Gender Differences in Autism Spectrum Disorders in a Population-Based Twin Sample: testing three hypotheses for male preponderance.

The proposed research aims to investigate gender differences across the full range of the autism spectrum, in a population-based sample of twins. Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterised by difficulties in social behaviour and communication, with restricted/repetitive behaviours and interests. One of the most striking features of ASD is the high male to female ratio, which varies across the spectrum, but is usually estimated at 4-5:1. The higher rate of ASD in males has been seen as a clue to the etiology of ASD; e.g. Baron-Cohen's 'extreme male brain' theory (Baron-Cohen, 2002) or the Female Protective Effect (FPE; e.g. Robinson et al., 2013). However, it is also possible that ASD is less well recognised in females, either due to male-stereotypes or genuine compensation. It is important to know whether current diagnostic practices miss females who would benefit from identification and intervention.

The proposed study aims to address directly the question of whether females with high ASD traits are being missed by diagnostic practices or are instead coping/compensating and do not need a diagnosis. To do this the proposed research will compare four participant groups; females and males who meet diagnostic criteria for ASD, and females and males who score highly for ASD traits, but who do not meet diagnostic criteria. A battery of gold-standard diagnostic tools, cognitive tasks, measures of coping, quality of life, co-morbidities and mental and physical health will be completed by the four groups. This design will allow not only comparison of symptom presentation and cognitive profiles across genders, but also examination of whether high trait females without a diagnosis are compensating or instead 'suffering in silence'. It is vital to understand whether, and why, we fail to diagnose ASD in females, in order to clarify whether the current gender disparity is purely biological or also a reflection, in part, of problems with a male-focused conceptualisation, recognition, assessment or diagnosis of ASD.

The proposed study is part of a longitudinal ASD twin study, nested within the larger Twins Early Development Study (TEDS). This design allows for the inclusion of non ASD co-twins and thus a more family wide exploration of gender, as well as specific examination of the FPE hypothesis, which suggests that a greater etiological 'load' is needed to result in ASD in females than males. Along with the FPE the proposed study tests two further, novel hypotheses: the 'Female Masking Effect' whereby females are less likely to receive a diagnosis of ASD because they are missed by male-focused diagnostic processes, and the 'Female Compensatory Effect' whereby females are less likely to receive a diagnosis of ASD because (in the absence of IQ/co-morbid problems) they cope better with high ASD traits via compensation and therefore do not need a diagnosis.

The population-based design of the proposed study and the inclusion of the full ASD spectrum, address previous limitations with research in this area, such as possible sampling bias (due to use of clinic or volunteer register samples) and circularity (due to inclusion of only those meeting current diagnostic criteria).

The proposed study has the potential to change the way we think about ASD; currently the accepted ratio of 4-5:1 informs research design and sample selection, and females are often excluded from research. The proposed study will tell the research/clinical/stakeholder communities whether and why this ratio may reflect bias in recognition/assessment/diagnosis, with far reaching implications for future research. In addition, the study has potential benefits for females with high traits/ASD by listening to and learning from their experiences. The proposed study has the potential to improve recognition of ASD in females, as a first step to targeting services and rebalancing the scientific and public perception of ASD.

There are four groups who will benefit from the proposed research. 1)The academic community and researchers working in the fields of ASD and other areas of female mental health and wellbeing will benefit from improved knowledge about females with ASD. Our population-based research with the full ASD spectrum, including high trait non-diagnosed cases, will provide much needed quantitative and qualitative information about the female presentation of ASD. Our research papers and presentations will clarify for the research community whether females are being missed by current ASD concepts and diagnostic processes, and whether the male preponderance is, in part, a reflection of gender differences in compensation and/or masking. This improved information will lead to better recognition and theoretical understanding of the female presentation of ASD. The proposed research will have far reaching conceptual impact for the research community in terms of reframing the debate about, and subsequent research into, gender in ASD.

2)Clinicians diagnosing and working with individuals with ASD and their families will benefit from our research. The research will provide evidence-based findings that will inform the current debate on the diagnosis of females with ASD, and could influence clinical aspects of ASD assessment, increasing the effectiveness of this and of targeting of service provision for females and their families. In addition to clinicians working specifically within ASD, the proposed research will also benefit those focusing on other mental health conditions more generally. If it is the case that females with ASD are missed by current diagnostic processes, it is highly likely that they are misdiagnosed with other conditions (e.g. psychosis) and/or that diagnostic over-shadowing is occurring from genuine co-morbidities (e.g. anorexia, anxiety). The proposed study findings will benefit those working in this field in terms of improving understanding and recognition of ASD in females.

3)Teachers of students with ASD, other mental health conditions or special educational needs will benefit from this research. The qualitative element of the study aims to discover issues most pertinent for females with ASD and high traits, including those relating to educational experiences. This information, teamed with the quantitative results on the presentation of ASD, will aid those working in educational settings. We will test hypotheses about compensation, and our findings may help educators maximise students' compensatory skills. During adolescence/young adulthood social demands may outstrip compensation in ASD, and we will also test hypotheses about unmet educational and social needs for females with ASD/high traits. Our research can establish whether female difficulties are over-looked, with implications for improving recognition in schools/further education. The findings of the proposed study will be used to highlight information about the female presentation of ASD, needs for specific help in education settings and possible strategies to help females develop to their full potential.

4)Women and girls with ASD (and those with high traits) and their families will benefit from the proposed research, as well as being key contributors through the qualitative and quantitative studies. The research will address how ASD is manifested in females versus males, and test three hypothesised sources of male preponderance. Better understanding will help females with ASD via improved recognition, diagnosis, and support. The research aims to develop evidence-based proposals for improving services for females with ASD (including, putatively, those currently unrecognised), to enhance quality of life and wellbeing.

The proposed research has the potential to contribute to the nation's health by vastly increasing our knowledge of gender differences in ASD, and improving recognition of, and services for, women and girls with ASD.