabilities. Mothers participated in 8 days of diary telephone interviews and provided saliva samples. Multilevel models revealed that mothers of individuals with developmental disabilities had lower awakening cortisol levels than comparison mothers. Work stress interacted with parental status to predict the awakening cortisol level on the following morning. When mothers of individuals with developmental disabilities experienced a work stressor, their awakening cortisol level was significantly higher on the subsequent morning, but for comparison mothers, work stressors were not significantly associated with cortisol level. Findings extend understanding of the differential impacts of specific types of stressors on physiological functioning of mothers of individuals with and without developmental disabilities.
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http://dx.doi.org/10.1111/fare.12055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192722PMC
February 2014

Low-normal FMR1 CGG repeat length: phenotypic associations.

Front Genet 2014 9;5:309. Epub 2014 Sep 9.

Waisman Center, University of Wisconsin-Madison Madison, WI, USA.

This population-based study investigates genotype-phenotype correlations of "low- normal" CGG repeats in the fragile X mental retardation 1 (FMR1) gene. FMR1 plays an important role in brain development and function, and encodes FMRP (fragile X mental retardation protein), an RNA-binding protein that regulates protein synthesis impacting activity-dependent synaptic development and plasticity. Most past research has focused on CGG premutation expansions (41-200 CGG repeats) and on fragile X syndrome (200+ CGG repeats), with considerably less attention on the other end of the spectrum of CGG repeats. Using existing data, older adults with 23 or fewer CGG repeats (2 SDs below the mean) were compared with age-peers who have normal numbers of CGGs (24-40) with respect to cognition, mental health, cancer, and having children with disabilities. Men (n = 341 with an allele in the low-normal range) and women (n = 46 with two low-normal alleles) had significantly more difficulty with their memory and ability to solve day to day problems. Women with both FMR1 alleles in the low-normal category had significantly elevated odds of feeling that they need to drink more to get the same effect as in the past. These women also had two and one-half times the odds of having had breast cancer and four times the odds of uterine cancer. Men and women with low-normal CGGs had higher odds of having a child with a disability, either a developmental disability or a mental health condition. These findings are in line with the hypothesis that there is a need for tight neuronal homeostatic control mechanisms for optimal cognitive and behavioral functioning, and more generally that low numbers as well as high numbers of CGG repeats may be problematic for health.
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http://dx.doi.org/10.3389/fgene.2014.00309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158814PMC
September 2014

FMR1 CGG expansions: prevalence and sex ratios.

Am J Med Genet B Neuropsychiatr Genet 2013 Jul 5;162B(5):466-73. Epub 2013 Jun 5.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

We have estimated the prevalence of FMR1 premutation and gray zone CGG repeat expansions in a population-based sample of 19,996 male and female adults in Wisconsin and compared the observed sex ratios of the prevalence of FMR1 CGG premutation and gray zone expansions to theoretical sex ratios. The female premutation prevalence was 1 in 148 and comparable to past research, but the male premutation prevalence of 1 in 290 is somewhat higher than most previous estimates. The female:male premutation prevalence ratio is in line with the theoretically predicted sex ratio. The prevalence of CGG repeats in the gray zone (45-54 repeats) was 1 in 33 females and 1 in 62 males. The prevalence of the "expanded" gray zone (defined here as 41-54 CGG repeats) was 1 in 14 females and 1 in 22 males, leading to a female:male ratio of 1.62 (95% confidence interval 1.39-1.90). This female:male ratio was significantly lower than the expected ratio of 2.0. We examined results from three previously published FMR1 prevalence studies and found similar female:male ratios for CGG repeats in this "expanded" gray zone range (pooled female:male ratio across all four studies 1.66, 95% confidence interval 1.51-1.82). Further research is needed to understand the apparent excess prevalence of males with CGG repeats in this range.
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http://dx.doi.org/10.1002/ajmg.b.32176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885228PMC
July 2013

Allostatic load in parents of children with developmental disorders: moderating influence of positive affect.

J Health Psychol 2014 Feb 8;19(2):262-72. Epub 2013 Jan 8.

University of Wisconsin-Madison, USA.

This study examines whether parents of children with developmental disorders are at risk of elevated allostatic load relative to control parents and whether positive affect moderates difference in risk. In all, 38 parents of children with developmental disorders and 38 matched comparison parents were analyzed. Regression analyses revealed a significant interaction between parent status and positive affect: parents of children with developmental disorders had lower allostatic load when they had higher positive affect, whereas no such association was evident for comparison parents. The findings suggest that promoting greater positive affect may lower health risks among parents of children with developmental disorders.
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http://dx.doi.org/10.1177/1359105312468193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652902PMC
February 2014

Evaluation of an activities of daily living scale for adolescents and adults with developmental disabilities.

Disabil Health J 2013 Jan 17;6(1):8-17. Epub 2012 Oct 17.

Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.

Background: Activity limitations are an important and useful dimension of disability, but there are few validated measures of activity limitations for adolescents and adults with developmental disabilities.

Objective/hypothesis: To describe the development of the Waisman Activities of Daily Living (W-ADL) Scale for adolescents and adults with developmental disabilities, and systematically evaluate its measurement properties according to an established set of criteria.

Methods: The W-ADL was administered among four longitudinally studied groups of adolescents and adults with developmental disabilities: 406 with autism; 147 with fragile-X syndrome; 169 with Down syndrome; and 292 with intellectual disability of other or unknown origin. The W-ADL contains 17 activities and each is rated on a 3-point scale (0 = "does not do at all", 1 = "does with help", 2 = "independent"), and a standard set of criteria were used to evaluate its measurement properties.

Results: Across the disability groups, Cronbach's alphas ranged from 0.88 to 0.94, and a single-factor structure was most parsimonious. The W-ADL was reliable over time, with weighted kappas between 0.92 and 0.93. Criterion and construct validity were supported through substantial associations with the Vineland Screener, need for respite services, caregiving burden, and competitive employment. No floor or ceiling effects were present. There were significant group differences in W-ADL scores by maternally reported level of intellectual disability (mild, moderate, severe, profound).

Conclusions: The W-ADL exceeded the recommended threshold for each quality criterion the authors evaluated. This freely available tool is an efficient measure of activities of daily living for surveys and epidemiological research concerning adolescents and adults with developmental disabilities.
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http://dx.doi.org/10.1016/j.dhjo.2012.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531884PMC
January 2013
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