What Is Known/What Is New
What Is Known
- Tailored reproductive recurrence information is available to adults with Hirschsprung disease and parents of affected children.
- No studies to date in these groups have assessed interest in reproductive genetic information or factors that predict this interest.
What Is New
- Interest in reproductive genetic information is high in adults with Hirschsprung disease and parents of children with Hirschsprung disease.
- Although these groups differ in some perceptions of Hirschsprung disease, it is nearly uniformly viewed as severe.
- Both parents of children with Hirschsprung disease and affected adults should be offered genetic counseling where their attitudes and options for reproductive genetic information can be explored.
Hirschsprung disease (HSCR) is a multifactorial condition with >80% heritability where genomics is advancing understanding of risk factors. It is associated with multiple rare genetic variants that demonstrate variable penetrance and exacerbate common genetic susceptibility from enhancer variants in the RET gene (1). Genetic evaluation including physical examination, family history, and genetic testing can rule out syndromic forms of the disease that affect management and recurrence risks. For isolated disease, empiric recurrence risk estimates, constrained by models of genetic inheritance, are available (2), along with genetic testing, which may yield variants informative for prenatal testing and preimplantation genetic diagnosis (PGD). Thereby, the degree of interest in genetic counseling and testing for reproductive information in the HSCR community is a relevant and important target for study. Studies in other genetic conditions have suggested that interest in prenatal testing is associated with an individual's experiences and perceptions of a condition and quality of life (3,4).
Individuals with an elevated risk to have a child with HSCR include unaffected parents of children with HSCR and adults who themselves have HSCR. Studies have assessed quality of life in both groups, but little is known about perceptions of HSCR. Given the early-life presentation, it may be hypothesized that parents of affected children and affected individuals themselves differ in their perceptions of the disorder and quality of life concerns, as has been demonstrated with other congenital diseases (5). Differing perceptions and experiences between these groups may affect interest in information about recurrence risks. In this study, we reference Lazarus and Folkman's transactional theory of stress and coping (6) to assess quality of life and illness perceptions as cognitive appraisals of HSCR, then seek to determine whether these appraisals affect interest in reproductive genetic information.
Eligible participants were individuals ages 18 years or older who have a child with HSCR or are affected with HSCR themselves. Participants were recruited from June to September of 2016 through announcements to HSCR support groups, a study Facebook page with advertisements, and letters sent to participant households in an ongoing HSCR genetic study. Study materials were titled “Views and Experiences of Hirschsprung Disease” to avoid bias of more responses from those with strong views about reproductive genetic services. All study advertisements included a link to complete the study survey online (Qualtrics platform (7)) and contact information to request a paper survey. The survey is provided in Supplemental Digital Content 1 (http://links.lww.com/MPG/B651).
The study was approved by the Johns Hopkins Medical Institutions Institutional Review Board. Each survey was prefaced by a study fact sheet with a statement that completion of the survey served as implied consent to the study. Eligibility was assessed in the first 2 questions and those not eligible were directed to end the survey. Eligible participants were asked to choose 1 of 3 groups that best described themselves: parent of a child with HSCR, adult with HSCR, or adult with HSCR who also has a child with HSCR.
Interest in Reproductive Genetic Information
Participants were asked 3 questions about their interest in reproductive genetic information; one each about reproductive genetic counseling (RGC), prenatal genetic testing (PNT), and PGD. For each, a description of the service and information it can provide was given and patients were asked if they would be interested in the service if they are or were hypothetically expecting a child. The option responses were yes, no, and unsure. These questions were placed midsurvey.
Perceived severity was assessed through a single question asking participants to rate HSCR as: not at all severe, not very severe, somewhat severe, or very severe. The Illness Perceptions Questionnaire-Revised (IPQ-R) was used to collect a measure of participants’ views of HSCR using an instrument validated in individuals with varying disease types (8) and in caregivers (9). We collected subscale measures about HSCR of perceived chronicity (Timeline), cyclical nature (Timeline Cyclical), negative consequences on the affected individual's life (Consequences), control over the condition (Personal Control), control through treatment (Treatment Control), personal understanding (Illness Coherence), and negative emotional responses (Emotional Representations). Each subscale has demonstrated good internal consistency (Cronbach alpha ranges between 0.79 and 0.89 on the subscales) (8). Each IPQ-R subscale was calculated by taking the mean of all 5-point Likert scale responses and multiplying by the number of items in the subscale (allowing up to 20% missing data). The IPQ-R Causes scale was also collected. For the Causes scale participants rated their agreement with each of 13 potential attributed causes on a 5-point Likert scale and data for each cause were analyzed categorically. Affected adults who also have an affected child were asked to complete IPQ-R subscales first from their perspective of HSCR in themselves and then in their child.
Quality of Life
The Quality of Life Index (QLI) (10) was used, with permission, to measure participants’ quality of life. The scale incorporates both satisfaction and importance of each construct and has demonstrated good internal consistency (Cronbach alpha ≥90). Scores for total quality of life and subscales for health and functioning, social and economic, psychological/spiritual, and family were calculated. Item responses for satisfaction were weighted with that item's importance response and subscale mean scores (allowing up to 20% missing data) then adjusted to a 30-point scale.
Participant's adaptation to living with HSCR or caring for a child with HSCR was measured using the Psychological Adaptation Scale (PAS), which has demonstrated high internal consistency (Cronbach alpha = 0.94) (11) and has been validated through confirmatory factor analysis to fit 4 domains of adaptation: coping efficacy, self-esteem, social integration, and spiritual well-being (12). An overall adaptation scale and subscale for each domain were calculated as a mean of each participant's responses on a 5-point Likert scale (allowing up to 20% missing data). Affected adults who also have an affected child were asked to complete the PAS first from the perspective of having HSCR and then from caring for a child with HSCR. Further potential covariates of depressive symptoms and bowel function were assessed using the Center for Epidemiological Studies Depression Scale Revised (CESD-R) (13) and Bowel Function Score (BFS) (14), respectively. CESD-R scores were calculated as sums, allowing for no missing data. BFS scores were collected for affected adult participants and by parental proxy for the children of unaffected parents. Parent proxy scores were only collected for children ages 4 years and older because the BFS is validated only in ages 4 years and older. BFS scores were calculated as sums with no missing data allowed, with higher scores representing more normal bowel function.
Participant sex, age, highest education level, race, and ethnicity were collected. Participants were also asked the age and sex of any children they have with HSCR and if further family history of HSCR was present.
Survey data were imported into SPSS (15) for statistical analysis. Frequencies and means were calculated for all categorical and continuous variables, respectively, overall and within study groups. Chi-square analyses were used to test for differences in perceived causes and severity of HSCR between groups. T-tests, with equal variance tested, were used to test for differences between groups in all other IPQ-R subscales, the QLI, PAS, CESD-R, and BFS. Participant interest in each form of reproductive genetic information was calculated and chi-square analyses were used to test for differences between groups. Bivariate logistic regression was used to assess association of each potential predictor and covariate with interest in each form of reproductive genetic information. Based on the bivariate logistic regression results, models were fitted using multivariate logistic stepwise regression with entry at P ≤ 0.15 and exit at P > 0.15 to identify predictor variables while controlling for potential confounders. For the primary predictor variables of QLI and IPQ-R subscales, we had >95% power to detect a difference at α = 0.05 between groups.
A total of 454 survey responses were received (437 online and 17 paper). In data cleaning, 86 survey responses were removed (26 did not meet eligibility, 3 were duplicates [identified by participant comments or identical IP addresses and demographics], and 57 had no complete scales for predictor variables) for a total of 368 complete surveys included. Data completion rates dropped off by placement of each measure in the survey, giving data on 1 or more IPQ-R subscales on 366 participants, severity for 351, QLI on 310, PAS on 309, CESD-R on 295, and BFS for 208 (reflects collection for only those 4 years of age or older). For the outcomes of reproductive genetic information interest, responses were available on RGC and PNT for 311 participants and PGD for 310.
Participant characteristics are displayed in Table 1. Affected adults who also had an affected child (n = 19) generally fell between the 2 other study groups (affected adults without an affected child [n = 56] and unaffected parents of affected children [n = 293]) in responses, but were more similar to other affected adults. Because of this and the small group size of those who are both affected themselves and have an affected child, participants were placed into 2 groups for all further analyses: affected adults (with or without an affected child) and unaffected parents of affected children, referred to here as affected adults and unaffected parents, respectively.
Analyses Between Study Groups
Overall, participants rated HSCR as a severe condition, with 41.0% and 51.0% rating it as somewhat or very severe, respectively (Fig. 1). There was no statistically significant difference in severity ratings between the groups. Mean IPQ-R subscale scores for both affected adults and unaffected parents are also presented in Figure 1. Affected adults showed higher perceptions of the chronicity of HSCR (t = 1.99, P = 0.047), whereas unaffected parents had higher perceptions of the consequences of HSCR for the affected individual (t = 3.05, P = 0.002), and more negative emotional representations of the condition (t = 6.26, P < 0.001). In order to maximize differences between groups for the analysis in Figure 1, scores relating to perceptions of HSCR in themselves were used for affected adults who also have an affected child. Independent samples t tests did not show any associations between study group and quality of life, adaptation, or depressive symptom scale or subscale scores. Affected adults did report higher bowel function scores (μ = 13.82, SD = 3.52) than those for affected children (μ = 11.80, SD = 4.39) (t = 3.46, P = 0.002).
Although a majority of both affected adults and unaffected parents agreed or strongly agreed that “genetics” was a cause of HSCR, 91.7% and 72.3%, respectively, this was statistically significantly higher in affected adults (χ2 = 11.84, P < 0.001). There was a larger difference in attribution of “hereditary—it runs in my family” between groups (χ2 = 37.71, P < 0.001), with the majority of agree/strongly agree in affected adults (63.9%) not shared by unaffected parents (25.6%). Unaffected parents (57.7%) were more likely to agree or strongly agree with “Chance or Bad Luck” as a cause of HSCR than affected adults (30.6%) (χ2 = 16.86, P < 0.001). All other options offered as causes had a minority of participants agree or strongly agree that it may have been the cause (stress or worry 17.4%, diet or eating habits 10.0%, pollution in the environment 9.9%, altered immunity 6.3%, germ or virus 4.2%, my own behavior 4.0%, overwork 4.0%, alcohol 2.3%, smoking 2.3%, accident or injury 1.7%) and showed no differences between groups.
Interest in Reproductive Genetic Information
The majority of participants showed interest in some form of reproductive genetic information (Fig. 2). This held true across study groups for RGC and PNT. Interest in PGD was, however, lower than interest in RGC and PNT overall and was statistically significantly lower in unaffected parents than in affected adults (χ2 = 13.78, P = 0.001). Bivariate regression for selection of variables for inclusion in the stepwise logistic regression model included study group, all sociodemographic variables, perceived severity, IPQ-R subscales, IPQ-R causal attributions to “genetics” and “hereditary,” overall QLI, overall PAS, CESD-R, and BFS. For IPQ-R and PAS, affected adults views of the condition in their child were used because it relates more directly to the outcome of interest in reproductive genetic information. Multiple logistic regression analysis was initially completed both using only those individuals who gave a definitive response of “yes” or “no” and separately with groupings of “yes/unsure” compared to “no.” No significant differences were found, so Table 2 reports findings grouping participants who responded “yes” and “unsure.”
Regression analysis indicated that interest in all 3 forms of reproductive genetic information is related to whether or not an individual is themselves affected with HSCR. Affected adults were 2.6 or greater times more likely to indicate some interest in each form of reproductive genetic information. However, having further family history of HSCR indicated 2.9 times less interest in RGC and 2.4 times less interest in PNT than those who did not have a family history. The model also suggested that individuals with greater adaptation have statistically significant greater interest in RGC. More negative emotional representations of HSCR were associated with higher interest in all forms of reproductive genetic information, although only statistically significant in PNT and PGD.
Our findings support the hypothesis that adults with HSCR and parents of children with HSCR differ in some critical aspects of their perceptions of the condition. Yet despite this, participants in this study overall strongly endorsed the view of HSCR as a severe condition and a majority of participants, in both groups, indicated an interest in genetic counseling and the testing services (prenatal testing and PGD) that may be offered through genetic counseling.
The increased chronicity of HSCR perceived by affected adults may reflect a lifetime of experience with the condition and be attributed to clinical studies indicating that HSCR may affect bowel function well into adulthood (16–18). Yet, the greater perceived consequences of the condition and higher attributions of negative emotional representations that were seen in unaffected parents suggest particular challenges for parents in seeing their child deal with treatment, complications, and sequelae of HSCR. Indeed, previous studies have shown that families experience condition-specific distress related to bowel dysfunction (19). Likewise, the finding that quality of life did not differ between affected adults and parents of affected children is comparable to other studies finding that overall quality of life in both groups, studied separately, are similar to controls (20–22). However, the differences in specific domains of quality of life for adults with HSCR seen in other studies (20,21) but not seen here, may reflect more medically focused quality of life scales used in other studies.
An association of interest in reproductive information with having the condition and having more negative perceptions of a disease has been found in other genetic conditions (3). However, the important finding here to guide clinical care is that across affected adults and parents of affected children who participated in this study a large majority indicated definite or possible interest in reproductive genetic counseling and prenatal testing, with a smaller majority interested in PGD. Although no data have been published on rates of referral of HSCR patients and families to genetic services, anecdotally from our experience with a large genetic study, it is low indicating a missed opportunity to offer a desired medical service to families. Moreover, up to 30% of patients have additional anomalies suggesting either a Hirschsprung-associated genetic syndrome or a pathogenic chromosomal variant (23) and should be the target of comprehensive genetic evaluations and genetic counseling. Furthermore, the regression models showing an association of interest in reproductive genetic information with experiences with HSCR, emotional representations of the condition, and adaptation further support the value of a psychosocial model of genetic counseling in which these factors can be explored in an effort to support informed and value- and preference-based reproductive decisions. Although payor reimbursement may affect a patient's ability to receive genetic counseling, costs of services vary significantly (24,25). As such, access issues are best addressed with genetics providers as patients seek services.
This study provides, to our knowledge, the first research of interest in reproductive genetic information for families with HSCR. Although prenatal testing and PGD will not be available for families in which clinical testing cannot identify a causative and highly penetrant genetic variant, empiric recurrence rates (ranging from <1% to 33%) (2) are available to all members of the groups included in the study. A strength of this study is the inclusion of both affected adults and parents of affected children—allowing a view of this topic across both primary groups of individuals at highest risk to have a child with HSCR and informing both pediatric and adult care. Although the use of multiple recruitment strategies provides a broad sample, those who are involved in HSCR support groups, research, or social media channels may constitute an unrepresentative patient sample. Replication of the study in clinic populations, where access is based on disease state, may limit potential bias in sampling. Furthermore, although this study assessed the quality of life of participants themselves, results on the influence of quality of life may differ if the study assessed the affected child's quality of life by parent proxy or direct child quality of life measures. Lastly, the descriptions of prenatal testing and PGD provided in the survey did not include a full discussion of the current limitations of each, including reduced penetrance of genetic variants and inability to predict severity of disease, but this would be an important part of any genetic counseling session discussing these technologies.
Despite some differences in how patients with HSCR and parents view the condition, overall both groups see the condition as severe and are interested in information that may guide their reproductive decision making. Those who provide care for these patient groups should offer referral to genetic evaluation and counseling to these families, where those who are interested in such information can obtain personalized recurrence information and be assisted in making informed and preference-based decisions.
The authors thank the study participants for sharing their experiences and views about HSCR with the study team. The authors also thank Brenda J Coulter, RN and Angela Beasley for their comments on the survey design.
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