RESEARCH ARTICLE
Genetic Testing and Corresponding Services Among Individuals With Autism Spectrum Disorder (ASD) Michael L. Cuccaro,1* Kayla Czape,1 Michael Alessandri,2 Joycelyn Lee,1 Abigail Rupchock Deppen,1 Elise Bendik,1 Nicole Dueker,1 Laura Nations,3 Margaret Pericak-Vance,1 and Susan Hahn1 1
Dr. John T. McDonald Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida 2
Department of Psychology, University of Miami, Coral Gables, Florida
3
Carolina Institute for Intellectual Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina
Manuscript Received: 18 October 2013; Manuscript Accepted: 27 June 2014
The purpose of this study was to assess use of genetic testing and corresponding genetic services for children with Autism Spectrum Disorder (ASD). Survey data from 397 parents of individuals with ASD was collected using the Center for Autism and Related Disabilities client registry. Participants reported that 41.2% of the individuals with ASD had undergone any type of genetic testing. However, only 21.3% of individuals with ASD had been referred to a genetics specialist. Diagnosis and level of functioning were significantly associated with both referral to a genetics specialist and having undergone any genetic testing. In addition, Hispanic ancestry was associated with increased referral to genetic testing. Concerns about the limited benefits of genetic testing and prohibitive costs were potential barriers to pursuing genetic testing. Overall, low numbers of individuals with ASD have a history of undergoing genetic testing or receiving genetic services. Possible reasons include low referral rates as well as concerns by parents about cost and relevance, and lack of availability. These findings confirm the historical trend for providing genetic testing and genetic services to those with the greatest impairments. Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Cuccaro ML, Czape K, Alessandri M, Lee J, Deppen AR, Bendik E, Dueker N, Nations L, Pericak-Vance M, Hahn S. 2014. Genetic testing and corresponding services among individuals with autism spectrum disorder (ASD). Am J Med Genet Part A. 164A:2592–2600.
INTRODUCTION
for ASD in the future. Practice guidelines regarding genetic testing for ASDs, once limited to genetic testing for suspected syndromes or severe phenotypes, now recommend that CMA be offered as a firsttier test for ASD [Manning and Hudgins, 2010; Miller et al., 2010; Schaefer and Mendelsohn, 2013] and that a “genetic consultation should be offered to all persons/families with ASDs [Manning and Hudgins, 2010; Miller et al., 2010; Schaefer and Mendelsohn, 2013].” At present, clinical recommendations for genetic testing of individuals with ASD have been met with a surprising mix of apathy and controversies—at a minimum there appear to be conflicting messages from different groups [Shea et al., 2013]. Recent symposia and workshops sponsored by Autism Speaks and the National Institutes of Health have explored incorporating genetic testing and corresponding genetic services (i.e., consultation with a genetics specialist) into clinical care for individuals with
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder with estimates as high as one in 88 children [Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators, 2012]. Advances in genomic technologies have accelerated gene discoveries for ASD resulting in increased diagnostic yield—estimated to be 21% following incorporation of chromosomal microarray (CMA) [Qiao et al., 2009; Bremer et al., 2011]. As the yield grows, so does the integration and use of genetic services in clinical settings that serve individuals with ASD [Devlin and Scherer, 2012]. This trend will most likely continue and increase genetic testing options
The authors declare no conflicts of interest. Grant sponsor: National Institute of Mental Health; Grant number: MH080647. Correspondence to: Michael L. Cuccaro, Ph.D., Department of Human Genetics, 1501 NW 10th Avenue, M-860, Miami, FL, 33136. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 4 August 2014 DOI 10.1002/ajmg.a.36698
Key words: autism spectrum disorder; genetic testing; parental attitudes; survey research
Ó 2014 Wiley Periodicals, Inc.
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CUCCARO ET AL. ASD [Interagency Autism Coordinating Committee, 2011; Scherer and Dawson, 2011]. However, concerns have been raised about incorporating genetic testing and services in their current form given the complexity of ASD etiology and the potential for results of uncertain significance [Scherer and Dawson, 2011]. Of equal concern is how such genomic information will be transferred to parents and how parents will assimilate and use the information from genetic testing? Further, it has been suggested that current delivery models for communicating results from genetic testing in the ASD community digress from commonly accepted genetic service models and may lead to a misunderstanding of the disorder [Rossi et al., 2013]. Despite the potential ethical and social implications surrounding genetic testing for ASD [Jordan and Tsai, 2010; Manning and Hudgins, 2010; Miller et al., 2010; Walsh et al., 2011], there remains a strong push to move forward with widespread genetic testing. Studies show that parents of children with ASD believe that ASD has a strong genetic etiology [Mercer et al., 2006; Selkirk et al., 2009; Vande Wydeven et al., 2012] and want genetic services that are able to accurately pinpoint the cause of ASD in their child [Miller, 2010]. However, these same studies indicate that parents of children with ASD are not actively pursuing genetic testing and services as documented by low uptake rates [Mercer et al., 2006; Selkirk et al., 2009; Vande Wydeven et al., 2012]. Vande Wydeven and colleagues [Vande Wydeven et al., 2012] analyzed surveys from 155 parents of individuals with ASD and found that 32% of the parents reported that their child with ASD had undergone genetic testing and that only 20% had ever been seen by a geneticist or genetic counselor. According to the authors, these low frequencies may be the result of referral patterns (i.e., primary care providers for individuals with ASD do not routinely direct parents to genetics professionals). These patterns are at odds with parental beliefs about the importance of genetics, as well as, interest in obtaining such information. In addition, Chen and colleagues reported that parents of individuals with ASD who did receive genetic services were often frustrated by delivery efforts [Chen et al., 2013]. Thus, the use of genetic testing and corresponding services for individuals with ASD has been stymied around benefit of genetic testing as well as a limited understanding of parental experiences and opinions. Certainly, there is a paucity of information about parental experiences with genetic testing and corresponding genetic services. Such information could inform the current debate about the use of genetic testing and corresponding services for individuals with ASD and their families. The goal of the current study was to gather information about history of genetic testing experiences and corresponding genetic services among individuals with ASD via a parental survey. In addition, we evaluated those factors associated with prior use of genetic testing and genetic services. We also gathered information about parental knowledge, beliefs, and attitudes regarding both genetic testing and genetic services.
MATERIALS AND METHODS Participants The Centers for Autism and Related Disabilities (CARD) Parent survey was completed by 408 parents of children with ASD via three email listservs provided by the CARD. CARD centers are
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TABLE I. Descriptive Information for Overall Dataset (N ¼ 397) Age 10 years > 10 years Diagnosis Autism Asperger Disorder PDD-NOS LOF High functioning Average functioning Low functioning Ethnicity Hispanic Non-Hispanic Not reported Insurance Status Private Insurance Medicaid/Medicare No Insurance Children with ASD One Two
N
%
187 191
49% 51%
199 90 98
50% 23% 25%
253 77 43
64% 19% 11%
201 174 22
51% 44% 5%
257 111 29
65% 28% 7%
359 38
90% 10%
PDD-NOS ¼ Pervasive Developmental Disorder-Not Otherwise Specified; LOF ¼ Level of functioning; ASD ¼ Autism Spectrum Disorder.
state-funded outreach and support centers providing multidisciplinary lifespan services to individuals with ASD of all functioning levels. The three CARD listservs (Miami, Orlando, and Jacksonville) represent a combined group of approximately 12,000 individuals. Based on an estimated open rate of 20%, 2400 individuals would have received the survey yielding a return rate of 17%. All individuals enrolled on the registry have an established diagnosis of ASD. Participants (i.e., individuals completing the CARD Parent Survey) were required to be the parent of a child with an ASD. If a family had more than one child with ASD the parent was asked to complete the survey questions with the younger individual in mind; responses were restricted to one parent per individual. Of this group, we excluded 11 surveys from participants whose children had an accompanying genetic disorder (e.g., Fragile X syndrome, Rett syndrome, or Tuberous Sclerosis) resulting in 397 participants who met our criteria for eligibility and constitute the final study population (see Table I).
CARD Parent Survey The 49-item CARD Parent Survey (see Supplementary Material in supporting information online) was developed by clinical psychologists and genetic counselors with extensive experience in ASD and the genetic tests available for children with ASD. Initial items were generated by the group based on clinical experience, published studies about genetic testing attitudes and beliefs, and information from key informant interviews. The final survey questions were
2594 decided on by the group and pilot tested for readability and ease of administration. The survey assessed, in skip logic format, familiarity with genetic testing terms and genetic counseling concepts (e.g., recurrence risk), beliefs about causes of ASD, and experiences with and understanding of diagnostic genetic testing. Parents were asked about whether they had ever been referred to a genetics specialist (Have any of your child’s doctors ever suggested that your child see a genetics doctor [geneticist]?) and if their child had undergone any genetic testing for Fragile X, Rett Syndrome, PTEN, or karyotype or chromosomal microarray testing (e.g., has your child ever had a genetic test for Fragile X syndrome?).
Procedures The CARD Parent Survey was administered using Survey Monkey. Survey links were sent electronically to all clients enrolled on the three regional CARD listservs. Surveys were accompanied by an explanation of the study and a consent document approved by the University of Miami Institutional Review Board. In the recruitment email, parents of individuals with ASD were asked to complete a short survey about genetic services and genetic testing for diagnostic purposes with the stated purpose of better understanding the opinions and needs of parents of children with ASD regarding clinical genetics services and genetic tests. Those who agreed to participate were routed through a web link to the online questionnaire. Participants were contacted up to three times through the listserv to participate in the study over a four-week period. Only one response per IP address was permitted, limiting potential participation duplication.
Statistical Methods Participant characteristics and survey responses were described with frequencies for categorical traits and chi-square tests were performed to test for select group differences. Logistic regression was used to identify variables associated with both referral for genetic testing and having undergone genetic testing. Referral to genetic testing was defined as yes vs. no or not sure; having undergone genetic testing was defined as ever having undergone any of five genetic tests vs. not having undergone any genetic test. Predictor variables in our logistic regression analyses included ethnicity (Hispanic or non-Hispanic), age group (< 10 years of age or > 10 years of age), insurance status (private, Medicaid/Medicare, or none), parent- estimated level of functioning (high, average, or low), ASD diagnosis (autism, Asperger’s disorder, or PDD-NOS), and number of children with ASD (one or two). Chi-square tests were conducted with predictor variables of interest to determine which variables to add to our logistic regression model. Correcting for our two primary analyses and additional comparisons outside of our model building efforts we established our study wide significance level at 0.01. All tests were two-sided.
RESULTS As noted above, 408 parents completed surveys. Of this group we excluded 11 surveys from participants whose children had a known genetic disorder. The results described below are based on our final
AMERICAN JOURNAL OF MEDICAL GENETICS PART A dataset of 397 participants who met our criteria for eligibility and constitute the final study population. A summary of the survey data can be found in the supplementary material online.
Information about Sample Descriptive statistics for our study participants are presented in Table I. The cohort was predominantly Caucasian (82%) and approximately half of the entire cohort described themselves as Hispanic (51%). The majority of the families (90%) reported having a single child with ASD. The most frequent ASD diagnosis was autism (50%) and most of the children were described by their parents as high functioning (64%). Finally, a substantial number of children were covered by private insurance (67%). A large percentage of parents either completed college (68%) or had attended and completed some college (25%). Finally, 10% of our sample reported that they had participated in genetic research.
Knowledge and Beliefs about Genetics The majority of participants stated that they were familiar with and knew the meaning of genes (92%), DNA (94%), chromosome (86%), and genetic testing (87%). By contrast, knowledge of the term chromosomal microarray or equivalent terms was rated much lower. Only 21% were familiar with and knew the meaning of the term; 48% of respondents stated that they had never heard of the term. Interestingly, knowledge of the term chromosomal microarray was significantly different between parents whose children had a history of any genetic testing and those whose children had no history (x2 ¼ 32.76, df ¼ 2, P < 0.001). Among parents whose children had undergone testing, 35.2% were familiar with the term CMA vs. only 11.8% among parents whose children had never undergone genetic testing.
Beliefs and Attitudes about Genetic Testing Overall, 70.2% of participants strongly or somewhat disagreed that “genetic testing should not be done.” In the application of genetic testing to health care, more than 90% of participants were in strong or moderately strong agreement that “genetic testing is useful in health care.” Overall, participants did not find genetic testing morally objectionable as 88% strongly or somewhat disagreed that “genetic testing makes me uncomfortable from a moral standpoint.” Specific to autism related disorders, 90% of the participants strongly or moderately disagreed that “genetic testing for autism related disorders should not be done.” Finally, 86% of participants agreed or somewhat agreed with the statement I am interested in finding out if genetic factors are a cause of my child’s ASD (Fig. 1).
Causes of ASD Participants were asked to indicate what they believed to be the main causes for their child’s ASD from 12 options (see Fig. 2). The most frequently cited reasons were genetic influences (51%) and vaccinations (31%). More than a third of the participants endorsed don’t know (36%).
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FIG. 1. Parental agreement with the statement “I am interested in finding out if genetic factors are a cause of my child’s ASD.”
Recurrence Risk Participants estimated the likelihood of having another child with ASD by assigning both a percentage risk (0%–100%) and a categorical risk using a Likert scale (extremely high, high, moderate, low, extremely low, and not sure). In the overall dataset, the median percentage risk among respondents for having another child with ASD was 50% (mean 37%, sd ¼ 25) which far exceeds the commonly cited 5%–19% recurrence risk for ASD [Ozonoff et al., 2011; Schaefer and Mendelsohn, 2013]. Results of the categorical risk assignment showed that 21.2% of parents believed that they had an extremely high chance or high chance of having another child with ASD. In addition, since the overall sample included both parents of a single child with ASD and two children with ASD, we examined recurrence risk estimates separately. Among parents who had only one child with ASD the median estimated recurrence risk was 50% (mean 36%, 95% CI 33%–39%); among parents with two children with ASD the median estimated recurrence risk was also 50% but the mean estimated recurrence risk was much higher 51% (95% CI 40%–62%).
We then evaluated the relationship between parent-estimated risk of having another child with ASD and the number of children they had with ASD (i.e., one vs. two children with an ASD). We focused on categorical risk as this most likely reflected parental concern vs. estimates of recurrence risk using percentage. This decision was also motivated by inspection of these values for individual participants. For a number of individuals we noted a marked lack of correspondence between the percentage risk and categorical risk estimates (i.e., some parents reported that they believed they had a high or extremely high risk of having another child with ASD yet reported very low percentage risk. Using all categories (including N ¼ 67 not sure ratings) our results indicated that parent estimated risk for having another child with ASD differed significantly between those with one child with ASD and those with two children with ASD (Pearson chi-square, P < 0.001). Note that 21.1% of parents who had two children with ASD rated their chance for having another child with ASD as extremely high compared to 2% of parents with a single child with ASD. Figure 3 shows the distribution of parent ratings of risk for all five categories. We reanalyzed the recurrence risk estimates excluding the not sure responses and the results were similar (Pearson chi-square, P < 0.001).
Referral to Geneticist Only 21.3% of respondents (N ¼ 81) reported that their child had ever been referred to a geneticist. As seen in Table II univariate tests showed that participants whose child had been referred to a geneticist were more likely to have a child who they described as lower functioning. In addition, while only nominally significant, referral to a geneticist was associated with having a child who was Hispanic and in the younger age group ( 10 years of age). These variables were included in our logistic regression model. A logistic regression analysis was conducted to identify the association of these variables to history of being referred to a geneticist (referred ¼ 81, not referred ¼ ; 9 not sure responses were excluded; 8 participants did not respond). When these three
FIG. 2. Parental beliefs about the causes of ASD.
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FIG. 3. Parent estimates of recurrrence risk for ASD as a function of number of children with ASD.
predictors were entered into a logistic regression analysis, a test of the full model was statistically significant (P < 0.001) indicating that these predictors distinguished between individuals who had been referred to genetic testing and those who had not been referred. The Hosmer–Lemeshow test, a standard goodness-of fit index, indicated that the model was an adequate fit for the data (x2 ¼ 8.94, df ¼ 6, P ¼ .177). However, the model only accounted for 11% (Nagelkerke’s R Square) of the variance in whether or not an individual was referred to genetics. Further, the model did not substantially improve classification from the null model as
TABLE II. Characteristics of Individuals Referred to Genetic Services
Age 10 years > 10 years Diagnosis Autism Asperger disorder PDD-NOS LOF High functioning Average functioning Low functioning Ethnicity Hispanic Non-Hispanic Insurance Status Private Insurance Medicaid/Medicare No Insurance Children with ASD One Two
Referred
Not referred
P-value
60% 40%
48% 52%
0.072
53% 16% 31%
51% 25% 24%
0.170
54% 22% 24%
71% 21% 8%
0.001
67% 33%
50% 50%
0.011
68% 30% 2%
66% 28% 6%
0.442
86% 14%
91% 9%
0.217
PDD-NOS ¼ Pervasive Developmental Disorder-Not Otherwise Specified; LOF ¼ Level of functioning; ASD ¼ Autism Spectrum Disorder.
the predictors improved successful classification of referral to a geneticist only slightly from 79% to 79.3%. Table III shows the logistic regression results for referral to a geneticist. This model indicates that the greatest odds for referral to a geneticist, accounting for both ethnicity and age, occurs if a child with ASD is low functioning (OR ¼ 3.02, 95% CI 1.26–7.23). Further, the likelihood of a referral to a geneticist, again accounting for all other variables in the model, was increased in Hispanics relative to non-Hispanics (OR ¼ 1.92, 95% CI 1.086–3.41) although this result was only nominally significant. Among the parents (N ¼ 81) who reported that their child had been referred to a geneticist, only 65.8% (N ¼ 52) followed through with the referral (i.e., were seen by a geneticist). Among those respondents whose child saw a geneticist, 56% (N ¼ 29) reported having contact with a genetic counselor as part of the visit. Of the parents who reported that they had seen a geneticist, 68% described the contact as extremely helpful or somewhat helpful. Finally, for those participants who did not follow through on the genetics consultation, the most frequently cited reasons were I didn’t think it would affect my child’s medical care and insurance or cost issues.
Genetic Testing All participants were asked to report whether their child had ever undergone any of the following types of genetic testing (karyotype, Fragile X testing, CMA, Rett syndrome, PTEN). As seen in Figure 3, 41.2% (N ¼ 161) of respondents had a child who had undergone any type of genetic testing (mode ¼ one; 23.3%). As seen in Figure 4, the most frequently reported type of genetic testing was Fragile X testing (39.2%). Univariate tests (Table IV) showed that participants who had a history of any genetic testing were more likely to describe their child as lower functioning with a diagnosis of autism (vs. Asperger disorder or PDD-NOS) and who was Hispanic (Fisher’s exact test P ¼ 0.016). A logistic regression analysis was performed to identify the association of these variables to history of ever having had genetic testing (no genetic testing N ¼ 230; any genetic testing N ¼ 161);
FIG. 4. Percentage of individuals with ASD who have undergone genetic testing and type of testing.
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TABLE III. Logistic Regression Results for Dependent Measure “Referral to a Geneticist” Variables LOF Averagea High Low Ethnicity Non-Hispanica Hispanic Age > 10 years of agea < 10 years of age Constant
— 0.68 (0.35–1.33) 3.02 (1.26–7.23)
P-value 0.001 — 0.26 0.01
— 1.92 (1.09–3.41)
— 0.025
— 1.61(92–2.81) 15
– 0.10 0.00
OR (95% CI)
OR ¼ odds ratio; CI ¼ confidence interval; LOF ¼ level of functioning; a reference.
the range within the genetic testing category was from one to five possible tests. When these three predictors were entered into a logistic regression analysis, a test of the full model was statistically significant (P < 0.001) indicating that these predictors distinguished between individuals who had undergone any genetic testing and those who had not. The Hosmer–Lemeshow test, a
TABLE IV. Characteristics of Individuals With a History of Having had any Genetic Testing Age 10 years > 10 years Diagnosis Autism Asperger disorder PDD-NOS LOF High Functioning Average functioning Low functioning Ethnicity Hispanic Non-Hispanic Insurance Status Private Insurance Medicaid/Medicare No Insurance Children with ASD One Two
P-value
No Testing
Any Testing
47% 53%
54% 46%
0.173
53% 16% 31%
51% 25% 24%
< 0.001
76% 16% 8%
55% 27% 17%
< 0.001
48% 52%
61% 39%
0.016
64% 29% 7%
68% 27% 4%
0.476
91% 9%
89% 11%
0.729
standard goodness-of fit index, indicates that the model is an adequate fit the data (x2 ¼ 5.09, df ¼ 8, P ¼ .747). However, the model only accounted for 13.1% (Nagelkerke’s R Square) of the variance in whether or not an individual had ever undergone any genetic testing. Further, the model did not substantially improve classification from the null model as prediction success changed from 59.5% to 65.3% in correctly identifying whether an individual had ever undergone any genetic testing. Table V shows the logistic regression model for ever having undergone genetic testing. This model indicates that the greatest odds for ever having undergone genetic testing, accounting for both parent-estimated level of functioning and ethnicity, is ASD diagnosis. Relative to a diagnosis of Asperger disorder, individuals with a diagnosis of autism have a 3.4 time higher odds of having undergone any genetic testing (OR ¼ 3.407, 95% CI 1.704–6.814). The overall contribution of parent-estimated level of functioning while not significant, suggested that the high functioning group, when compared to the average functioning group and accounting for diagnosis and ethnicity, showed a significantly reduced likelihood of having had any genetic test (OR ¼ .548, 95% CI .307–980). Of note, the percentage of respondents whose children had one or more of several common genetic tests (41.2%) exceeded the percentage of individuals who had ever been referred to a geneticist as described above (21.3%). Among those who had ever had genetic testing, these tests were most often ordered by neurologists (68%). In addition, given that genetic testing and genetic services have changed over time (i.e., more tests, lower costs, greater availability) we evaluated the presence of time trends for history of having been referred to a geneticist and history of having undergone any genetic testing using the Cochran–Armitage trend test [Agresti, 2002]. As illustrated in Figure 5, for each variable we see a significant linear trend such that increased age (i.e., time) is associated with lower prevalence of both referral to a geneticist (P < 0.001) and history of having had any genetic test (P ¼ 0.006).
TABLE V. Logistic Regression Results for Dependent Measure “History of Genetic Testing”
PDD-NOS ¼ Pervasive Developmental Disorder-Not Otherwise Specified; LOF ¼ Level of functioning; ASD ¼ Autism Spectrum Disorder.
Variables Diagnosis Asperger disordera Autism PDD-NOS LOF Averagea High Low Ethnicity Non-Hispanica Hispanic Constant
— 548 (307–980) 1.22 (546–2.74)
P-value 0.002 — 0.001 0.003 0.035 — 0.042 0.625
— 1.34 (849–2.12) 328
— 0.208 0.007
OR (95% CI) — 3.41 (1.70–6.81) 2.96 (1.43–6.12)
OR ¼ odds ratio; CI ¼ confidence interval; LOF ¼ level of functioning. a reference.
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FIG. 5. Percentage of individuals positive for history of referral to a geneticist or having undergone any genetic testing as a function of age groups.
DISCUSSION This study was designed to assess both the frequency of referral to genetic services and history of genetic testing for individuals with ASD via a survey of parents of individuals with ASD. In addition, we evaluated attitudes and beliefs about these experiences. Consistent with recently published studies [Selkirk et al., 2009; Narcisa et al., 2012; Vande Wydeven et al., 2012], parents of individuals with ASD reported a strong belief that genetics plays a major role in the development of ASD. Further, many parents of individuals with ASD endorsed the utility of genetic testing to identify the cause of ASD and believe such testing should be done [Chen et al., 2013]. Despite these beliefs about its utility and expressed interest in genetic testing and related services, only 21% of parents reported that their child had been referred for genetic testing. These findings are consistent with studies showing that approximately only one in five children with ASD have a history of being referred to a geneticist [Narcisa et al., 2012; Vande Wydeven et al., 2012], Not surprisingly, attributes associated with referral to a geneticist were in line with greater impairment (i.e., lower functioning). Specifically, while accounting for age and ethnicity, there was a three times greater odds of being referred to a geneticist in the lower functioning group. In addition, there were nominally significant associations with age and ethnicity, as both younger (i.e., those less than 10 years of age) and Hispanic ASD individuals, accounting for other variables in the model, were almost twice as likely to be referred to a geneticist. Actual genetic testing experiences were also in line with, if not slightly higher, than previous studies [Narcisa et al., 2012; Vande Wydeven et al., 2012], as approximately 40% of individuals with ASD in our study had undergone any genetic testing. This slightly higher prevalence is understandable given the broad age range of participants and our definition of genetic testing to include any test. Attributes associated with having undergone any genetic testing included diagnosis and level of functioning. However, the model suggests that the odd of having undergone genetic testing, accounting for other variables, was significantly reduced among higher functioning individuals. For diagnosis, those with a diagnosis of autism or PDD-NOS, the odds of ever having had a genetic test was
AMERICAN JOURNAL OF MEDICAL GENETICS PART A approximately three to three and a half times greater than those with Asperger disorder. Equally interesting is the high proportion of participants who reported being unsure of whether their child had ever had genetic testing. For karyotyping and CMA testing, approximately one in four parents reported that they were unsure if their children had ever had these tests; while for Fragile X testing, 11% were unsure about whether their child had undergone such testing. Our results conform to prior studies showing both under-utilization of genetic professionals and low uptake of genetic testing. Clearly, for individuals with ASD, history of referral to a geneticist or undergoing any genetic testing are tied to developmental levels with diagnosis perhaps being a proxy for developmental level. As such this suggests that individuals with ASD at the upper end of the spectrum may be evaluated differently. An additional finding of interest was related to recurrence risk or the belief that they would have another child with ASD. While it was not surprising to note that parents of two children with ASD believed that their likelihood of having another child with ASD was very high, our overall results showed that parent-estimated recurrence risks for ASD in families with a single child with ASD was also very high. Their recurrence risk estimates (mean ¼ 36%; median ¼ 50%) are gross over-estimations of the 10–20% empirical risk offered for families for whom a genetic cause has not been identified and a hereditary pattern is not evident [Constantino et al., 2010; Ozonoff et al., 2011]. Consultation with genetics professional, such as a geneticist or genetic counselor would provide families with accurate risk estimation. Given that genetic testing may reveal a cause for ASD in as many as 21% of cases [Shen et al., 2010; Betancur, 2011] such testing could adjust this recurrence risk quite dramatically. The results of such information could influence parental stress and uncertainty, enable diagnostic testing for family members, and provide options for preconception/ prenatal diagnosis. For example, a family who believes they have a 30–50% recurrence risk may learn their child has a de novo chromosomal deletion which lowers their recurrence risk to 1%. The opposite may also be true. A family who believed they were at a low risk may learn they are at 50% risk. The need to understand and improve on referral to genetic services for individuals with ASD is becoming more pressing. This study, as well as others has shown that odds of being referred to a geneticist or genetics specialist are strongly tied to level of functioning. Further, we found an equally low prevalence of individuals with ASD receiving genetic tests in the absence of corresponding genetic services. For instance, we observed that genetic tests were most often ordered by pediatric neurologists and pediatricians. While our data are cross-sectional and represent a broad age range there is a suggestion that use of genetics services and genetic testing has increased as evidenced by the significant linear trends. Parents of younger children with ASD reported higher frequencies of genetic testing and referral to genetic services. However, there is still a disconcerting discrepancy between the prevalence of genetic testing and referral to genetic services in the younger children. This discrepancy is not altogether surprising in that individuals with ASD are seen by a multitude of professionals. The dilemma is that as genetic testing options increase, their use is likely to increase as well; these newer options are far more complicated and, as
CUCCARO ET AL. pointed out by Yudell and colleagues [Yudell et al., 2012; Rossi et al., 2013], could be poorly communicated and lead to misunderstanding of the role of genetics in ASD. A related issue that may impact use is the amount of uncertainly expressed by parents around the role of genetics professionals. Specifically, when asked about whether their child would benefit from seeing a genetics professional, nearly half of the parents were unsure. It is possible that this result does not directly represent “uncertainty” but rather represents lack of familiarity with the role of genetics professionals in diagnosis and management of children with ASD. In addition, utilization may be affected by parental concerns about cost, as well as the impact on their child’s developmental outcome (i.e., to what extent will it impact treatment and education). An important consideration in regards to utilization patterns is that a large percentage of our parents were college-educated and were covered through private health insurance plans. While this most likely affects generalization of results, it is intriguing that even the most educated parents who had economic resources had difficulties accessing genetic testing and genetic services or were concerned that costs would be prohibitive if they tried to access testing or services. This concern is interesting and suggests that genetic services may be even less utilized among parents with fewer resources. A recent report by Shea and colleagues notes that among Medicaid enrolled children with ASD, historical data shows very low uptake of genetic services [Shea et al., 2013]. Finally, in contrast to previous studies, our dataset was ethnically diverse with more than half of our respondents/parents of selfreported Hispanic ancestry. Of interest, our Hispanic parents were more likely to have been referred to a geneticist than their nonHispanic counterparts. These results, while preliminary, are the first to highlight potential differences among parents of individuals with ASD from different ethnic backgrounds. The importance of continuing to explore such differences will be critical in tailoring delivery of genetic services to diverse groups. As with previously completed studies that have surveyed parents of individuals with ASD, our study suffers from key limitations, including the cross-sectional retrospective design. The retrospective design may introduce a recall bias as parents were asked to recall facts about referral to genetic services or whether their child ever had a genetic test. This could lead to inaccurate estimates of prior testing and related experiences. While our results converge with previously reported findings [Selkirk et al., 2009; Narcisa et al., 2012; Vande Wydeven et al., 2012] it would be advantageous to gather real time data (e.g., large scale medical records reviews) regarding use of genetic testing and services to develop a more accurate picture of utilization. A second limitation, given the nature of the data collection, is that we were unable to compare our responders and non-responders. It appears that our respondents were skewed toward those with higher education. Further, it may be that they were also more likely to have access to the Internet and were more aware of or interested in genetics. While this potential bias in our sample may limit interpretation of our findings it also suggests our results represent the most favorable statistics regarding these issues (i.e., among those with the greatest education we still see a low utilization rate). A third limitation is that we did not capture information about the sex of the child and other demographics, which prevented us from determining their effect on attitudes and
2599 beliefs about genetic testing. Lastly, the wide age range of our participants was a potential limitation. This is evident in the data showing trends in ever having undergone genetic testing. While current recommendations do not explicitly state that genetic testing is for younger individuals, we acknowledge that parents of older individuals with ASD may be less likely to pursue such testing. Future studies may focus on the experiences of younger individuals with ASD and exploring time trends. While rapid developments in technologies to identify genetic causes of ASD have generated tremendous enthusiasm, they have also overshadowed efforts to explore the practical, ethical, and social implications of delivering these services to parents and families. Our data support the need for enhancing both parental and medical provider knowledge of and utilization of genetics services for individuals with ASD. Despite recognition of the potential impact of genetic information in the care of individuals with ASD, genetics services have been under-utilized and parents have misperceptions of ASD etiology and recurrence risk. Given the changes in comprehensive genetic testing and referral to genetic services as recommended by practice guidelines it is crucial to accelerate strategies for educating parents and professionals about genetic services and developing optimal strategies for their delivery.
ACKNOWLEDGMENTS We thank the parents of individuals with autism who participated in this study and personnel at the Centers for Autism and Related Disabilities (CARD) who provided support allowing us to complete this study. This work was supported by a grant from the National Institute of Mental Health (MH080647) and by a gift from the Hussman Foundation.
REFERENCES Agresti A. 2002. Categorical data analysis. Hoboken, New Jersey: John Wiley & Sons. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators. 2012. Prevalence of autism spectrum disorders - autism and developmental disabilities monitoring network, 14 sites, united states, 2008. MMWR Surveill Summ 61:1–19. Betancur C. 2011. Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting. Brain Res 1380:42–77. Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E, Gillberg C, Nordgren A, Uppstromer A, Anderlid BM, Nordenskjold M, Schoumans J. 2011. Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 156:115–124. Chen LS, Xu L, Huang TY, Dhar SU. 2013. Autism genetic testing: A qualitative study of awareness, attitudes, and experiences among parents of children with autism spectrum disorders. Genet Med 15:274–281. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. 2010. Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry 167:1349–1356. Devlin B, Scherer SW. 2012. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22:229–237.
2600 Interagency Autism Coordinating Committee. 2011. 2011 IACC strategic plan for autism spectrum disorder research. Jordan BR, Tsai DF. 2010. Whole-genome association studies for multigenic diseases: Ethical dilemmas arising from commercialization–the case of genetic testing for autism. J Med Ethics 36:440–444. Manning M, Hudgins L. Professional Practice and Guidelines Committee. 2010. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 12:742–745. Mercer L, Creighton S, Holden JJ, Lewis ME. 2006. Parental perspectives on the causes of an autism spectrum disorder in their children. J Genet Couns 15:41–50. Miller DT. 2010. Genetic testing for autism: Recent advances and clinical implications. Expert Rev Mol Diagn 10:837–840. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. 2010. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764. Narcisa V, Discenza M, Vaccari E, Rosen-Sheidley B, Hardan AY, Couchon E. 2012. Parental interest in a genetic risk assessment test for autism spectrum disorders. Clin Pediatr (Phila) 52:139–146. Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson S, Carver LJ, Constantino JN, Dobkins K, Hutman T, Iverson JM, Landa R, Rogers SJ, Sigman M, Stone WL. 2011. Recurrence risk for autism spectrum disorders: A baby siblings research consortium study. Pediatrics 128:e488–495.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Schaefer GB, Mendelsohn NJ. Professional Practice and Guidelines Committee. 2013. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 15:399– 407. Scherer SW, Dawson G. 2011. Risk factors for autism: Translating genomic discoveries into diagnostics. Hum Genet 130:123–148. Selkirk CG, McCarthy Veach P, Lian F, Schimmenti L, LeRoy BS. 2009. Parents’ perceptions of autism spectrum disorder etiology and recurrence risk and effects of their perceptions on family planning: Recommendations for genetic counselors. J Genet Couns 18:507–519. Shea L, Newschaffer CJ, Xie M, Myers SM, Mandell DS. 2013. Genetic testing and genetic counseling among medicaid-enrolled children with autism spectrum disorder in 2001 and 2007. Hum Genet 133: 111–116. Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J, Weissman L, Raffalli P, Jeste S, Demmer LA, Peters HK, Brewster SJ, Kowalczyk SJ, Rosen-Sheidley B, McGowan C, Duda AW 3rd, Lincoln SA, Lowe KR, Schonwald A, Robbins M, Hisama F, Wolff R, Becker R, Nasir R, Urion DK, Milunsky JM, Rappaport L, Gusella JF, Walsh CA, Wu BL, Miller DT. Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration. 2010. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 125:e727–735. Vande Wydeven K, Kwan A, Hardan AY, Bernstein JA. 2012. Underutilization of genetics services for autism: The importance of parental awareness and provider recommendation. J Genet Couns 21:801–813. Walsh P, Elsabbagh M, Bolton P, Singh I. 2011. In search of biomarkers for autism: Scientific, social and ethical challenges. Nat Rev Neurosci 12:603– 612. Yudell M, Tabor HK, Dawson G, Rossi J, Newschaffer C. Working Group in Autism Risk Communication and Ethics. 2012. Priorities for autism spectrum disorders risk communication and ethics. Autism 17:701–722.
Qiao Y, Riendeau N, Koochek M, Liu X, Harvard C, Hildebrand MJ, Holden JJ, Rajcan-Separovic E, Lewis ME. 2009. Phenomic determinants of genomic variation in autism spectrum disorders. J Med Genet 46:680–688.
SUPPORTING INFORMATION
Rossi J, Newschaffer C, Yudell M. 2013. Autism spectrum disorders, risk communication, and the problem of inadvertent harm. Kennedy Inst Ethics J 23:105–138.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Genetic Testing and Corresponding Services Among Individuals With Autism Spectrum Disorder (ASD) Michael L. Cuccaro,1* Kayla Czape,1 Michael Alessandri,2 Joycelyn Lee,1 Abigail Rupchock Deppen,1 Elise Bendik,1 Nicole Dueker,1 Laura Nations,3 Margaret Pericak-Vance,1 and Susan Hahn1 1
Dr. John T. McDonald Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida 2
Department of Psychology, University of Miami, Coral Gables, Florida
3
Carolina Institute for Intellectual Disabilities, University of North Carolina School of Medicine, Chapel Hill, North Carolina
Manuscript Received: 18 October 2013; Manuscript Accepted: 27 June 2014
The purpose of this study was to assess use of genetic testing and corresponding genetic services for children with Autism Spectrum Disorder (ASD). Survey data from 397 parents of individuals with ASD was collected using the Center for Autism and Related Disabilities client registry. Participants reported that 41.2% of the individuals with ASD had undergone any type of genetic testing. However, only 21.3% of individuals with ASD had been referred to a genetics specialist. Diagnosis and level of functioning were significantly associated with both referral to a genetics specialist and having undergone any genetic testing. In addition, Hispanic ancestry was associated with increased referral to genetic testing. Concerns about the limited benefits of genetic testing and prohibitive costs were potential barriers to pursuing genetic testing. Overall, low numbers of individuals with ASD have a history of undergoing genetic testing or receiving genetic services. Possible reasons include low referral rates as well as concerns by parents about cost and relevance, and lack of availability. These findings confirm the historical trend for providing genetic testing and genetic services to those with the greatest impairments. Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Cuccaro ML, Czape K, Alessandri M, Lee J, Deppen AR, Bendik E, Dueker N, Nations L, Pericak-Vance M, Hahn S. 2014. Genetic testing and corresponding services among individuals with autism spectrum disorder (ASD). Am J Med Genet Part A. 164A:2592–2600.
INTRODUCTION
for ASD in the future. Practice guidelines regarding genetic testing for ASDs, once limited to genetic testing for suspected syndromes or severe phenotypes, now recommend that CMA be offered as a firsttier test for ASD [Manning and Hudgins, 2010; Miller et al., 2010; Schaefer and Mendelsohn, 2013] and that a “genetic consultation should be offered to all persons/families with ASDs [Manning and Hudgins, 2010; Miller et al., 2010; Schaefer and Mendelsohn, 2013].” At present, clinical recommendations for genetic testing of individuals with ASD have been met with a surprising mix of apathy and controversies—at a minimum there appear to be conflicting messages from different groups [Shea et al., 2013]. Recent symposia and workshops sponsored by Autism Speaks and the National Institutes of Health have explored incorporating genetic testing and corresponding genetic services (i.e., consultation with a genetics specialist) into clinical care for individuals with
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder with estimates as high as one in 88 children [Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators, 2012]. Advances in genomic technologies have accelerated gene discoveries for ASD resulting in increased diagnostic yield—estimated to be 21% following incorporation of chromosomal microarray (CMA) [Qiao et al., 2009; Bremer et al., 2011]. As the yield grows, so does the integration and use of genetic services in clinical settings that serve individuals with ASD [Devlin and Scherer, 2012]. This trend will most likely continue and increase genetic testing options
The authors declare no conflicts of interest. Grant sponsor: National Institute of Mental Health; Grant number: MH080647. Correspondence to: Michael L. Cuccaro, Ph.D., Department of Human Genetics, 1501 NW 10th Avenue, M-860, Miami, FL, 33136. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 4 August 2014 DOI 10.1002/ajmg.a.36698
Key words: autism spectrum disorder; genetic testing; parental attitudes; survey research
Ó 2014 Wiley Periodicals, Inc.
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CUCCARO ET AL. ASD [Interagency Autism Coordinating Committee, 2011; Scherer and Dawson, 2011]. However, concerns have been raised about incorporating genetic testing and services in their current form given the complexity of ASD etiology and the potential for results of uncertain significance [Scherer and Dawson, 2011]. Of equal concern is how such genomic information will be transferred to parents and how parents will assimilate and use the information from genetic testing? Further, it has been suggested that current delivery models for communicating results from genetic testing in the ASD community digress from commonly accepted genetic service models and may lead to a misunderstanding of the disorder [Rossi et al., 2013]. Despite the potential ethical and social implications surrounding genetic testing for ASD [Jordan and Tsai, 2010; Manning and Hudgins, 2010; Miller et al., 2010; Walsh et al., 2011], there remains a strong push to move forward with widespread genetic testing. Studies show that parents of children with ASD believe that ASD has a strong genetic etiology [Mercer et al., 2006; Selkirk et al., 2009; Vande Wydeven et al., 2012] and want genetic services that are able to accurately pinpoint the cause of ASD in their child [Miller, 2010]. However, these same studies indicate that parents of children with ASD are not actively pursuing genetic testing and services as documented by low uptake rates [Mercer et al., 2006; Selkirk et al., 2009; Vande Wydeven et al., 2012]. Vande Wydeven and colleagues [Vande Wydeven et al., 2012] analyzed surveys from 155 parents of individuals with ASD and found that 32% of the parents reported that their child with ASD had undergone genetic testing and that only 20% had ever been seen by a geneticist or genetic counselor. According to the authors, these low frequencies may be the result of referral patterns (i.e., primary care providers for individuals with ASD do not routinely direct parents to genetics professionals). These patterns are at odds with parental beliefs about the importance of genetics, as well as, interest in obtaining such information. In addition, Chen and colleagues reported that parents of individuals with ASD who did receive genetic services were often frustrated by delivery efforts [Chen et al., 2013]. Thus, the use of genetic testing and corresponding services for individuals with ASD has been stymied around benefit of genetic testing as well as a limited understanding of parental experiences and opinions. Certainly, there is a paucity of information about parental experiences with genetic testing and corresponding genetic services. Such information could inform the current debate about the use of genetic testing and corresponding services for individuals with ASD and their families. The goal of the current study was to gather information about history of genetic testing experiences and corresponding genetic services among individuals with ASD via a parental survey. In addition, we evaluated those factors associated with prior use of genetic testing and genetic services. We also gathered information about parental knowledge, beliefs, and attitudes regarding both genetic testing and genetic services.
MATERIALS AND METHODS Participants The Centers for Autism and Related Disabilities (CARD) Parent survey was completed by 408 parents of children with ASD via three email listservs provided by the CARD. CARD centers are
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TABLE I. Descriptive Information for Overall Dataset (N ¼ 397) Age 10 years > 10 years Diagnosis Autism Asperger Disorder PDD-NOS LOF High functioning Average functioning Low functioning Ethnicity Hispanic Non-Hispanic Not reported Insurance Status Private Insurance Medicaid/Medicare No Insurance Children with ASD One Two
N
%
187 191
49% 51%
199 90 98
50% 23% 25%
253 77 43
64% 19% 11%
201 174 22
51% 44% 5%
257 111 29
65% 28% 7%
359 38
90% 10%
PDD-NOS ¼ Pervasive Developmental Disorder-Not Otherwise Specified; LOF ¼ Level of functioning; ASD ¼ Autism Spectrum Disorder.
state-funded outreach and support centers providing multidisciplinary lifespan services to individuals with ASD of all functioning levels. The three CARD listservs (Miami, Orlando, and Jacksonville) represent a combined group of approximately 12,000 individuals. Based on an estimated open rate of 20%, 2400 individuals would have received the survey yielding a return rate of 17%. All individuals enrolled on the registry have an established diagnosis of ASD. Participants (i.e., individuals completing the CARD Parent Survey) were required to be the parent of a child with an ASD. If a family had more than one child with ASD the parent was asked to complete the survey questions with the younger individual in mind; responses were restricted to one parent per individual. Of this group, we excluded 11 surveys from participants whose children had an accompanying genetic disorder (e.g., Fragile X syndrome, Rett syndrome, or Tuberous Sclerosis) resulting in 397 participants who met our criteria for eligibility and constitute the final study population (see Table I).
CARD Parent Survey The 49-item CARD Parent Survey (see Supplementary Material in supporting information online) was developed by clinical psychologists and genetic counselors with extensive experience in ASD and the genetic tests available for children with ASD. Initial items were generated by the group based on clinical experience, published studies about genetic testing attitudes and beliefs, and information from key informant interviews. The final survey questions were
2594 decided on by the group and pilot tested for readability and ease of administration. The survey assessed, in skip logic format, familiarity with genetic testing terms and genetic counseling concepts (e.g., recurrence risk), beliefs about causes of ASD, and experiences with and understanding of diagnostic genetic testing. Parents were asked about whether they had ever been referred to a genetics specialist (Have any of your child’s doctors ever suggested that your child see a genetics doctor [geneticist]?) and if their child had undergone any genetic testing for Fragile X, Rett Syndrome, PTEN, or karyotype or chromosomal microarray testing (e.g., has your child ever had a genetic test for Fragile X syndrome?).
Procedures The CARD Parent Survey was administered using Survey Monkey. Survey links were sent electronically to all clients enrolled on the three regional CARD listservs. Surveys were accompanied by an explanation of the study and a consent document approved by the University of Miami Institutional Review Board. In the recruitment email, parents of individuals with ASD were asked to complete a short survey about genetic services and genetic testing for diagnostic purposes with the stated purpose of better understanding the opinions and needs of parents of children with ASD regarding clinical genetics services and genetic tests. Those who agreed to participate were routed through a web link to the online questionnaire. Participants were contacted up to three times through the listserv to participate in the study over a four-week period. Only one response per IP address was permitted, limiting potential participation duplication.
Statistical Methods Participant characteristics and survey responses were described with frequencies for categorical traits and chi-square tests were performed to test for select group differences. Logistic regression was used to identify variables associated with both referral for genetic testing and having undergone genetic testing. Referral to genetic testing was defined as yes vs. no or not sure; having undergone genetic testing was defined as ever having undergone any of five genetic tests vs. not having undergone any genetic test. Predictor variables in our logistic regression analyses included ethnicity (Hispanic or non-Hispanic), age group (< 10 years of age or > 10 years of age), insurance status (private, Medicaid/Medicare, or none), parent- estimated level of functioning (high, average, or low), ASD diagnosis (autism, Asperger’s disorder, or PDD-NOS), and number of children with ASD (one or two). Chi-square tests were conducted with predictor variables of interest to determine which variables to add to our logistic regression model. Correcting for our two primary analyses and additional comparisons outside of our model building efforts we established our study wide significance level at 0.01. All tests were two-sided.
RESULTS As noted above, 408 parents completed surveys. Of this group we excluded 11 surveys from participants whose children had a known genetic disorder. The results described below are based on our final
AMERICAN JOURNAL OF MEDICAL GENETICS PART A dataset of 397 participants who met our criteria for eligibility and constitute the final study population. A summary of the survey data can be found in the supplementary material online.
Information about Sample Descriptive statistics for our study participants are presented in Table I. The cohort was predominantly Caucasian (82%) and approximately half of the entire cohort described themselves as Hispanic (51%). The majority of the families (90%) reported having a single child with ASD. The most frequent ASD diagnosis was autism (50%) and most of the children were described by their parents as high functioning (64%). Finally, a substantial number of children were covered by private insurance (67%). A large percentage of parents either completed college (68%) or had attended and completed some college (25%). Finally, 10% of our sample reported that they had participated in genetic research.
Knowledge and Beliefs about Genetics The majority of participants stated that they were familiar with and knew the meaning of genes (92%), DNA (94%), chromosome (86%), and genetic testing (87%). By contrast, knowledge of the term chromosomal microarray or equivalent terms was rated much lower. Only 21% were familiar with and knew the meaning of the term; 48% of respondents stated that they had never heard of the term. Interestingly, knowledge of the term chromosomal microarray was significantly different between parents whose children had a history of any genetic testing and those whose children had no history (x2 ¼ 32.76, df ¼ 2, P < 0.001). Among parents whose children had undergone testing, 35.2% were familiar with the term CMA vs. only 11.8% among parents whose children had never undergone genetic testing.
Beliefs and Attitudes about Genetic Testing Overall, 70.2% of participants strongly or somewhat disagreed that “genetic testing should not be done.” In the application of genetic testing to health care, more than 90% of participants were in strong or moderately strong agreement that “genetic testing is useful in health care.” Overall, participants did not find genetic testing morally objectionable as 88% strongly or somewhat disagreed that “genetic testing makes me uncomfortable from a moral standpoint.” Specific to autism related disorders, 90% of the participants strongly or moderately disagreed that “genetic testing for autism related disorders should not be done.” Finally, 86% of participants agreed or somewhat agreed with the statement I am interested in finding out if genetic factors are a cause of my child’s ASD (Fig. 1).
Causes of ASD Participants were asked to indicate what they believed to be the main causes for their child’s ASD from 12 options (see Fig. 2). The most frequently cited reasons were genetic influences (51%) and vaccinations (31%). More than a third of the participants endorsed don’t know (36%).
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FIG. 1. Parental agreement with the statement “I am interested in finding out if genetic factors are a cause of my child’s ASD.”
Recurrence Risk Participants estimated the likelihood of having another child with ASD by assigning both a percentage risk (0%–100%) and a categorical risk using a Likert scale (extremely high, high, moderate, low, extremely low, and not sure). In the overall dataset, the median percentage risk among respondents for having another child with ASD was 50% (mean 37%, sd ¼ 25) which far exceeds the commonly cited 5%–19% recurrence risk for ASD [Ozonoff et al., 2011; Schaefer and Mendelsohn, 2013]. Results of the categorical risk assignment showed that 21.2% of parents believed that they had an extremely high chance or high chance of having another child with ASD. In addition, since the overall sample included both parents of a single child with ASD and two children with ASD, we examined recurrence risk estimates separately. Among parents who had only one child with ASD the median estimated recurrence risk was 50% (mean 36%, 95% CI 33%–39%); among parents with two children with ASD the median estimated recurrence risk was also 50% but the mean estimated recurrence risk was much higher 51% (95% CI 40%–62%).
We then evaluated the relationship between parent-estimated risk of having another child with ASD and the number of children they had with ASD (i.e., one vs. two children with an ASD). We focused on categorical risk as this most likely reflected parental concern vs. estimates of recurrence risk using percentage. This decision was also motivated by inspection of these values for individual participants. For a number of individuals we noted a marked lack of correspondence between the percentage risk and categorical risk estimates (i.e., some parents reported that they believed they had a high or extremely high risk of having another child with ASD yet reported very low percentage risk. Using all categories (including N ¼ 67 not sure ratings) our results indicated that parent estimated risk for having another child with ASD differed significantly between those with one child with ASD and those with two children with ASD (Pearson chi-square, P < 0.001). Note that 21.1% of parents who had two children with ASD rated their chance for having another child with ASD as extremely high compared to 2% of parents with a single child with ASD. Figure 3 shows the distribution of parent ratings of risk for all five categories. We reanalyzed the recurrence risk estimates excluding the not sure responses and the results were similar (Pearson chi-square, P < 0.001).
Referral to Geneticist Only 21.3% of respondents (N ¼ 81) reported that their child had ever been referred to a geneticist. As seen in Table II univariate tests showed that participants whose child had been referred to a geneticist were more likely to have a child who they described as lower functioning. In addition, while only nominally significant, referral to a geneticist was associated with having a child who was Hispanic and in the younger age group ( 10 years of age). These variables were included in our logistic regression model. A logistic regression analysis was conducted to identify the association of these variables to history of being referred to a geneticist (referred ¼ 81, not referred ¼ ; 9 not sure responses were excluded; 8 participants did not respond). When these three
FIG. 2. Parental beliefs about the causes of ASD.
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FIG. 3. Parent estimates of recurrrence risk for ASD as a function of number of children with ASD.
predictors were entered into a logistic regression analysis, a test of the full model was statistically significant (P < 0.001) indicating that these predictors distinguished between individuals who had been referred to genetic testing and those who had not been referred. The Hosmer–Lemeshow test, a standard goodness-of fit index, indicated that the model was an adequate fit for the data (x2 ¼ 8.94, df ¼ 6, P ¼ .177). However, the model only accounted for 11% (Nagelkerke’s R Square) of the variance in whether or not an individual was referred to genetics. Further, the model did not substantially improve classification from the null model as
TABLE II. Characteristics of Individuals Referred to Genetic Services
Age 10 years > 10 years Diagnosis Autism Asperger disorder PDD-NOS LOF High functioning Average functioning Low functioning Ethnicity Hispanic Non-Hispanic Insurance Status Private Insurance Medicaid/Medicare No Insurance Children with ASD One Two
Referred
Not referred
P-value
60% 40%
48% 52%
0.072
53% 16% 31%
51% 25% 24%
0.170
54% 22% 24%
71% 21% 8%
0.001
67% 33%
50% 50%
0.011
68% 30% 2%
66% 28% 6%
0.442
86% 14%
91% 9%
0.217
PDD-NOS ¼ Pervasive Developmental Disorder-Not Otherwise Specified; LOF ¼ Level of functioning; ASD ¼ Autism Spectrum Disorder.
the predictors improved successful classification of referral to a geneticist only slightly from 79% to 79.3%. Table III shows the logistic regression results for referral to a geneticist. This model indicates that the greatest odds for referral to a geneticist, accounting for both ethnicity and age, occurs if a child with ASD is low functioning (OR ¼ 3.02, 95% CI 1.26–7.23). Further, the likelihood of a referral to a geneticist, again accounting for all other variables in the model, was increased in Hispanics relative to non-Hispanics (OR ¼ 1.92, 95% CI 1.086–3.41) although this result was only nominally significant. Among the parents (N ¼ 81) who reported that their child had been referred to a geneticist, only 65.8% (N ¼ 52) followed through with the referral (i.e., were seen by a geneticist). Among those respondents whose child saw a geneticist, 56% (N ¼ 29) reported having contact with a genetic counselor as part of the visit. Of the parents who reported that they had seen a geneticist, 68% described the contact as extremely helpful or somewhat helpful. Finally, for those participants who did not follow through on the genetics consultation, the most frequently cited reasons were I didn’t think it would affect my child’s medical care and insurance or cost issues.
Genetic Testing All participants were asked to report whether their child had ever undergone any of the following types of genetic testing (karyotype, Fragile X testing, CMA, Rett syndrome, PTEN). As seen in Figure 3, 41.2% (N ¼ 161) of respondents had a child who had undergone any type of genetic testing (mode ¼ one; 23.3%). As seen in Figure 4, the most frequently reported type of genetic testing was Fragile X testing (39.2%). Univariate tests (Table IV) showed that participants who had a history of any genetic testing were more likely to describe their child as lower functioning with a diagnosis of autism (vs. Asperger disorder or PDD-NOS) and who was Hispanic (Fisher’s exact test P ¼ 0.016). A logistic regression analysis was performed to identify the association of these variables to history of ever having had genetic testing (no genetic testing N ¼ 230; any genetic testing N ¼ 161);
FIG. 4. Percentage of individuals with ASD who have undergone genetic testing and type of testing.
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TABLE III. Logistic Regression Results for Dependent Measure “Referral to a Geneticist” Variables LOF Averagea High Low Ethnicity Non-Hispanica Hispanic Age > 10 years of agea < 10 years of age Constant
— 0.68 (0.35–1.33) 3.02 (1.26–7.23)
P-value 0.001 — 0.26 0.01
— 1.92 (1.09–3.41)
— 0.025
— 1.61(92–2.81) 15
– 0.10 0.00
OR (95% CI)
OR ¼ odds ratio; CI ¼ confidence interval; LOF ¼ level of functioning; a reference.
the range within the genetic testing category was from one to five possible tests. When these three predictors were entered into a logistic regression analysis, a test of the full model was statistically significant (P < 0.001) indicating that these predictors distinguished between individuals who had undergone any genetic testing and those who had not. The Hosmer–Lemeshow test, a
TABLE IV. Characteristics of Individuals With a History of Having had any Genetic Testing Age 10 years > 10 years Diagnosis Autism Asperger disorder PDD-NOS LOF High Functioning Average functioning Low functioning Ethnicity Hispanic Non-Hispanic Insurance Status Private Insurance Medicaid/Medicare No Insurance Children with ASD One Two
P-value
No Testing
Any Testing
47% 53%
54% 46%
0.173
53% 16% 31%
51% 25% 24%
< 0.001
76% 16% 8%
55% 27% 17%
< 0.001
48% 52%
61% 39%
0.016
64% 29% 7%
68% 27% 4%
0.476
91% 9%
89% 11%
0.729
standard goodness-of fit index, indicates that the model is an adequate fit the data (x2 ¼ 5.09, df ¼ 8, P ¼ .747). However, the model only accounted for 13.1% (Nagelkerke’s R Square) of the variance in whether or not an individual had ever undergone any genetic testing. Further, the model did not substantially improve classification from the null model as prediction success changed from 59.5% to 65.3% in correctly identifying whether an individual had ever undergone any genetic testing. Table V shows the logistic regression model for ever having undergone genetic testing. This model indicates that the greatest odds for ever having undergone genetic testing, accounting for both parent-estimated level of functioning and ethnicity, is ASD diagnosis. Relative to a diagnosis of Asperger disorder, individuals with a diagnosis of autism have a 3.4 time higher odds of having undergone any genetic testing (OR ¼ 3.407, 95% CI 1.704–6.814). The overall contribution of parent-estimated level of functioning while not significant, suggested that the high functioning group, when compared to the average functioning group and accounting for diagnosis and ethnicity, showed a significantly reduced likelihood of having had any genetic test (OR ¼ .548, 95% CI .307–980). Of note, the percentage of respondents whose children had one or more of several common genetic tests (41.2%) exceeded the percentage of individuals who had ever been referred to a geneticist as described above (21.3%). Among those who had ever had genetic testing, these tests were most often ordered by neurologists (68%). In addition, given that genetic testing and genetic services have changed over time (i.e., more tests, lower costs, greater availability) we evaluated the presence of time trends for history of having been referred to a geneticist and history of having undergone any genetic testing using the Cochran–Armitage trend test [Agresti, 2002]. As illustrated in Figure 5, for each variable we see a significant linear trend such that increased age (i.e., time) is associated with lower prevalence of both referral to a geneticist (P < 0.001) and history of having had any genetic test (P ¼ 0.006).
TABLE V. Logistic Regression Results for Dependent Measure “History of Genetic Testing”
PDD-NOS ¼ Pervasive Developmental Disorder-Not Otherwise Specified; LOF ¼ Level of functioning; ASD ¼ Autism Spectrum Disorder.
Variables Diagnosis Asperger disordera Autism PDD-NOS LOF Averagea High Low Ethnicity Non-Hispanica Hispanic Constant
— 548 (307–980) 1.22 (546–2.74)
P-value 0.002 — 0.001 0.003 0.035 — 0.042 0.625
— 1.34 (849–2.12) 328
— 0.208 0.007
OR (95% CI) — 3.41 (1.70–6.81) 2.96 (1.43–6.12)
OR ¼ odds ratio; CI ¼ confidence interval; LOF ¼ level of functioning. a reference.
2598
FIG. 5. Percentage of individuals positive for history of referral to a geneticist or having undergone any genetic testing as a function of age groups.
DISCUSSION This study was designed to assess both the frequency of referral to genetic services and history of genetic testing for individuals with ASD via a survey of parents of individuals with ASD. In addition, we evaluated attitudes and beliefs about these experiences. Consistent with recently published studies [Selkirk et al., 2009; Narcisa et al., 2012; Vande Wydeven et al., 2012], parents of individuals with ASD reported a strong belief that genetics plays a major role in the development of ASD. Further, many parents of individuals with ASD endorsed the utility of genetic testing to identify the cause of ASD and believe such testing should be done [Chen et al., 2013]. Despite these beliefs about its utility and expressed interest in genetic testing and related services, only 21% of parents reported that their child had been referred for genetic testing. These findings are consistent with studies showing that approximately only one in five children with ASD have a history of being referred to a geneticist [Narcisa et al., 2012; Vande Wydeven et al., 2012], Not surprisingly, attributes associated with referral to a geneticist were in line with greater impairment (i.e., lower functioning). Specifically, while accounting for age and ethnicity, there was a three times greater odds of being referred to a geneticist in the lower functioning group. In addition, there were nominally significant associations with age and ethnicity, as both younger (i.e., those less than 10 years of age) and Hispanic ASD individuals, accounting for other variables in the model, were almost twice as likely to be referred to a geneticist. Actual genetic testing experiences were also in line with, if not slightly higher, than previous studies [Narcisa et al., 2012; Vande Wydeven et al., 2012], as approximately 40% of individuals with ASD in our study had undergone any genetic testing. This slightly higher prevalence is understandable given the broad age range of participants and our definition of genetic testing to include any test. Attributes associated with having undergone any genetic testing included diagnosis and level of functioning. However, the model suggests that the odd of having undergone genetic testing, accounting for other variables, was significantly reduced among higher functioning individuals. For diagnosis, those with a diagnosis of autism or PDD-NOS, the odds of ever having had a genetic test was
AMERICAN JOURNAL OF MEDICAL GENETICS PART A approximately three to three and a half times greater than those with Asperger disorder. Equally interesting is the high proportion of participants who reported being unsure of whether their child had ever had genetic testing. For karyotyping and CMA testing, approximately one in four parents reported that they were unsure if their children had ever had these tests; while for Fragile X testing, 11% were unsure about whether their child had undergone such testing. Our results conform to prior studies showing both under-utilization of genetic professionals and low uptake of genetic testing. Clearly, for individuals with ASD, history of referral to a geneticist or undergoing any genetic testing are tied to developmental levels with diagnosis perhaps being a proxy for developmental level. As such this suggests that individuals with ASD at the upper end of the spectrum may be evaluated differently. An additional finding of interest was related to recurrence risk or the belief that they would have another child with ASD. While it was not surprising to note that parents of two children with ASD believed that their likelihood of having another child with ASD was very high, our overall results showed that parent-estimated recurrence risks for ASD in families with a single child with ASD was also very high. Their recurrence risk estimates (mean ¼ 36%; median ¼ 50%) are gross over-estimations of the 10–20% empirical risk offered for families for whom a genetic cause has not been identified and a hereditary pattern is not evident [Constantino et al., 2010; Ozonoff et al., 2011]. Consultation with genetics professional, such as a geneticist or genetic counselor would provide families with accurate risk estimation. Given that genetic testing may reveal a cause for ASD in as many as 21% of cases [Shen et al., 2010; Betancur, 2011] such testing could adjust this recurrence risk quite dramatically. The results of such information could influence parental stress and uncertainty, enable diagnostic testing for family members, and provide options for preconception/ prenatal diagnosis. For example, a family who believes they have a 30–50% recurrence risk may learn their child has a de novo chromosomal deletion which lowers their recurrence risk to 1%. The opposite may also be true. A family who believed they were at a low risk may learn they are at 50% risk. The need to understand and improve on referral to genetic services for individuals with ASD is becoming more pressing. This study, as well as others has shown that odds of being referred to a geneticist or genetics specialist are strongly tied to level of functioning. Further, we found an equally low prevalence of individuals with ASD receiving genetic tests in the absence of corresponding genetic services. For instance, we observed that genetic tests were most often ordered by pediatric neurologists and pediatricians. While our data are cross-sectional and represent a broad age range there is a suggestion that use of genetics services and genetic testing has increased as evidenced by the significant linear trends. Parents of younger children with ASD reported higher frequencies of genetic testing and referral to genetic services. However, there is still a disconcerting discrepancy between the prevalence of genetic testing and referral to genetic services in the younger children. This discrepancy is not altogether surprising in that individuals with ASD are seen by a multitude of professionals. The dilemma is that as genetic testing options increase, their use is likely to increase as well; these newer options are far more complicated and, as
CUCCARO ET AL. pointed out by Yudell and colleagues [Yudell et al., 2012; Rossi et al., 2013], could be poorly communicated and lead to misunderstanding of the role of genetics in ASD. A related issue that may impact use is the amount of uncertainly expressed by parents around the role of genetics professionals. Specifically, when asked about whether their child would benefit from seeing a genetics professional, nearly half of the parents were unsure. It is possible that this result does not directly represent “uncertainty” but rather represents lack of familiarity with the role of genetics professionals in diagnosis and management of children with ASD. In addition, utilization may be affected by parental concerns about cost, as well as the impact on their child’s developmental outcome (i.e., to what extent will it impact treatment and education). An important consideration in regards to utilization patterns is that a large percentage of our parents were college-educated and were covered through private health insurance plans. While this most likely affects generalization of results, it is intriguing that even the most educated parents who had economic resources had difficulties accessing genetic testing and genetic services or were concerned that costs would be prohibitive if they tried to access testing or services. This concern is interesting and suggests that genetic services may be even less utilized among parents with fewer resources. A recent report by Shea and colleagues notes that among Medicaid enrolled children with ASD, historical data shows very low uptake of genetic services [Shea et al., 2013]. Finally, in contrast to previous studies, our dataset was ethnically diverse with more than half of our respondents/parents of selfreported Hispanic ancestry. Of interest, our Hispanic parents were more likely to have been referred to a geneticist than their nonHispanic counterparts. These results, while preliminary, are the first to highlight potential differences among parents of individuals with ASD from different ethnic backgrounds. The importance of continuing to explore such differences will be critical in tailoring delivery of genetic services to diverse groups. As with previously completed studies that have surveyed parents of individuals with ASD, our study suffers from key limitations, including the cross-sectional retrospective design. The retrospective design may introduce a recall bias as parents were asked to recall facts about referral to genetic services or whether their child ever had a genetic test. This could lead to inaccurate estimates of prior testing and related experiences. While our results converge with previously reported findings [Selkirk et al., 2009; Narcisa et al., 2012; Vande Wydeven et al., 2012] it would be advantageous to gather real time data (e.g., large scale medical records reviews) regarding use of genetic testing and services to develop a more accurate picture of utilization. A second limitation, given the nature of the data collection, is that we were unable to compare our responders and non-responders. It appears that our respondents were skewed toward those with higher education. Further, it may be that they were also more likely to have access to the Internet and were more aware of or interested in genetics. While this potential bias in our sample may limit interpretation of our findings it also suggests our results represent the most favorable statistics regarding these issues (i.e., among those with the greatest education we still see a low utilization rate). A third limitation is that we did not capture information about the sex of the child and other demographics, which prevented us from determining their effect on attitudes and
2599 beliefs about genetic testing. Lastly, the wide age range of our participants was a potential limitation. This is evident in the data showing trends in ever having undergone genetic testing. While current recommendations do not explicitly state that genetic testing is for younger individuals, we acknowledge that parents of older individuals with ASD may be less likely to pursue such testing. Future studies may focus on the experiences of younger individuals with ASD and exploring time trends. While rapid developments in technologies to identify genetic causes of ASD have generated tremendous enthusiasm, they have also overshadowed efforts to explore the practical, ethical, and social implications of delivering these services to parents and families. Our data support the need for enhancing both parental and medical provider knowledge of and utilization of genetics services for individuals with ASD. Despite recognition of the potential impact of genetic information in the care of individuals with ASD, genetics services have been under-utilized and parents have misperceptions of ASD etiology and recurrence risk. Given the changes in comprehensive genetic testing and referral to genetic services as recommended by practice guidelines it is crucial to accelerate strategies for educating parents and professionals about genetic services and developing optimal strategies for their delivery.
ACKNOWLEDGMENTS We thank the parents of individuals with autism who participated in this study and personnel at the Centers for Autism and Related Disabilities (CARD) who provided support allowing us to complete this study. This work was supported by a grant from the National Institute of Mental Health (MH080647) and by a gift from the Hussman Foundation.
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SUPPORTING INFORMATION
Rossi J, Newschaffer C, Yudell M. 2013. Autism spectrum disorders, risk communication, and the problem of inadvertent harm. Kennedy Inst Ethics J 23:105–138.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
