OBJECTIVES
The primary question for this review is: What is the reported prevalence rate of ASD in all individuals with DS compared to the prevalence rate of ASD in the typical population when diagnostic tools are used?
The secondary research questions for this review are:
- What is the reported mean age of diagnosis of ASD in DS?
- What are the primary distinguishing characteristics of ASD in DS?
- Do medical co-morbidities affect the prevalence rate of ASD in DS?
ELIGIBILITY CRITERIA
This study will consider studies that reported on children, adolescents, and adults with an existing diagnosis of DS and diagnosed by the standard assessments used for DS (clinical and genetic testing) and ASD.
We will use the Condition, Context and Population (CoCoPop) as per the format in Joanna Briggs Institute (JBI) (50). The JBI format was chosen as their methodology has specific formal guidance for reviews of prevalence and includes a critical appraisal tool specific for prevalence studies. This will facilitate an analysis specific to the type of evidence for prevalence and potentially provide stronger conclusions of the data (51). The criteria for each of these is detailed in the text below and further in Tables 2 and 3
Condition
This review will consider studies that report on the prevalence and/or incidence of ASD in the DS population. Prevalence is defined as “The fraction or proportion of the population that has the condition (i.e., cases)” (52). Incidence is defined as the rate of new events in a group of people of fixed size, all of which are observed over time (52).
Context
This review will consider studies that reported on children, adolescents, and adults with an existing diagnosis of DS and diagnosed by the standard assessments used for DS (clinical and genetic testing) and ASD. We will also consider the diagnoses made by team assessment by (psychologist, psychiatrist & developmental pediatrician), when it is based on DSM-III, DSM-IV or DSM-V criteria for the diagnosis of ASD or if they use ASD screeners. Studies will be considered from all countries that have data reporting prevalence on this topic. We will not apply language restrictions, and studies published in languages other than English will be considered for translation.
Participants
Table 2
Participants Inclusion and Exclusion Criteria
Inclusion
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Exclusion
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Original studies in which researchers report on the prevalence of ASD in individuals with DS were included. Studies in which data allowed for the calculation of prevalence were also included.
Studies in which researchers described the prevalence of ASD in the general population were included if specific information on the DS population was available (i.e., the number of individuals with DS and ASD, total number of individuals with DS tested, and tool used).
The studies could have been published in peer-reviewed journals or presented as conference abstracts.
The diagnosis of ASD should have been based on diagnostic tests rather than screening tools.
Studies in all languages from all countries internationally will be considered.
|
Studies in which information regarding the number of individuals with DS and ASD, the total number of individuals with DS tested, and tools used to diagnose ASD were not available were excluded.
Studies using ASD screening tools only will be excluded if no team assessment (psychologist, psychiatrist & developmental pediatrician) was done after the screening tool.
Multiple publications from the same cohort will be excluded unless any additional information was available.
Animal studies will be excluded.
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Note. ASD = Autism spectrum disorder, DS = Down syndrome
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Table 3
Tools Inclusion and Exclusion criteria
ASD Inclusion tools
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ASD Exclusion tools
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Tools that will be considered
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Inclusion tools - Brief description
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Tools that will be excluded if used in isolation (no team assessment done)
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Exclusion tools - Brief description
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The Autism Diagnostic Observational Schedule (ADOS™-2)
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A semi-structured, standardized assessment scoring activities or social presses on a 4-point scale (21)
|
Modified Checklist for Autism in Toddlers, Revised with Follow-Up
(M-CHAT-R/F)
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A modified checklist for toddlers with a parent-completed questionnaire screening for autism in the general population (33)
|
The Autism Diagnostic Interview-Revised
(ADI-R)
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A semi-structured, investigator-based interview for caregivers of children and adults for whom autism or pervasive developmental disorders are possible diagnoses between the mental ages from 18 months into adulthood (11, 12)
|
Screening Tool for Autism in Toddlers and Young Children (STAT)
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An interactive screening tool for suspected autism in children 24 to 36 months. It consists of 12 activities assessing play, requesting, directing attention and motor initiation (53)
|
The Development and Well-being Assessment
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A package of questionnaires, interviews, and rating techniques designed to generate ICD-10 and DSM-IV psychiatric diagnoses on five to 16-year-old patients. Interviewers administer a structured interview to parents about psychiatric symptoms and their resultant impact. Teachers complete a brief questionnaire covering the main conduct, emotional, and hyperactivity symptoms and any resultant impairment. A computer program uses this information to predict likely diagnoses. Finally, clinicians use this to allocate a diagnosis (11, 12)
|
Communication and Symbolic Behavior Scales Developmental Profile
(CSBS-DP)
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A standardized screening tool for communication and symbolic abilities between 6 to 24-month levels. It consists of an Infant-Toddler Checklist and a parent-completed screening tool (54)
|
The Childhood Autism Rating Scale
(CARS)
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A clinical scale for the trained clinician to rate items that are indicative of ASD after direct observation and to determine the symptom severity through quantifiable ratings, between the ages of 2 years to late adulthood (11, 12)
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The Social Communication Questionnaire
(SCQ)
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A parent-report screen used in children 4 years (31)
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Gilliam Autism Rating Scale – Second Edition (GARS-2)
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A parent or teacher-based tool assists in the identification and diagnosis of autism between the ages of 3 to 22 years (11, 12)
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Parents’ Evaluation of Developmental Status (PEDS)
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A general developmental screening tool that uses a parent-interview form (55)
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Developmental Dimensional and Diagnostic Interview
(3di)
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A parental interview using a computerized format (11, 12)
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The Parent’s Observations of Social Interactions (POSI)
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A parent-report screening instrument for ASD in children 16 to 35 months (56)
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Diagnostic Interview for Social and Communication Disorder (DISCO)
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A semi-structured interview with a person who knows the individual, preferably from birth it focuses on patterns of behaviour over time (11, 12)
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Ages and Stages Questionnaires (ASQ)
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A general developmental screening tool (57). Not specific ASD screening
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Team assessment (psychologist, psychiatrist, and developmental pediatrician)
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Done in accordance with according to DSM-IV or DSM-V criteria for the diagnosis of ASD (11, 12)
|
The Developmental Behaviour Checklist-Autism Screening Algorithm
(DBC-ASA)
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A parent-report tool to assess behavioural and emotional disturbance in 4- to 18-year-old individuals with intellectual disability (58)
|
|
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Developmental Behavior Checklist-Early Screen
(DBC-ES)
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A screen for autism in developmentally delayed children 18 to 48 months of age (59)
|
|
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Rapid Interactive Screening Test for Autism in Toddlers (RITA-T)
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An interactive clinical tool for children 18 – 36 months (60)
|
|
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Social Responsiveness Scale
(SRS)
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A 65-item rating scale can be used as a screener in clinical or educational settings, an aid to clinical diagnosis, or a measure of response to intervention. Completed by a parent or teacher in just 15 to 20 minutes, the SRS provides a clear picture of a child’s social impairments, assessing social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. It is appropriate for use with children from 4 to 18 years of age (61)
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Note. 3di, Developmental Dimensional and Diagnostic Interview; ADDC, Autistic Disorders Diagnostic Checklist; ADI-R, Autism Diagnostic Interview – Revised; ADOS-G, Autism Diagnostic Observation Schedule – Generic; A-PL-ADOS, Pre-linguistic ADOS; ASD, Autism spectrum disorder; ASQ, Autism Screening Questionnaire; ASS-Q, Asperger Syndrome Screening Questionnaire; CARS, Childhood Autism Rating Scale; CSBS-DPDS, Communication and Symbolic Behavior Scales Developmental Profile; DBC-ASA, Developmental Behaviour Checklist-Autism Screening Algorithm; DBC-ES, Developmental Behavior Checklist-Early Screen; DISCO, Diagnostic Interview for Social and Communication Disorder; Down syndrome; DSM, Diagnostic and Statistical Manual of Mental Disorders; DSMIG, Down Syndrome Medical Interest Group; GARS-2, Gilliam Autism Rating Scale – Second Edition; HBS, Handicaps, Behaviours and Skills Schedule; ICD-10, International Classification of Diseases-10; ID, Intellectual disability; M-CHAT, Modified Checklist for Autism in Toddlers – Revised; POSI, Parent’s Observations of Social Interactions; PCC, Population, Concept, Context; PRISMA-P, Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols (PRISMA-P) guidelines; RITA-T, Rapid Interactive Screening Test for Autism in Toddlers; SCQ, Social Communication Questionnaire; STAT, Screening Tool for Autism in Toddlers and Young Children.
STUDY DESIGN
This prevalence study will be conducted in accordance with the Joanna Briggs Institute methodology for systematic reviews of prevalence and incidence (50).
The review will consider observational and descriptive study designs as these designs will have the anticipated information on prevalence (50). These will include prospective and retrospective cohort studies, case-control studies, cross-sectional studies, case series and case reports of any design from all countries. In addition, primary studies identified in published systematic reviews that meet the inclusion criteria will be considered. Text and opinion papers will also be considered for inclusion in this systematic review to capture all available data if they meet our selection criteria. Registry and census data will also be included.
This wide range of studies was chosen as a starting point in order to capture data comprehensively. Studies that do not meet the full inclusion criteria for the diagnosis itself may contain relevant information; for example, the mean age of presentation of symptoms consistent with ASD may be included. These excluded studies will be presented in a table with reasons for their exclusion.
Animal studies will not be included. Studies published from at least 1947 will be included as this is around the time when ASD was first described in the literature. The reference lists of articles will be scanned.
Experts in the developmental pediatric field and experts in Down syndrome will be consulted to identify studies relevant to our topic. Abstracts of conference proceedings, such as the Down Syndrome Medical Interest Group (DSMIG), will be searched.
Articles in any language will be considered if they can be translated into English. If the translation is not possible, they will be excluded but listed in a table in the appendix.
METHODS
Search strategy
The search strategy will aim to locate both published and unpublished studies. It will be phased, firstly in Ovid Medline, using a combination of index terms and keywords around Down syndrome, Trisomy 21, AND [autism. mp. or exp Autistic Disorder/ OR exp Asperger Syndrome/ or exp Autistic Disorder/ or exp Child Development Disorders, Pervasive/ or pervasive developmental disorder. mp. Or exp Developmental Disabilities/]. An initial limited search of Ovid Medline, Embase and PsychINFO was undertaken to identify articles on the topic (Appendix I ). There were no previous similar reviews. The text words contained in the titles and abstracts of relevant articles and the index terms used to describe the articles from this limited search will then be used to develop a more refined full search strategy in the second phase for MEDLINE, Embase, PsychINFO, Scopus and CINAHL. The search strategy, including all identified keywords and index terms, will be adapted for each included information source.
Study selection
EndNote X9 will be used for citation collation. Duplicates will be removed manually. Covidence will be used for screening by two independent reviewers. Disagreements will be resolved through a third reviewer.
Data extraction and analysis
Two reviewers (RB and JS) independently will screen the titles and abstracts of all the potentially relevant studies. At this stage, the search will purposely be broad to allow for the inclusion of all potentially relevant studies. Publications meeting the inclusion criteria will have a full-text review to validate their eligibility. Each article will be assessed independently by (RB and JS). A third author (PC) will review all studies that met the inclusion criteria at this stage will be reviewed by a third author (PC) to ensure appropriateness for inclusion in the final analysis. Disagreements of eligibility will be reconciled by discussion and review with the rest of the authors to ensure appropriateness for inclusion in the final analysis. The extraction will be done after full-text screening using a data extraction tool developed by the reviewers.
A standardized data abstraction form will be used to enter the study-related variables (Appendix II). The data extracted from the identified studies will include specific details about the population, concept and context. Two tables will be generated with the first table having information on the key characteristics of each study, including author, year of publication, geographical setting, type of study, demographics of the participants, the period over which the study was conducted, the method of identification or diagnosis of ASD, age at which participants were assessed and the tools used for diagnosis in the studies (Table 4, Appendix II). The second table will have information on the key findings such as the age at which ASD was diagnosed, the prevalence of ASD based on diagnostic tools and limitations of the studies (Table 5, Appendix II).
Excluded studies closely meeting the inclusion criteria will be included in a separate table as they may contain many elements of our inclusion criteria but not present the specific criteria of our interest separately. Further investigation of their data may provide significant results. The authors will be contacted to access additional information and reassess the eligibility of these studies. Excluded studies will be documented with reasons for their exclusion.
As the process evolves, the data extraction form may require modification to ensure all relevant information is included. Additionally, the critical appraisal tool for JBI (62) will help identify differences and similarities between the included studies. The answers to the JBI critical appraisal tool will be detailed in Table 6, Appendix II).
We will use random-effects models for meta-analysis and subgroup analysis. If the I² value is less than 50%, a pooled estimate will be generated in the form of a forest plot.
Risk of bias assessment of included studies
The risk of bias will be assessed by two reviewers (RB and JS), using the quality assessment tool for prevalence studies from the Joanna Briggs Institute (Appendix III) using the following criteria: (1) Was the sample frame appropriate to address the target population? (2) Was the study population sampled appropriately? (3) Was the sample size adequate? (4) Were the study subjects and settings described in detail? (5) Was the data analysis conducted with sufficient coverage of the identified sample? (6) Were valid methods used for identification of the condition? (7) Was the condition measured in a standard, reliable way for all the participants? (8) Was there appropriate statistical analysis? (9) Was the response rate adequate, and if not, was the low response rate managed appropriately? The criteria were rated as either yes, no, not clear, or not applicable. We will use a scoring system to rate the risk of bias. Scores will be assigned as “1” if answered with “Yes” and scored “0” if answered with “no” or “not clear.” Studies will be rated as high, moderate, and low risk of bias when quality is scored 0–3, 4–6, and 7–8 respectively. Cross-checking of the assessments will be done by a third reviewer (PTC), and disagreements will be resolved.When necessary, authors of the included studies will be contacted, requesting additional information from their studies. The answers to this will be detailed in an additional table in the main manuscript (62).
Data synthesis
If the studies are comparable in terms of their PICO elements especially where it relates to the diagnosis of ASD (homogenous), and the heterogeneity is low, then we will pool studies in a quantitative analysis in a meta-analysis. If the studies vary too much in their PICO elements, then we will only describe them narratively and in tables, to aid in data presentation. Stata will be used.
We will use random effects model for the meta-analysis and subgroup analysis. If I² value is less than 50%, a pooled estimate will be generated in form of a forest plot. .
Analysis of subgroups or subsets
We will conduct a sensitivity analysis of different types of participants by age, region, decade of study, type of study and medical co-morbidities, especially infantile spasm, obstructive sleep apnea and congenital heart disease, in order to test the robustness of our meta-analytic findings. Moreover, we will conduct a sensitivity analysis of studies categorized as having a high risk of bias (RoB). We will exclude studies on high risk of bias to estimate their impact on the overall pooled prevalence estimates, and how robust our pooled estimates are.