Janet K. Williams

Children admitted to the Pediatric Intensive Care Unit (PICU) are critically-ill and vulnerable to pain. When a child cannot self-report their pain, a nurse must use various other means to assess pain. At times, a child requires the use of mechanical ventilation. Additionally, to maintain adequate oxygen levels, a child may require to be medically paralyzed which makes the child unable to move. Then, there is no valid method to assess and manage pain. This dissertation aimed to discover how nurses are managing pain in children who cannot self-report their pain and cannot move. It was found that nurses reported using behavioral pain assessment scales. However, using this, the score would indicate no pain since the child cannot move. Additionally, some nurses used the term “assume pain present” but it is unknown how nurses are using it. During interviews, nurses described using physiological variables (heart rate) to assess pain which has limitations. Without a valid assessment method, nurses developed patterns of thinking, such as trial and error, to make decisions. “Assume pain present” was described here; however, variation existed between nurses. Potential exists for using “assume pain present” when situations that are known to be painful are present versus physiological variables that fluctuate constantly. Overall, this dissertation indicates a need to develop a standard guideline on when and how to use “assume pain present” in clinical practice. Lastly, decision support tools need to be created to aid the PICU nurse to know when various pain assessment methods can be used.

Sleep health and sufficient sleep are particularly important during adolescence when important physical, cognitive, emotional, and social changes occur. Given the potential role of PAX6 in pineal development and circadian regulation, adolescents with PAX6 haploinsufficiency may be more likely to experience sleep-related problems compared to adolescents without these deletions or mutations. Haploinsufficiency of PAX6 can result from WAGR syndrome, a contiguous gene deletion syndrome in which multiple genes are involved, or point mutations and microdeletions affecting only PAX6, which result in isolated aniridia. The purpose of this dissertation is to examine pineal volume, melatonin concentrations, and sleep disturbance in individuals with PAX6 haploinsufficiency, as well describe validity of self-report measures of sleep problems in adolescents. Results are presented in three papers.Although PAX6 haploinsufficiency is rare and minimal research has focused on the role of PAX6 in circadian regulation, irregular patterns of sleep-wake rhythm have been studied in children and adolescents with neurodevelopmental disorders (e.g. autism spectrum disorders), another population with possible abnormalities in melatonin physiology. The first paper presents an integrative review to synthesize the literature regarding the sleep-related measures currently being used to assess sleep disturbance in adolescents with a neurodevelopmental disorder. The second paper reports significantly reduced pineal volume, reduced melatonin secretion, and greater parent-report of sleep disturbance in individuals with PAX6 haploinsufficiency versus controls. Paper 3 further characterizes the sleep-related-phenotype associated with an abnormality in the PAX6 gene using self-report questionnaires and actigraphy in adolescents with PAX6 haploinsufficiency, as well as performs preliminary validation studies on age-appropriate self-report tools to measure sleep in adolescents. Results demonstrate similar self-reported daytime sleepiness, sleep disturbance, and sleep-related impairment in adolescents with PAX6 haploinsufficiency compared to the healthy comparison group; however, actigraphy data documented increased time from lights off to sleep in the PAX6 haploinsufficiency group. Self-reported sleep questionnaire scores and objective actigraphy variables (e.g. total sleep time) were significantly correlated in the healthy comparison group only; however, a lack of correlation among sleep-related measures in adolescents with PAX6 haploinsufficiency suggests potential limitations in using self-reported sleep measures in this population. This study used a combination of physiological and patient-reported health measures, and although WAGR syndrome and isolated aniridia due to PAX6 insufficiency are rare disorders, describing the sleep-related phenotypes in this population contributes to knowledge of assessment and treatment of sleep disorders in general, facilitating research in additional adolescent populations.

Background: Hypertrophic Cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are genetic cardiovascular diseases that cause sudden cardiac death. When an individual is diagnosed with an inherited disease such as HCM/LQTS it is critical that their biological relatives are notified of their increased risk. Newly diagnosed individuals in turn notify other at-risk family members through a successive process called cascade screening. This facilitates screening of at-risk biological relatives through genetic testing and/or clinical testing, and treatment for HCM/LQTS prior to development of life-threatening complications. However, for cascade screening to detect all potential cases the disease risk must be effectively communicated to all at-risk relatives. The responsibility for notifying family members of this risk largely falls to the first person diagnosed in the family (proband). Empiric evidence suggests that around half of at-risk relatives are not screened in accordance with cascade screening recommendations, potentially due to information about HCM/LQTS risk not being communicated effectively in their families. Factors have been identified that influence communication about genetic risk in families with non-cardiac disease; however, it is not known if or how these factors apply in families with genetic cardiac disease. These include network factors, which describe characteristics of relationships between family members and non-network factors, which describe characteristics of individuals including individual factors, disease factors, and sociocultural factors. There is a critical need to understand communication in families with HCM/LQTS in order to facilitate effective genetic risk communication in families, improve adherence to cascade screening recommendations, and prevent death and complications from cardiovascular diseases. Objectives: The purpose of this study was to improve our understanding of the relationships among network and non-network factors and communication of genetic risk for HCM/LQTS between probands and their relatives. I proposed the following aims: Aim 1: Describe family social network structures and communication paths about risk for HCM/LQTS from probands to their relatives. Aim 2: Identify which network and non-network factors are associated with who is told about risk for HCM/LQTS. Methods: The sample for this study included individuals with HCM or LQTS recruited through the University of Iowa Cardiology Clinics (UI) and the University of Wisconsin Inherited Arrhythmia Clinic (UW). Data were collected using a structured interview, family pedigree, and survey. Analysis included egocentric social network analysis, descriptive, bivariate, and multilevel logit regression modeling. Results: Participants in this study had an average of 24 living at-risk relatives in their families. Overall, just over half (52%) of these at-risk relatives had been reported to have been told about their risk. However, within families, the percentage of relatives told about their risk ranged from 0%-100%. Ninety percent of first-degree relatives were told about their risk, 61% of second-degree relatives were told and 33% of third-degree relatives were told. Recruitment site affiliation was determined to be a confounder and so analyses were calculated separately for UI and UW. In both the UI and UW samples, network factors including closer geographic distance, increased emotional closeness, increased relationship quality, increased frequency of communication, higher betweenness centrality, and closer degree of biological relation were independently associated with increased odds of communication of risk. In the UI sample, non-network factors that were independently associated with increased odds of communication of risk included younger age at diagnosis; having LQTS; having positive genetic test results; having an ICD; younger current age; being female; having increased role limitations due to physical functioning; feeling anxious about telling family members about risk; feeling communication was a burden; feeling that communication was a responsibility or duty; being happy to be able to share important information; and identifying financial issues, pregnancies, or upcoming marriages as playing a role in communication. In a multivariate model, increased frequency of communication, closer degree of biological relation, having an ICD, and identifying financial issues and pregnancies as contributors to communication were significantly associated with communication of genetic risk information. In the UW sample, non-network factors that were independently associated with increased odds of communication of risk included younger age, decreased emotional wellbeing, increased role limitations due to emotional wellbeing, and decreased energy and fatigue. In a multivariate model, increased frequency of communication and closer degree of biological relation were significantly associated with communication. Although over half of at-risk relatives were told about their risk, just over half of those (53.8%) were reported to have screened for disease, which represents 27% of all at-risk relatives. Of those tested, 35% were reported as diagnosed with HCM/LQTS. Conclusion: Communication of genetic risk for HCM/LQTS in families is inadequate and contributes to the problem of relatives not being screened for disease. Insight on the factors that influence communication in families at risk of sudden cardiac death can guide development of interventions, policies, and future research aimed at improving genetic risk communication and cascade screening, and preventing death and complications from inherited cardiac diseases. This research is applicable for genetic conditions where population based screening methods are not effective and rely on families to communicate risk and need for screening.

Precision medicine envisions a future of effective diagnosis, treatment, and prevention grounded in precise understandings of the genetic and environmental determinants of disease. Given that the original genome-wide association studies represented a predominately European White population, and that diversity in genomic studies must account for genetic variation both within and across racial categories, new research studies are at a heightened risk for inadequate representation. Currently biological samples are being made available for sequencing in biobanks across the USA, but the diversity of those samples is unknown. The aims of this study were to describe the types of recruitment and enrollment materials used by US biobanks and the diversity of the samples contained within their collection. Biobank websites and brochures were evaluated for reading level, health literacy, and factors known to encourage the recruitment of minorities, such as showing pictures of diverse populations. Biobank managers were surveyed by mail on the methods and materials used for enrollment, recruitment, consent, and the self-reported race/ethnicity of biobank participants. From 51 US biobanks (68% response rate), recruitment and enrollment materials were in English only, and most of the websites and brochures exceeded a fifth-grade reading level. When compared to the 2015 US Census, self-reported race/ethnicity of participants was not significantly different for Whites (61%) and blacks (13%). The percentages were significantly lower for Hispanics and Latinos (18 vs. 7%, p = 0.00) and Hawaiian/Pacific Islanders (0.2 vs. 0.01%; p = 0.01) and higher for Asians (13 vs. 5%, p = 0.01). Materials for recruitment predominantly in English may limit participation by underrepresented populations.