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Prevalence and comorbidity of autism spectrum disorder in Spain: study protocol for a systematic review and meta-analysis of observational studies

  • Manuel Ridao3,
  • Isabel Hurtadoiv,
  • Amparo Núñez-Beltránfive,
  • Ricard Gènova-Malerasvi,
  • Adolfo Alonso-Arroyo7,8,
  • Aurelio Tobías9,
  • Rafael Aleixandre-Benavent8,10,
  • Miguel A. Catalá11 &
  • Rafael Tabarés-Seisdedosii

Systematic Reviews volume 8, Article number:141 (2019) Cite this article

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Abstract

Background

Autism spectrum disorder (ASD) is a complex developmental disorder characterised by impaired social interaction and communication, and restrictive and repetitive behaviour. Previous systematic reviews have traditionally assessed the prevalence of ASD on global or regional context, with very few meta-analyses at the state level. The objective of this study will exist to systematically evaluate published and unpublished observational studies that present prevalence and comorbidity of ASD among children, adolescent and adult population in Kingdom of spain.

Methods/design

We designed and registered a report protocol for a systematic review and meta-analysis of descriptive epidemiology data. Observational studies (cohort, cantankerous-sectional) reporting the prevalence of ASD and conducted in a broad range of people (east.m. general population, outpatient and/or school settings) will exist included. The primary outcome volition be the prevalence of ASD. Secondary outcomes will be the prevalence of any physical or mental comorbidity in association with ASD. No limitations volition be imposed on publication status, study bear catamenia, and language of dissemination. Comprehensive literature searches will be conducted in seven electronic databases (from Jan 1980 onwards), including PubMed/MEDLINE, EMBASE, Scopus, Web of Science, PsycINFO, IME—Spanish Medical Alphabetize and IBECS—Spanish Bibliographic Alphabetize of Wellness Sciences. Gray literature will be identified through searching dissertation databases, Google Scholar and conference abstracts. Two team members will independently screen all citations, full-text articles, and abstract information. Potential conflicts will be resolved through discussion. The written report methodological quality (or bias) will be appraised using an appropriate tool. If feasible, we will carry random furnishings meta-analysis of observational data. Prevalence estimates will be stratified according to gender, age and geographical location. Boosted analyses will be conducted to explore the potential sources of heterogeneity (e.g. methodological quality, sample size, diagnostic criteria).

Discussion

This systematic review and meta-analysis of observational information will identify, evaluate and integrate the epidemiological knowledge underlying the prevalence of ASD in Spain. The results of this report volition exist of involvement to multiple audiences including patients, their families, caregivers, healthcare professional person, scientists and policy makers. Results will exist published in a peer-reviewed journal. Implications for futurity epidemiological research volition be discussed.

Systematic review registration

PROSPERO CRD42018090372

Peer Review reports

Background

Autism spectrum disorder (ASD) is a circuitous developmental disorder characterised by early-onset deficits in social communication and reciprocal interactions every bit well every bit the presence of restricted, stereotypical behaviour [1,two,three,4]. ASD presents a set of behavioural issues that may produce functional harm in social, schoolhouse, or work operation and in the everyday activities of patients and their families [1, 2, v, 6]. Pathogenesis of the disorder is not completely understood, only there may be many different causes that make a kid more than likely to have an ASD, including genetic predisposition, ecology and psychosocial factors [1,2,iii,4].

The prevalence of ASD is now considered to be around 1% in many countries and regions worldwide [vii,eight,9,10,11], although estimates of 2% accept been suggested in some published reports [7, 12]. Similar prevalence estimates accept been reported in adults [thirteen, 14]. ASD seems to bear upon more male than female individuals [xv], and comorbidity is common (e.g. more than 50% may present concurrent physical or mental conditions) [one, 16,17,18,19,twenty,21]. Most recent global burden of illness estimates revealed 62.ii million people with ASD around the world in 2016 [6].

Systematic reviews of epidemiological data (whether at a national, regional or global levels) are important in the description of the geographical distribution of wellness bug [22, 23]. Systematic reviews of epidemiological data can also place gaps in noesis and inform future wellness intendance planning and research agendas [24]. Specifically, they can be useful to get more precise estimates of disease frequency, monitor trends and changes in disease brunt over time, and contribute to the design of further studies (e.g. etiological and interventional studies). Previous systematic reviews and meta-analyses have traditionally assessed the prevalence of ASD on global or regional contexts [vii, 8, 25,26,27,28], with very few examples of descriptive epidemiology meta-analyses conducted at the country level (due east.g. India, China, Hong Kong and Taiwan) [29,30,31].

In contempo years, several observational studies take been conducted in dissimilar geographical locations and population groups [vii]. According to recent epidemiological studies, in Kingdom of spain, the prevalence of ASD would be 0.61% in children aged 18 months to iii years in the Canary Islands [32], 0.85% in children aged 0–14 years in Galicia [33], 0.92% in children aged 18 months to 3 years in Castile-León [34], and ii% in samples of children aged 3–6 years in Catalonia [35]. To the best of our cognition, no previous systematic reviews and meta-analyses have evaluated ASD prevalence data in Espana. Therefore, it would be relevant to identify, select, and critically assess the relevant epidemiological literature on ASD and to collect and analyse data from studies through integrated and iterative approaches.

The objective of this study volition be to systematically evaluate published and unpublished observational epidemiological studies that present prevalence and comorbidity of ASD among children, boyish and adult population in a Southwestern European country: Spain.

Methods

Protocol

This written report protocol is office of an ongoing evidence synthesis project on the descriptive epidemiology and surveillance of neurodevelopmental disorders [36]. The present protocol has been registered within the PROSPERO database (registration number CRD42018090372) and is beingness reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement [37, 38] (see checklist in Additional file i).

Information source and literature search

The primary source of literature will exist a structured search of 7 major electronic databases (from January 1980 onwards—considering the Diagnostic and Statistical Manual of Mental Disorders, Tertiary Edition [DSM-III] was published in 1980): PubMed/MEDLINE, EMBASE, Scopus, Spider web of Science, PsycINFO, and also national databases including IME—Índice Médico Español [Spanish Medical Alphabetize] and IBECS–Índice Bibliográfico Español en Ciencias de la Salud [Spanish Bibliographic Index of Health Sciences]). The secondary source of potentially relevant material will exist a search of the grey or difficult to locate literature, including two dissertation databases (TESEO—Base de datos de Tesis Doctorales [Spanish Information Base of Doctoral Thesis Dissertations] and ProQuest Dissertations and Theses Database), Google Scholar and conference abstracts from selected national or local symposia on mental wellness, neurology and paediatrics. Nosotros volition perform hand-searching of the reference lists of included studies, relevant reviews, national clinical do guidelines or other relevant documents. Content experts and authors who are prolific in the field will be contacted. The literature searches will exist designed and conducted by the review team which includes two experienced health information specialists. Our main literature search will be peer-reviewed by a senior health information specialist using the Peer Review of Electronic Search Strategies (PRESS) checklist [39]. The search will include a wide range of terms and keywords related to autism, epidemiological studies and the geographical expanse 'Spain'. For the department of geographic area, the search will exist based on a previously validated filter to minimise potential bias regarding the indexing of geographical items [twoscore]. This filter is synthetic effectually 3 complementary approaches: (1) the term 'Kingdom of spain' and its variants in various languages, (2) terms related mainly to region and province place names, and (3) acronyms for regional wellness services. A draft search strategy for PubMed/MEDLINE is provided in Additional file 2.

Eligibility criteria

Studies will exist selected according to the following criteria: participants, condition or outcome(due south) of interest, study design and context.

  • Participants (population): We will include studies involving children, adolescents and adult population (regardless of age or sex).

  • Condition or outcome(s) of interest: The primary issue will exist the prevalence of ASD indicating the number of people that have the disorder divided by the population number at a given betoken in fourth dimension. This is oft presented as a (prevalence) proportion. In this written report protocol, we use the term 'autism spectrum disorder' to refer to both autistic disorder (east.g. the 'classic' definition of autism) and 'other autism spectrum disorder combined' (e.g. Asperger's disorder; pervasive developmental disorders non otherwise specified, including singular autism; Rett'southward disorder; and babyhood disintegrative disorder) equally recommended elsewhere [7]. We will use author-reported definitions (according to accepted diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Nomenclature of Diseases (ICD) criteria: ICD-9: 299.00, 299.10, 299.80; ICD-ten: F84). Secondary outcomes volition be the prevalence of any comorbidity, indicating the being of whatsoever distinct additional (physical or mental) condition in association with ASD (e.g. according to main DSM-Iv or ICD-10 categories of diagnoses).

  • Study pattern and context: Eligible studies will be observational studies (cohort, cantankerous-sectional or health surveys) reporting prevalence data using validated or not-validated tools and conducted in a wide range of people in the Castilian general population, outpatient (including data from authoritative databases and registries) and/or school settings. Cross-sectional studies will be the nearly appropriate study blueprint to determine the prevalence of ASD. Cross-sectional health surveys are typically used to estimate the bespeak prevalence of common conditions of long elapsing and are generally less oft used for rare diseases such as ASD. For cohort studies, merely the first phase (cross-sectional) data will be considered. We will exclude studies in hospital/inpatient clinical settings because they are likely to be highly selected resulting in inaccurate estimations of the 'true prevalence' of the disorder (choice bias).

No limitations will be imposed on publication condition (unpublished studies will exist eligible for inclusion), study deport menses, and language of publication.

Screening and selection procedure

All articles identified from the literature search will be screened by two team members independently. Showtime, titles and abstracts of articles returned from initial searches will be screened based on the eligibility criteria outlined above. Second, full texts will be examined in detail and screened for eligibility. Third, references of all considered articles will be mitt-searched to identify any relevant study missed in the search strategy. Any disagreements will be resolved by word to come across a consensus, if necessary. A flow chart showing details of studies included and excluded at each stage of the study selection process volition be provided [41].

Data collection

A data extraction form will be designed and used to extract equivalent information from each study written report. Data of interest will include the following:

  • Report characteristics: report design, year of publication, journal, year (or period) of written report conduct, sample size, setting (community, school or outpatient), geographical location of written report conduct: N (Galicia, Asturias, Cantabria, Aragon, Basque Country, Navarre, La Rioja), Mediterranean (Balearics, Catalonia, Valencia), Centre (Castile-La Mancha, Castile-León, Madrid, Extremadura), and South-East (Andalusia, Murcia and Canary Islands); and other fields to capture data relevant to the assessment of written report methodological quality (encounter risk of bias and methodological quality assessment subsection).

  • Participant characteristics: population sampled, age (e.g. mean with standard deviation, range) and gender (e.g. percentage of female person participants).

  • Outcome results: definitions and assessment tools (e.m. DSM-3, DSM-IV, ICD-nine, ICD-10, other), information drove method (e.g. cocky-complete, questionnaire, interview and examination, clinical records), prevalence estimates (due east.g. number of subjects with the disorder, proportion and 95% confidence interval) and any prevalence estimates stratified past age, gender, severity or location. If issue results (due east.g. proportion and 95% confidence interval) are non directly provided and it is feasible, we will summate them from the number of cases and sample size provided in each single study.

Data extraction forms will exist piloted initially on a small-scale number of included studies. After, each of the included studies will be bathetic by two team members, independently, and potential conflicts will be resolved through give-and-take. Authors of master publications will exist contacted for information clarifications or missing event data, as necessary.

Adventure of bias and methodological quality assessment

The risk of bias of primary observational studies will be evaluated using a methodological quality critical appraisal checklist proposed in the Joanna Briggs Institute (JBI) systematic review methods manual [42, 43]. This methodological quality checklist for observational studies reporting prevalence data considers: sample representativeness, recruitment appropriateness, sample size, description of subjects and setting, coverage of data assay, ascertainment and measurement of the condition, thoroughness of reporting statistical analysis, and identification and accountability of potential misreckoning factors/subgroups (see Boosted file 3). We will provide a narrative summary of the risk of bias of the included studies, which will be supported by a table showing the results of the critical appraisement. Stars or points will be awarded for each quality item, and the highest quality studies will be awarded up to ten stars. Studies volition be judged to be at low risk of bias (≥ 7 points), moderate risk of bias (4–6 points) or high risk of bias (< 4 points). The risk of bias for each observational study volition be independently assessed by two reviewers. Discrepant scores will be resolved by word and consensus.

Methods for evidence synthesis

The information from each paper (e.g. report characteristics, context, participants, outcomes and findings) will exist used to build testify tables of an overall description of included studies. Rough prevalence estimates (number of cases/sample size) will exist presented along with 95% confidence intervals.

If feasible and appropriate, prevalence data points from chief observational studies will be used to perform random effects meta-analyses. Since heterogeneity is expected a priori, we will estimate the pooled prevalence and its 95% confidence interval using the random effects model with logit transformation and dorsum transformation as recommended elsewhere [8, 22]. The random effects model assumes the report prevalence estimates follow a normal distribution, considering both within-study and between-study variation. Forest plots will be used to visualise the extent of heterogeneity among studies. Prevalence estimates will be expressed as cases per x,000 people [eight, 31].

Nosotros will quantify statistical heterogeneity by estimating the variance between studies using I two statistic [44]. The I 2 is the proportion of variation in prevalence estimates that is due to genuine variation in prevalence rather than sampling (random) mistake. I ii ranges between 0% and 100% (with values of 0–25% and 75–100% taken to indicate depression and considerable heterogeneity, respectively). Nosotros will also report Tauii [45] and Cochran Q test [46] with a P value of < 0.05 considered statistically pregnant (heterogeneity).

Additional analyses

If sufficient studies are identified and data points are bachelor, potential sources of heterogeneity will be investigated further by subgroup or meta-regression analyses co-ordinate to baseline characteristics and methodological covariates. We plan to acquit analyses by gender (male vs female), age (e.1000. children vs adolescent vs adult, mid-point of age range as continuous variable), severity (e.g. mild, moderate or astringent), geographical location (east.g. North, Mediterranean, Centre and South-East), setting (e.g. customs/school vs outpatient), sample size (eastward.one thousand. < k, 1000–5000 or > 5000 participants), decade of publication (e.g. 1990, 2000 or 2010), study quality (e.g. low/moderate vs high-run a risk of bias), autism definition (eastward.g. autistic disorder vs other autism disorders combined), diagnostic arrangement (due east.yard. DSM vs ICD criteria) and most recent diagnostic criteria (e.g. 'DSM-4 or ICD-10' vs 'Not DSM-IV or ICD-10'). In add-on, we will explore prevalence trends with gender variations (in terms of the female person-to-male person prevalence ratios) [fifteen] and over time (with the yr of publication as the explanatory variable) [1] using random effects meta-regression models [47]. Small-scale study furnishings will be assessed by inspection of the funnel plots for asymmetry and with Egger's test [48] and Begg's test [49], with the results considered to indicate potential small study furnishings when P values < 0.10.

Software considerations

All analyses will be conducted in Stata version 15 (StataCorp LP, Higher Station, Texas, USA) [fifty, 51].

Ethics, broadcasting and research integrity

No ethical approval is required for the performance of this written report. The proposed systematic review and meta-assay volition be reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [41] and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) reporting guideline [52]. Whatever amendments made to this protocol when conducting the report will be outlined and reported in the final manuscript. Results will be disseminated through briefing presentations and publication in a peer-reviewed journal. All information underlying the findings reported in the final manuscript will exist deposited in a cross-disciplinary public repository—for case, the Open Science Framework (https://osf.io/) or Zenodo (https://zenodo.org/).

Patient and public involvement

I of the study protocol co-authors (AT) is the parent of a child with ASD and a member of a patient grouping (APRENEM Association for the Inclusion of People with ASD, Barcelona, Spain). We will evaluate whether the epidemiological studies included in the systematic review had any patient and/or public involvement [53, 54].

Discussion

The systematic review and meta-assay of observational data presented in this protocol volition identify, collect, evaluate and integrate the epidemiological noesis underlying the prevalence of ASD in Spain. Nosotros are not aware of another systematic review and meta-analysis addressing this specific upshot. In our opinion, this systematic review will help to establish the extent of the epidemiological show on ASD at a land level, in a reproducible and rigorous way.

The results of this written report will exist of interest to multiple audiences (including patients, their families, caregivers, healthcare professionals, researchers, scientists and decision makers). For example, the National Plan for Autism was issued in 2015 to develop specific measures to improve quality of life, promote awareness and identify and respond to the needs of those living with ASD [55]. The National Program considered several strategic lines in terms of diagnosis, integrated care, health intendance, didactics, employment and research, among others. However, routine population estimates of ASD prevalence (based on the most updated systematic literature reviews) are not reported [55, 56]. Outputs of this analysis could exist relevant to current policy questions.

There are several strengths and limitations of our planned systematic review methods. Nosotros will comprehensively evaluate epidemiological data (both published and unpublished) characterising the prevalence and comorbidity of ASD, exploring the extent of heterogeneity and potential biases in observational studies. Nosotros anticipate that nosotros volition identify cognition gaps to be filled by new epidemiological research because that the prevalence of neurodevelopmental disorders has been poorly covered in the literature [vii, 57]. On this regard, implications for future epidemiological enquiry will be discussed in the concluding manuscript. A central claiming is that based on knowledge from previous reviews on child mental wellness [7, 8, 25, 31, 57,58,59], we anticipate identifying studies using different study designs, populations, contexts and with a variable quality of reporting methods and results.

Finally, the availability of land-specific prevalence estimates of ASD over time will provide opportunities to undertake systematic assessments of the burden of disease and to promote evidence-based policy activeness [half-dozen, 60,61,62].

Abbreviations

ASD:

Autism spectrum disorder

DSM:

Diagnostic and Statistical Transmission of Mental Disorders

ICD:

International Classification of Diseases

MOOSE:

Meta-analysis Of Observational Studies in Epidemiology

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PRISMA-P:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Protocols

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Acknowledgements

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Upstanding blessing and consent to participate

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Funding

FC-L and RT-S are funded by the CIBERSAM/Institute of Health Carlos III. MR and IH are partially funded by the Spanish Health Services Enquiry on Chronic Patients Network (REDISSEC)/Plant of Health Carlos III. The funders were not involved in the design of the protocol or decision to submit the protocol for publication, nor volition they exist involved in whatever aspect of the behave of the study.

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Affiliations

  1. Department of Health Planning and Economics, National School of Public Health, Institute of Health Carlos III, Madrid, Kingdom of spain

    Ferrán Catalá-López

  2. Section of Medicine, University of Valencia/INCLIVA Health Enquiry Institute and CIBERSAM, Valencia, Espana

    Ferrán Catalá-López & Rafael Tabarés-Seisdedos

  3. Instituto Aragonés de Ciencias de la Salud (IACS), Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Zaragoza, Spain

    Manuel Ridao

  4. Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO-Salud Pública), Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Valencia, Spain

    Isabel Hurtado

  5. Independent Clinical Psychologist and Researcher, Madrid, Spain

    Amparo Núñez-Beltrán

  6. Directorate General for Public Health, Madrid Regional Health Council, Madrid, Spain

    Ricard Gènova-Maleras

  7. Department of History of Science and Documentation, University of Valencia, Valencia, Kingdom of spain

    Adolfo Alonso-Approach

  8. Information and Social and Health Research Unit (UISYS), University of Valencia and Spanish National Research Quango (CSIC), Valencia, Spain

    Adolfo Alonso-Approach & Rafael Aleixandre-Benavent

  9. Castilian National Inquiry Council (CSIC), Barcelona, Kingdom of spain

    Aurelio Tobías

  10. Institute for Innovation and Knowledge Direction (INGENIO)/Spanish National Research Council (CSIC) and Polytechnic University of Valencia (UPV), Valencia, Spain

    Rafael Aleixandre-Benavent

  11. Faculty of Medicine, Academy of Valencia, Valencia, Espana

    Miguel A. Catalá

Contributions

The study protocol was conceived past FC-L, with critical input from MR, IH, AN-B, RG-M, AA-A, AT, RA-B, MAC and RT-S. FC-L registered the protocol with the PROSPERO database and wrote the kickoff typhoon of the protocol. MR, MAC and RT-Southward provided input into the design and edited the typhoon protocol. All authors commented on the newspaper for of import intellectual content. FC-L accepts full responsibility for the finished paper and controlled the determination to publish. FC-L is the guarantor. All authors read and approved the concluding newspaper.

Authors' information

FC-50 is a PhD (Public Health) and MPH. MR is a PhD (Medicine) and MSc (Economics). IH is a PhD (Public Health) and BSc Hons (Psychology). AN-B is PsyD (Clinical Psychology) and MSc (Neurosciences). RG-Thou is a MSc (Census). AA-A is a PhD (Data and Documentation) and MA. AT is a PhD (Public Health) and MSc (Statistics). RA-B is a Doctor and PhD (Medical Documentation). MAC is a MD (Child Psychiatry) and PhD (Medical Documentation). RT-Due south is a Doctor (Psychiatry) and PhD.

Corresponding author

Correspondence to Ferrán Catalá-López.

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Catalá-López, F., Ridao, M., Hurtado, I. et al. Prevalence and comorbidity of autism spectrum disorder in Espana: study protocol for a systematic review and meta-analysis of observational studies. Syst Rev viii, 141 (2019). https://doi.org/10.1186/s13643-019-1061-1

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  • DOI : https://doi.org/x.1186/s13643-019-1061-one

Keywords

  • Autism spectrum disorder
  • Comorbidity
  • Epidemiological study
  • Meta-assay
  • Prevalence
  • Espana
  • Systematic review

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