Sex differences in ADHD symptom severity.

Sex differences in the rate of Attention Deficit Hyperactivity Disorder (ADHD) diagnoses are well documented in the literature. ADHD affects approximately 5–7 percent of the school age population, with a male to female ratio of about 3:1 in community-based samples of youth (Willcutt, 2012). There is disagreement on whether males likewise show more severe inattentive and comorbid neuropsychological symptoms among diagnosed individuals (Elkins, Malone, Keyes, Iacono, & McGue, 2011; Gaub & Carlson, 1997; Gershon, 2002; Kan et al., 2012). For example, in a population based, longitudinal study, affected females had larger effect sizes for behavioral and cognitive functioning deficits, but this could be explained by the better performance of unaffected females compared to unaffected males (Arnett, MacDonald, & Pennington, 2013). Thus, at this point it is unclear whether the behavioral and etiological features of ADHD are the same in both sexes. The sex discrepancy in ADHD is of interest because it could provide clues to the etiology of the disorder. Additionally, there is little research on females with ADHD (Gaub & Carlson, 1997), which limits our understanding of how they develop and cope with associated symptoms. The present study tests competing explanations for the sex difference in ADHD symptom severity, using a community-based twin sample that is enriched for ADHD symptoms. Theories on the ADHD Sex Difference Hypotheses explaining the ADHD sex difference are presented as ovals in the flow chart in Figure 1. The initial question, Is the difference valid (i.e. due to genuine etiologic differences)?, distinguishes two broad categories of hypotheses. If invalid, the three potential explanations include selection bias, lack of measurement invariance across sexes, and missing symptoms. Selection bias has been observed in clinically referred samples (Gershon, 2002). However, our own sample, although overselected for participants with ADHD symptoms, was recruited from community rather than clinical settings. “Case” families were identified based on parent and/or teacher symptom ratings, rather than previous clinical diagnoses, minimizing bias that could result from overparticipation by families with higher rates of ADHD. Further, the results of many other community samples (Graetz, Sawyer, Hazell, Arney, & Baghurst, 2001; Willcutt, 2012; Willcutt, Pennington, Chhabildas, Friedman, & Alexander, 1999) indicate that the gender difference is not due to bias. Thus, selection bias is not considered as a possible explanation in the current study. Figure 1 Lack of measurement invariance would mean that ADHD rating scales are not psychometrically equivalent for females and males, such that the measure differs in internal or external validity by sex. Over-referral of males for clinical services in the past could have biased the selection of symptoms that define the diagnostic construct, a possibility that has been supported for conduct disorder, in which relational aggression is more common in females (Zahn-Waxler, Crick, Shirtcliff, & Woods, 2006). In other words, the same underlying liability can be expressed differently as a function of sex. Studies of familial patterns have shown conflicting results regarding rates of psychiatric disorder in relatives of male versus ADHD probands (e.g. Faraone, Biederman, Keenan & Tsuang, 1991; Stawicki & Nigg, 2003). However, measurement invariance for ADHD symptoms across sexes has been established in several community and clinical samples (Collett, Crowley, Gimpel, & Greenson, 2000; Conners, Sitarenios, Parker, & Epstein, 1998; Hudziak et al., 1998; Martel, von Eye, & Nigg, 2010; Reid et al., 2000), suggesting that this is not a valid explanation. We will examine internal and external validities across sex in the current sample to further rule out this hypothesis. A third possibility is the “missing symptoms” hypothesis. A group of symptoms that was not included in either the DSM-IV or DSM-5 criteria, the Sluggish-Cognitive Tempo (SCT) cluster, presents an alternative, theoretically plausible candidate for ADHD symptoms that are more commonly expressed by females. These symptoms are present more frequently in children with the predominantly inattentive subtype of DSM-IV ADHD, but maintained independence in factor analysis of a community sample (Hartman, Willcutt, Rhee, & Pennington, 2004). While previous research did not find a difference in SCT levels between ADHD males and females in another community sample (Carlson & Mann, 2002), no study that we know of has examined the severity of these symptoms among females who do not already meet criteria for ADHD. The present study will test whether inclusion of these symptoms in the ADHD profile eliminates the sex difference. Within the second broad category of hypotheses, which requires the sex difference in ADHD prevalence to be valid (i.e. not an artifact of selection or measurement), two possible explanations are proposed in Figure 1: the Mean Difference Model (MDM), and the Variance Difference Model (VDM). The MDM proposes that the female liability distribution is shifted in the less-affected direction relative to that of males, similar to a multiple threshold model originally described by Carter (1972). Given equivalent variances across sexes and an absolute cutoff for the disorder, fewer females will fall into the affected tail of the overall distribution (Figure 2). Hence, there will be more affected males. Figure 2 The other valid explanation that we propose is the VDM, which was tested in reading disorder by Hawke, Olson, Willcutt, Wadsworth & DeFries (2009). These authors found that more variance in males' reading performance accounted for the higher number of males who met criteria for the disorder, despite equivalent mean performance between sexes (see Figure 2). Given the strong comorbidity between reading disorder and ADHD (Pennington, 2002), it is logical that the same explanation could apply to the sex difference in ADHD prevalence. Since the VDM predicts a two-tailed variance difference, we would also expect to see a higher male to female ratio at the non-symptomatic end of the distribution when means are centered. The MDM and VDM are not mutually exclusive. With variance controlled in the MDM analyses and means controlled in the VDM analyses, there is a possibility that both models explain the sex difference in ADHD to some extent. Mediation by Cognitive Endophenotypes We propose that the MDM and VDM apply not only to the symptom distributions, but also to intermediate pathogenetic factors that lie between the etiology and behavior, such as endophenotypes. Cognitive endophenotypes for ADHD are heritable, cognitive risk factors that explain some variance in the disorder and are theoretically more closely tied to the underlying genotype than are the behavioral symptoms of ADHD (Bidwell, Willcutt, DeFries, & Pennington, 2007; Gottesman & Gould, 2003). Youth with ADHD are impaired in a variety of cognitive domains, including IQ, executive functions, and processing speed (For reviews, see Frazier, Demaree, & Youngstrom, 2004; Kofler et al., 2013; Oosterlaan, Logan, & Sergeant, 1998; Pennington, 2002). Although they cannot account for all of the variance in ADHD, cognitive endophenotypes are nonetheless good candidates for explaining individual characteristics of the disorder, including the sex difference. If we find support for the MDM or VDM at the symptom level, then we also hypothesize that valid cognitive endophenotypes will demonstrate a pattern of male to female ratios that corresponds to the MDM or VDM. Cognitive endophenotypes that display this expected pattern of sex differences will be tested as mediators of the association between sex and ADHD severity.