LETTERS TO THE EDITOR
Dr. Howe has received support for training from the Maternal Child Health Bureau (MCHB) under training grant T77MC09797. Dr. Morrow has received support from the National Institutes of Health (NIH) / National Institute of General Medical Sciences (NIGMS) P20GM103645-01A1 and a Career Award in Medical Science from the Burroughs Wellcome Fund. The authors gratefully acknowledge resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and participating AGRE families. The AGRE is a program of Autism Speaks and is supported in part by grant 1U24MH081810 from the National Institute of Mental Health (NIMH) to Clara M. Lajonchere (principal investigator). The authors also acknowledge the use of data for the analyses obtained from the Autism Speaks Autism Treatment Network (ATN) database and thank the ATN participants and ATN Research Group for their valuable contribution to this research. The authors thank the families who agreed to participate in the Autism Consortium (AC). The AC is a collaborative effort of Boston Medical Center, Children’s Hospital Boston, Cambridge Health Alliance, the Massachusetts General Hospital Lurie Center, and Tufts Medical Center. The authors are grateful to all the families at the participating Simons Simplex Collection (SSC) sites and the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, and E. Wijsman). Disclosure: Dr. Howe has received support from Autism Consortium. Dr. Yatchmink has received grants and funding from the MCHB. Dr. Viscidi has received support from a T32 predoctoral training grant to conduct research on autism spectrum disorders. Dr. Morrow has received awards and/or funding from NIH/NIGMS under the Neuroscience COBRE Project, NIH/NIMH, NIH/National Center for Research Resources (NCRR) under Perinatal Medicine COBRE, Rhode Island Hospital, Brown University, the Simons Foundation Autism Research Initiative, and the Society of Biological Psychiatry. He holds a patent for Methods for Treatment of Microcephaly-Associated Autism Disorders (U.S. Patent Application No.: 61/739,351; International Application No.: PCT/US2013/076609). 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.04.003
REFERENCES 1. Frazier TW, Georgiades S, Bishop SL, Hardan AY. Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J Am Acad Child Adolesc Psychiatry. 2014;53:329-340. 2. Fischbach GD, Lord C. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010;68: 192-195. 3. Lai MC, Lombardo MV, Pasco G, et al. A behavioral comparison of male and female adults with high functioning autism spectrum conditions. PLoS One. 2011;6:e20835. 4. Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents. J Autism Dev Disord. 2012;42: 1304-1313.
Dr. Frazier et al. reply: he letter to the editor by Morrow et al.1 asserts that variability in ascertainment influences the pattern of sex differences in the autism phenotype. They briefly present results of analyses examining sex differences across 4 separate samples (Autism Consortium, Autism Genetic Resource Exchange, Autism Treatment
T 700
www.jaacap.org
Network, and Simons Simplex Collection), with inconsistent findings across samples after stratifying by age and IQ. The inconsistency of results is intriguing and might imply that sex differences in the autism phenotype tend to be small in magnitude, making them difficult to detect across samples and especially difficult to detect across subsamples of age and IQ. We would encourage them to look at effect sizes in addition to significance to see whether there is less variability in the magnitude of differences and to consider statistical power in each of the subsamples they examine. Even with these caveats in mind, we agree with the central tenet of the commentary, that sampling variability can influence sex differences, and would like to point out several additional potential confounds to which future studies should carefully attend. These include balanced sampling of the demographic and clinical characteristics of male and female subjects (selection bias), measurement equivalence, inclusion of broad and focused measurements, and attention to sources (such as caregiver report, clinician observation, or objective testing). Balanced ascertainment of male and female demographic and clinical characteristics is essential to comparability of naturally occurring groups beyond the sampling variability described in the commentary. In addition to age and IQ, it is important to consider common comorbidities, race/ethnicity, family characteristics (birth order, marital status, etc.), socioeconomic status, history of regression of skills, and expressive speech (verbal versus nonverbal). Others might exist, but future studies would be wise to consider each of these as potential modifiers of sex differences. Single- versus multiple-incidence families also can be a useful variable to examine, although we suspect that sex discrepancies are not greatly influenced by this variable. Our own work has shown symptom differences by family incidence type, but these differences tend to be modest in magnitude.2 An unknown but probably nontrivial proportion of single-incidence families would become multiple-incidence families with additional births (stoppage effect), further diluting differences. In our study of sex differences, we checked for balanced ascertainment across 15 variables and found it to be quite good. However, this will not be the case in all samples, and propensity methods should be used, even in situations where the balance is only slightly askew.3 We also checked for measurement equivalence of
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 6 JUNE 2014
LETTERS TO THE EDITOR
symptom measurements. Although this step is generally ignored, it is essential for ensuring that the construct being evaluated is comparable between the sexes.4 In this study and other work, we have found comparability between the sexes for most measurements, but equivalence cannot be assumed between siblings with and without autism spectrum disorder (ASD). Rater source is also a crucial factor to consider in phenotypic evaluation. Parents are an excellent source of information, but sex comparisons in children can be influenced by the sex of the rater. Including clinician ratings and objective testing permits examination of whether observed sex discrepancies are solely a function of rater variance. Ideal future investigations of sex differences in autism would include multiple information sources for each construct evaluated. We believe our study of sex differences is a step forward by attending to, as best as possible given the available data, the above issues and by focusing on broad and specific behavioral and cognitive constructs. Sex differences at the specific level can be just as clinically meaningful as broad differences. For example, decreased level of parent-reported restricted interests in female patients with ASD will not be apparent from examining Autism Diagnostic Interview-Revised or Autism Diagnostic Observation Schedule summary scores but can greatly influence the detection of high-functioning ASD cases. Future studies would benefit from further exploring the nature of differentially endorsed restricted interest items because these might provide insight into decreased expression of this symptom set in female patients, a well-replicated effect across samples.5,6 Given the potential for differential endorsement, it might be necessary to include sex-specific inclusion criteria to ensure balanced capture of male and female subjects with ASD in future research. Similarly, our results suggest that higher levels of irritability and externalizing behavior in female patients with ASD (also a replicated finding5) might imply the need for greater monitoring of behavior problems in female patients with ASD, sex-adjusted norms in the assessment process, and/or sex-specific inclusion criteria in treatment studies of challenging behavior. It is our hope that the present work will spur investigations into these issues and additional consideration of moderating factors influencing sex differences. Future studies would do well to consider each of the methodologic issues described in the commentary by Morrow et al. and this response.
Thomas W. Frazier,
PhD
The Center for Pediatric Behavioral Health and Center for Autism Cleveland Clinic Cleveland, OH
[email protected]
Stelios Georgiades,
PhD
McMaster University and Offord Centre for Child Studies Hamilton, ON Canada
Somer L. Bishop,
PhD
Center for Autism and the Developing Brain Weill Cornell Medical College New York
Antonio Y. Hardan,
MD
Stanford University Stanford, CA
This work was made possible by a pilot research grant from the Simons Foundation Autism Research Initiative and by funding to the Case Western Reserve University/Cleveland Clinic CTSA grant number UL1 RR024989 provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Simons Foundation or NIH. The authors also acknowledge the contributions of families participating in the Simons Simplex Collection. Disclosure: Please see the disclosure statement in the original article published in March 2014. 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.04.002
REFERENCES 1. Frazier TW, Georgiades S, Bishop SL, Hardan AY. Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J Am Acad Child Adolesc Psychiatry. 2014;53:329-340. 2. Constantino JN, Zhang Y, Frazier TW, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry. 2010;167:1349-1356. 3. Rosenbaum PR. Design of Observational Studies. New York: Springer; 2010. 4. Borsboom D, Romeijn JW, Wicherts JM. Measurement invariance versus selection invariance: is fair selection possible? Psychol Methods. 2008;13:75-98. 5. Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents. J Autism Dev Disord. 2012;42: 1304-1313. 6. Szatmari P, Liu XQ, Goldberg J, et al. Sex differences in repetitive stereotyped behaviors in autism: implications for genetic liability. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:5-12.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 6 JUNE 2014
All statements expressed in this column are those of the authors and do not reflect the opinions of the Journal of the American Academy of Child and Adolescent Psychiatry. See the Instructions for Authors for information about the preparation and submission of Letters to the Editor.
www.jaacap.org
701
Dr. Howe has received support for training from the Maternal Child Health Bureau (MCHB) under training grant T77MC09797. Dr. Morrow has received support from the National Institutes of Health (NIH) / National Institute of General Medical Sciences (NIGMS) P20GM103645-01A1 and a Career Award in Medical Science from the Burroughs Wellcome Fund. The authors gratefully acknowledge resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and participating AGRE families. The AGRE is a program of Autism Speaks and is supported in part by grant 1U24MH081810 from the National Institute of Mental Health (NIMH) to Clara M. Lajonchere (principal investigator). The authors also acknowledge the use of data for the analyses obtained from the Autism Speaks Autism Treatment Network (ATN) database and thank the ATN participants and ATN Research Group for their valuable contribution to this research. The authors thank the families who agreed to participate in the Autism Consortium (AC). The AC is a collaborative effort of Boston Medical Center, Children’s Hospital Boston, Cambridge Health Alliance, the Massachusetts General Hospital Lurie Center, and Tufts Medical Center. The authors are grateful to all the families at the participating Simons Simplex Collection (SSC) sites and the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, and E. Wijsman). Disclosure: Dr. Howe has received support from Autism Consortium. Dr. Yatchmink has received grants and funding from the MCHB. Dr. Viscidi has received support from a T32 predoctoral training grant to conduct research on autism spectrum disorders. Dr. Morrow has received awards and/or funding from NIH/NIGMS under the Neuroscience COBRE Project, NIH/NIMH, NIH/National Center for Research Resources (NCRR) under Perinatal Medicine COBRE, Rhode Island Hospital, Brown University, the Simons Foundation Autism Research Initiative, and the Society of Biological Psychiatry. He holds a patent for Methods for Treatment of Microcephaly-Associated Autism Disorders (U.S. Patent Application No.: 61/739,351; International Application No.: PCT/US2013/076609). 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.04.003
REFERENCES 1. Frazier TW, Georgiades S, Bishop SL, Hardan AY. Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J Am Acad Child Adolesc Psychiatry. 2014;53:329-340. 2. Fischbach GD, Lord C. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010;68: 192-195. 3. Lai MC, Lombardo MV, Pasco G, et al. A behavioral comparison of male and female adults with high functioning autism spectrum conditions. PLoS One. 2011;6:e20835. 4. Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents. J Autism Dev Disord. 2012;42: 1304-1313.
Dr. Frazier et al. reply: he letter to the editor by Morrow et al.1 asserts that variability in ascertainment influences the pattern of sex differences in the autism phenotype. They briefly present results of analyses examining sex differences across 4 separate samples (Autism Consortium, Autism Genetic Resource Exchange, Autism Treatment
T 700
www.jaacap.org
Network, and Simons Simplex Collection), with inconsistent findings across samples after stratifying by age and IQ. The inconsistency of results is intriguing and might imply that sex differences in the autism phenotype tend to be small in magnitude, making them difficult to detect across samples and especially difficult to detect across subsamples of age and IQ. We would encourage them to look at effect sizes in addition to significance to see whether there is less variability in the magnitude of differences and to consider statistical power in each of the subsamples they examine. Even with these caveats in mind, we agree with the central tenet of the commentary, that sampling variability can influence sex differences, and would like to point out several additional potential confounds to which future studies should carefully attend. These include balanced sampling of the demographic and clinical characteristics of male and female subjects (selection bias), measurement equivalence, inclusion of broad and focused measurements, and attention to sources (such as caregiver report, clinician observation, or objective testing). Balanced ascertainment of male and female demographic and clinical characteristics is essential to comparability of naturally occurring groups beyond the sampling variability described in the commentary. In addition to age and IQ, it is important to consider common comorbidities, race/ethnicity, family characteristics (birth order, marital status, etc.), socioeconomic status, history of regression of skills, and expressive speech (verbal versus nonverbal). Others might exist, but future studies would be wise to consider each of these as potential modifiers of sex differences. Single- versus multiple-incidence families also can be a useful variable to examine, although we suspect that sex discrepancies are not greatly influenced by this variable. Our own work has shown symptom differences by family incidence type, but these differences tend to be modest in magnitude.2 An unknown but probably nontrivial proportion of single-incidence families would become multiple-incidence families with additional births (stoppage effect), further diluting differences. In our study of sex differences, we checked for balanced ascertainment across 15 variables and found it to be quite good. However, this will not be the case in all samples, and propensity methods should be used, even in situations where the balance is only slightly askew.3 We also checked for measurement equivalence of
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 6 JUNE 2014
LETTERS TO THE EDITOR
symptom measurements. Although this step is generally ignored, it is essential for ensuring that the construct being evaluated is comparable between the sexes.4 In this study and other work, we have found comparability between the sexes for most measurements, but equivalence cannot be assumed between siblings with and without autism spectrum disorder (ASD). Rater source is also a crucial factor to consider in phenotypic evaluation. Parents are an excellent source of information, but sex comparisons in children can be influenced by the sex of the rater. Including clinician ratings and objective testing permits examination of whether observed sex discrepancies are solely a function of rater variance. Ideal future investigations of sex differences in autism would include multiple information sources for each construct evaluated. We believe our study of sex differences is a step forward by attending to, as best as possible given the available data, the above issues and by focusing on broad and specific behavioral and cognitive constructs. Sex differences at the specific level can be just as clinically meaningful as broad differences. For example, decreased level of parent-reported restricted interests in female patients with ASD will not be apparent from examining Autism Diagnostic Interview-Revised or Autism Diagnostic Observation Schedule summary scores but can greatly influence the detection of high-functioning ASD cases. Future studies would benefit from further exploring the nature of differentially endorsed restricted interest items because these might provide insight into decreased expression of this symptom set in female patients, a well-replicated effect across samples.5,6 Given the potential for differential endorsement, it might be necessary to include sex-specific inclusion criteria to ensure balanced capture of male and female subjects with ASD in future research. Similarly, our results suggest that higher levels of irritability and externalizing behavior in female patients with ASD (also a replicated finding5) might imply the need for greater monitoring of behavior problems in female patients with ASD, sex-adjusted norms in the assessment process, and/or sex-specific inclusion criteria in treatment studies of challenging behavior. It is our hope that the present work will spur investigations into these issues and additional consideration of moderating factors influencing sex differences. Future studies would do well to consider each of the methodologic issues described in the commentary by Morrow et al. and this response.
Thomas W. Frazier,
PhD
The Center for Pediatric Behavioral Health and Center for Autism Cleveland Clinic Cleveland, OH
[email protected]
Stelios Georgiades,
PhD
McMaster University and Offord Centre for Child Studies Hamilton, ON Canada
Somer L. Bishop,
PhD
Center for Autism and the Developing Brain Weill Cornell Medical College New York
Antonio Y. Hardan,
MD
Stanford University Stanford, CA
This work was made possible by a pilot research grant from the Simons Foundation Autism Research Initiative and by funding to the Case Western Reserve University/Cleveland Clinic CTSA grant number UL1 RR024989 provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Simons Foundation or NIH. The authors also acknowledge the contributions of families participating in the Simons Simplex Collection. Disclosure: Please see the disclosure statement in the original article published in March 2014. 0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.04.002
REFERENCES 1. Frazier TW, Georgiades S, Bishop SL, Hardan AY. Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J Am Acad Child Adolesc Psychiatry. 2014;53:329-340. 2. Constantino JN, Zhang Y, Frazier TW, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry. 2010;167:1349-1356. 3. Rosenbaum PR. Design of Observational Studies. New York: Springer; 2010. 4. Borsboom D, Romeijn JW, Wicherts JM. Measurement invariance versus selection invariance: is fair selection possible? Psychol Methods. 2008;13:75-98. 5. Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents. J Autism Dev Disord. 2012;42: 1304-1313. 6. Szatmari P, Liu XQ, Goldberg J, et al. Sex differences in repetitive stereotyped behaviors in autism: implications for genetic liability. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:5-12.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 6 JUNE 2014
All statements expressed in this column are those of the authors and do not reflect the opinions of the Journal of the American Academy of Child and Adolescent Psychiatry. See the Instructions for Authors for information about the preparation and submission of Letters to the Editor.
www.jaacap.org
701
