Recommendation

Evaluating the quality of systematic reviews in preclinical animal studies of neurodevelopmental conditions

based on reviews by Marietta Papadatou-Pastou and Richel Bilderbeek
A recommendation of:
toto

Genetically-modified animals as models of neurodevelopmental conditions: an umbrella review

Abstract
Submission: posted 29 August 2022
Recommendation: posted 23 January 2023, validated 23 January 2023

Recommendation

Single gene alterations have been estimated to account for nearly half of neurodevelopmental conditions (NDCs), providing a crucial opportunity for animal models to understand the underlying mechanisms, causes and potential treatments. The use of systematic reviews (SRs) can, in principle, provide a powerful means to synthesise this evidence-base; however, the reporting quality of previous SRs in preclinical animal research has been found lacking (Hunniford et al., 2021). In the current study, Wilson et al. (2023) will undertake an umbrella review – a systematic review of systematic reviews – to assess the characteristics and reporting quality of SRs that, in turn, synthesise research in genetically-modified animals to model NDCs. In particular, the authors will extract key features of reviews (including, among others, the aim and primary research questions, relevant animal model, and number of studies in the SR), in addition to quality indicators such as risk of bias and completeness of reporting. In doing so, the authors aim to enhance guidance on the conduct and reporting of systematic reviews in this area.
 
The Stage 1 manuscript was evaluated over two rounds of in-depth review. Based on detailed responses to the reviewers' comments, the recommender judged that the manuscript met the Stage 1 criteria and therefore awarded in-principle acceptance (IPA).
 
URL to the preregistered Stage 1 protocol: https://osf.io/952qk
 
Level of bias control achieved: Level 4. At least some of the data/evidence that will be used to answer the research question already exists AND is accessible in principle to the authors BUT the authors certify that they have not yet accessed any part of that data/evidence.
 
List of eligible PCI RR-friendly journals:
 
References
 
1. Hunniford V. T., Montroy J., Fergusson D. A., Avey M. T., Wever K. E., McCann S. K., Foster M., Fox G., Lafreniere M., Ghaly M., Mannell S., Godwinska K., Gentles A., Selim S., MacNeil J., Sikora L., Sena E. S., Page M. J., Macleod M., Moher D., & Lalu M. M. (2021). Epidemiology and reporting characteristics of preclinical systematic reviews. PLOS Biology, 19:e3001177. https://doi.org/10.1371/journal.pbio.3001177
 
2. Wilson, E., Currie, G., Macleod, M., Kind, P. & Sena, E. S. (2023). Genetically-modified animals as models of neurodevelopmental conditions: an umbrella review, in principle acceptance of Version 3 by Peer Community in Registered Reports. https://osf.io/952qk
Cite this recommendation as:
Chris Chambers (2023) Evaluating the quality of systematic reviews in preclinical animal studies of neurodevelopmental conditions. Peer Community in Registered Reports, . https://rr.peercommunityin.org/articles/rec?id=308
Conflict of interest:
The recommender in charge of the evaluation of the article and the reviewers declared that they have no conflict of interest (as defined in the code of conduct of PCI) with the authors or with the content of the article.

Evaluation round #2

DOI or URL of the report: https://osf.io/7c5wu/

Version of the report: v2

Author's Reply, 12 Jan 2023

Decision by , posted 16 Dec 2022, validated 16 Dec 2022

The two original reviewers have now re-evaluated your manuscript. As you will see, there are some remaining points to address in the review by Papadatou-Pastou, but they are all relatively minor compared to the previous round. I expect these should be straightforward to resolve, and provided you are able to do so thoroughly in the next revision then I should be able to issue Stage IPA without further in-depth review.

I look forward to receiving your revised manuscript. Please note that due to our December shutdown, you won't be able to submit your revised manuscript until PCI RR reopens on January 3rd. I will action your manuscript as quickly as possible at that time.

Reviewed by , 09 Dec 2022

Dear authors,

I think you've done a good job with addressing the comments by me and the other reviewer. I already accepted and still do.

Thanks for your work and cheers, Richel Bilderbeek

Reviewed by , 13 Dec 2022

I thank the authors for responding to my comments with such great care. I see that most of my suggestions were implemented and I am particularly happy that the PRISMA guidelines are now adhered to and PRISMA checklists are provided in the osf.io project. (Indeed, the PRISMA list for protocols that the authors used fits the purpose better than the PRISMA 2020 checklist that I had originally suggested.)

Some remaining concerns or suggestion are as follows:


1. Risk of bias: The authors state that they will not conduct a risk of bias analysis, but they actually are - risk of bias is another term used for quality assessment (which is one of the three aims of the review). So, risk of bias (with a note maybe that it is performed under the term "quality assessment"?) could be added to the checklist and the abstract. 


2. One of my main suggestions (I also included it in the first round of reviews), is that an explanation of why NDC were chosen as the  conditions that will be the focus of this review, should be given. Moreover, why are you interested in those specific 102 genes (or Rett or Fragile X)? What is their clinical importance, for example? Moreover, why did you focus on genetically modified animals and not other animal models? These choices are fine, but they need to be justified in the introduction. In their response to my comment in the previous round of reviews the authors comment that they now mention the "litter effect" in terms of NDC research, but this does not justify why they want to focus on NDC in the first place.  


3.  In the PRISMA 2015 protocol checklist it is stated by the authors that the CRediT taxonomy was used, but it was not (e.g. "critical insights, preliminary searches", etc. are not part of the CRediT taxonomy; https://credit.niso.org). I do not object with the way credit is given now, but if the authors want to state that they used the CRediT taxonomy, they should make appropriate changes to their "Contributors" section. 

 

4. Item 5c in the PRISMA 2015 protocol checklist states: "Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol" - I believe the answer here is "none" (as the funders should have had no role in developing the protocol" and not "PhD studentship". 

 

5. Correct me if I am wrong, but I do not think preprints are included in PubMed, Embase, or Web of Science (and I think this also applies to conference abstracts). If this is the case, then where will preprints and conference abstracts be sought from?


6. Abstract: "...however, methods differ depending on the type of research being reviewed". Is this sentence necessary? I mean, will "type of research" be a variable of interest in your review?

 

7. Abstract: "We will annotate various characteristics from included systematic reviews and assess the reporting quality of each included review will be assessed using an adapted version of the PRISMA checklist (PRISMA-Pre). We will not conduct a risk of bias assessment." This sentence has a grammatical issue.


8. Abstract: "We will not conduct a meta-analysis. " I don't think this sentence is necessary (and eats away your precious word count!)


9. Minor comment: Please add a comma "," before "and" only if three or more items are listed (if you decide to use this "Oxford comma" please do it consistently). 


10. Introduction (first sentence): "De novo genetic alterations have been implicated in several neurodevelopmental conditions (NDCs), characterised by intellectual disability (ID), epilepsy, and autism spectrum condition (ASC). " Is this sentence needed? I mean, you do not focus on "de novo alterations" (in fact they are not mentioned again in the manuscript), so there is no reason to start the manuscript with this information. Do you mean genetics in general maybe?


11. Introduction (paragraph two): All these variables (that introduce error) are not an object of this review. Then why mention them in the introduction (esp. so early on)? You will not investigate bias on a study level, but on a systematic review level (and in fact only one of the many items of the PRISMA-Pre checklist, is "Report the risk of bias of the primary studies (individual studies/across outcomes)" - so, this cannot be so central in the introduction. Maybe if the introduction is restructured to first say how clinicians use systematic reviews, what systematic reviews are, how they can help identify bias and then (briefly) which are the forms of bias? In any case, the focus of this review is the quality of the systematic reviews, not the quality of the primary studies included in said reviews. I trust that the introduction might be improved if the senior authors used some of their expertise to build the rationale.


12. Introduction (paragraph two): Please explain what the "litter effect" is. 

 

13. Inclusion and exclusion criteria: "We will include systematic reviews or meta-analyses that include animal studies, either as a review limited to animal studies or ones which include them alongside other study types (e.g. clinical studies). We will exclude publications which are not systematic reviews or meta-analyses, as well as systematic reviews or meta-analyses which do not include animal studies." These two sentences say the same thing -why not say "We will only include..." and remove the second sentence? (Similarly for the second criterion, it feels like the second sentence repeats info already presented in the first sentence.)


14. Minor comment: Quite a number of typos are to be found in this version of the manuscript (e.g., abstract, "Search Strategy", second like "models" should be "model"). 


15. The following bullet points are not needed (as they are subheading that appear straight after anyways):


·       Bibliographic data

·       Characteristics

·       Reporting quality

 


Again, I thank the authors for responding to my concerns during the first round of reviews. I am looking forward to their responses for this round and to seeing the review conducted (in the future!)


Evaluation round #1

DOI or URL of the report: https://osf.io/7c5wu/

Author's Reply, 30 Nov 2022

Decision by , posted 21 Nov 2022, validated 21 Nov 2022

At the outset I would like to apologise for the delay in relaying this editorial decision. The original recommender who was handling your submission obtained two reviews quite quickly in September, and was then waiting on a third review which is now very late (and has been cancelled). At the same time, the recommender for your submission unfortunately became unavailable. As a result, I have taken over the handling of your submission and we have put in place  measures at PCI RR to prevent such delays occuring in the future.

As you will see, the reviews are critical but constructive and I believe this submission is a promising candidate for Stage 1 in-principle acceptance. Review 1 (provided by Papadatou-Pastou) is primarily concerned with the clarity of the aims and rationale, and while highly critical in places, the evaluation also provides numerous helpful recommendations for revision. Review 2 (provided by Bilderbeek) is more positive, noting mostly minor points to address. The reviewer has also annotated the Stage 1 manuscript. If you search for the text "richelbilderbeek" in the quoted article text below you will find each specific point.

Based on these reviews, I am happy to invite a comprehensive revision and response that addresses all points.

Reviewed by , 14 Sep 2022

Thank you for inviting me to review this registration. I have indeed reviewed the manuscript of the Stage 1 Registered Report entitled "Umbrella review of ASD animal  models: A  Stage 1  Registered  Report". First of all, let me congratulate the authors for not just pre-registering their review, but actually choosing to follow the Registered Reports path.


This review is interesting and should be a very valuable addition to the literature, once published. At the moment, though, I am afraid that the Stage 1 manuscript suffers from a number of serious flaws and needs to be rejected. The most important area for improvement is making clear what the rationale behind this review is and what it is trying to achieve.


Below you can find my comments and suggestions:


Abstract:


1. Mentioning intellectual disabilities (ID) is not needed, as this study focuses on ASD. I was actually confused while reading the abstract as to whether ID is part of the focus of this review or not. In a bit more detail, in the first sentence as well as in the phrase "summary of ASD/ID research", ID is mentioned, but in the search strategy section only ASD is mentioned. Moreover, only ASD is mentioned in the title. This is confusing to the reader as mentioned above - just by reading the title and abstract it should be clear whether ID is included in this review or not. 


2. The acronyms ASD and ID are not explained in the abstract.


3. Second line: Please replace "autism spectrum disorders" with "autism spectrum disorder" (singular). Please also replace "intellectual disabilities" with "intellectual disability". This is how they are mentioned in DSM-5.


4. "Living evidence summary" is a term reserved for the cases when the summary is regularly updated. In this case, the  review will be just published once, with no updates after it. So, this term is not appropriate. (Please correct me if I have misunderstood something here.)


5. I would suggest rewriting the abstract to take into account the PRISMA  2020 extension for Abstracts. A checklist is to be found here: https://prisma-statement.org/documents/PRISMA_2020_abstract_checklist.pdf. At the moment, a number of elements are missing from the abstract, for example inclusion and exclusion criteria as well as whether a risk of bias analysis will be conducted. I understand that there is a word limit for the abstract, but maybe the authors can fit in some of this info. They are also advised to submit the PRISMA 2020 extension for Abstracts checklist as part of the supplementary material.


Main text


Major points


1. The rationale behind this review is not clear. In the introduction there is some discussion about how systematic reviews identify areas of poor methodological quality or high risk of bias within a research literature. Is this the drive behind this review of systematic reviews? It is not clear to me how this will be achieved. Will the collected systematic reviews be then summarized with regards to the risk of bias they have identified? If so, shouldn't reporting risk of bias be one of the inclusion criteria? Or will the authors assess whether the reviews themselves have run such an analysis? It is mentioned that the authors will identify which tools will be used to measure risk of bias in the included studies, but not how their review will contribute towards identifying the risk of bias in the literature.


2. Another area that is not clear is whether literature on ID is going to be reviewed (at some point it becomes clear that the answer is no, but in the beginning of the introduction the reader is made to think that it is, as ID is mentioned in the very first sentence and then a definition of ID is given in the second sentence).


3. It should also be made clear (starting from the title) if this review concerns only genetically-modified animals or all animal models. Four types of animal models are used in preclinical research: (1) disease induction models, (2) xenograft animal models, (3) inbred strains, and (4) transgenic models, so it would be good to clarify if the focus of this review is only on the latter. 


4. An explanation (even short) of why ASD was chosen as the disease model that will be the focus of this review, should be given. 


5. The aims of this review are presented three times in the manuscript (abstract, introduction and methods), each time with a slightly different wording (minor point: the aims do not need to be repeated in the methods section). The slight change of wording is not problematic, but when the essence changes this confuses the reader. For the second aim we read "summarize the focus of these reviews" (abstract)/ "the aims of these reviews" (introduction) / "the aim of each review and what research questions does it seek to ask" (methods). These are slightly different aims. Especially with regards to "summarize the focus of these reviews" I am not sure if the authors refer to the fact that they also plan to present "a descriptive summary of data extracted from each included systematic review", as they mention in the methods section. In other words, it is no clear to me if the main aim of this review of reviews is to map systematic reviews already conducted, if it is to identify methodological issues in primary research (as mentioned in my first comment, e.g. risk of bias in the literature), or if it (further) aims to summarize the findings in the literature, by means of presenting (or even synthesizing) the findings of the included systematic reviews. 


6. On a related note, in addition to the three aims, in the methods section, a few other aims are identified: "(i) Whether the review only included animal studies, or also included clinical or in vitro studies, (ii) Which animal models the review included, (iii)The total number of studies included in the systematic review, (iv) The total number of studies investigating relevant animal models". These are listed under "systematic review aims and research question', which is not a suitable place. These are rather characteristics of the studies. Maybe the characteristics of the systematic reviews is another aim? This goes again to the fact that the objectives of this review are not clear.


7. The authors label their review an "umbrella review" (although in the methods they also refer to it as a "systematic review of systematic reviews".) However, the aim of an umbrella review is to determine what is known on a topic, what remains unknown, and to make recommendations for what requires further research. This is very different to giving a descriptive summary of data from each included systematic review -an umbrella review is about synthesizing these findings (and reaching overarching conclusions), not presenting summaries side by side. So, if the authors only want to focus on methodological issues (e.g., identify risk of bias) or to just present the number and different characteristics of published systematic reviews, this sounds more like a "scoping review of systematic reviews". Scoping reviews aim to map a research area and not to synthesize findings. However, if the authors opt for an umbrella review, then the relevant literature should be summarized in the intro.


Methods: 


1. The same criterion (animal models) is given both as an inclusion and as an exclusion criterion (with a slightly different wording, but it is the same criterion). Just mentioning it once suffices. The title of this section could even be modified to "inclusion and exclusion criteria", if the authors prefer it that way. 

2. On the same note, it is not clear to me what "Other criteria - conference abstracts and preprints" means as  an inclusion criterion. Do papers need to be conference abstracts and preprints to be included?


3 . Exclusion criteria: "Publications where we cannot access the full-text". It is the first time I come across this criterion. Genetically-modified animals are rather new (I mean a few decades) so I cannot see how one will fail to access the full text, either through their library, an inter-librayr loan or even by purchasing the full text directly. 

4. Inclusion criteria: The species of the animals should mentioned (if systematic reviews on all species will be reviewed, this should be mentioned too)

5. Exclusion criteria: "systematic reviews which do not search at least two bibliographic databases". Why is that an exclusion criterion? If one of the aims is to "identify the number of systematic reviews previously conducted", then shouldn't all systematic reviews be included? And then, one can perform a quality assessment of the included systematic reviews.


6. It was interesting to see that the authors plan to "screen studies based on full text to avoid erroneously excluding systematic reviews which do not report their inclusion criteria in their abstract" .This is fine, but -from my experience in systematic reviews and meta-analysis- a search could give back hundreds if not thousands of papers. So, the time resources needed to read each full text will not be realistic. I would suggest that the authors use a hierarchical process, by first screening titles (some papers will obviously be on a different field/irrelevant), then abstracts (or titles and abstracts together), and then the full text. Each time, one only excludes the papers they are sure do not meet the criteria and then takes the rest of the papers to the next step to see if the relevant information is there. I understand that some of the criteria might not be identifiable in the abstracts, but this is always the case in meta-analyses. This is why we never stop at the abstracts during screening. 


7. The authors should include a PRISMA 2020 checklist for their own review (on what they plan to do) and include it as supplementary material. By doing so, they can also identify a number of elements currently missing from their registration, e.g. whether they plan on conducting a risk-of-bias analysis (I understand there is discussion on biases in the manuscript, but in the methods it is not clear if this will be conducted and how). Some other elements are missing too -please check the PRISMA 2020 checklist. 


Minor
1. The phrase "will place no restriction on publication date or language" appears twice in the methods.

2. The definition given in the first sentence of the introduction applies to ASD only, but the way this sentence is written reads like it refers to all neurodevelopmental disorders (including ID, when a different definition for ID is given in the second sentence).


3. The introduction needs to be rewritten with a focus on less repetition, better flow and better justification for the need for this review. For example, paragraphs 2 & 3 & 4 could be merged. Paragraph 3 says more or less the same thing as the beginning of paragraph 4.


4. It is mentioned that the analysis code will be available online. Which analysis are the authors referring to? Reviews do not include analysis.


I understand that there are a lot of suggestions made above, but let me also say that it was great to see a detailed list of all the search terms to be used as well as a mention of the software to be used. Again, following the Registered Report route is highly commendable and I do hope a version of this work finds its way to the published literature in the future. Systematic reviews and meta-analysis are getting more and more technical, therefore there is learning curve, but I am sure the authors will get there very soon! 

Reviewed by , 09 Sep 2022

# Review

Verdict: Accepted.

I have read this pre-registration with much pleasure,
without encountering unexpected surprises: the suggested
research seems useful and the methods straightforward.

I did find some minor suggestions and worries, yet nothing to slow down this study.
Below I list these, formatted as [richelbilderbeek: my comment]. 
A better-formatted version can be found at https://github.com/richelbilderbeek/wilson_et_al_pci_rr_review .

I wish the authors good luck in doing this study!

Cheers, Richel Bilderbeek

## Criteria

> 1A. The scientific validity of the research question(s). This criterion addresses the extent to which the research question is scientifically justifiable. Valid scientific questions usually stem from theory or mathematics, an intended or possible application, or an existing evidence base, and should be defined with sufficient precision as to be answerable through quantitative or qualitative research. They should also fall within established ethical norms. Note that subjective judgments about the importance, novelty or timeliness of a research question are NOT a relevant criterion at PCI RR and do not form part of this assessment.

I am convinved that this is a valid research question.

> 1B. The logic, rationale, and plausibility of the proposed hypotheses, as applicable. This criterion addresses the coherence and credibility of any a priori hypotheses. The inclusion of hypotheses is not required– a Stage 1 RR can instead propose estimation or measurement of phenomena without expecting a specific observation or relationship between variables. However, where hypotheses are stated, they should be stated as precisely as possible and follow directly from the research question or theory. A Stage 1 RR should also propose a hypothesis that is sufficiently conceivable as to be worthy of investigation. The complete evaluation of any preliminary research (and data) in the Stage 1 submission (see Section 2.7) is included within this criterion.

Not applicable, this is a study that measures aspects of reviews.

> 1C. The soundness and feasibility of the methodology and analysis pipeline (including statistical power analysis or alternative sampling plans where applicable). This criterion assesses the validity of the study procedures and analyses, including the presence of critical design features (e.g. internal and external validity, blinding, randomisation, rules for data inclusion and exclusion, suitability of any included pilot data) and the appropriateness of the analysis plan. For designs involving inferential statistics and hypothesis-testing, this criterion includes the rigour of the proposed sampling plan, such as a statistical power analysis or Bayesian alternative, and, where applicable, the rationale for defining any statistical priors or the smallest effect size of interest. For programmatic RRs (see Section 2.15), this criterion captures the assessment of whether the separate study components are sufficiently robust and substantive to justify separate Stage 2 outputs.

I am moderately convinced of the soundness and feasibility of the methods in this study.

I use 'moderately' as I wonder (1) how many reviews there are approximately and (2) how
long it approximately takes for a person to do one review. 
I assume this simple calculation has been done, yet I would appreciate to see
it in the paper.

> 1D. Whether the clarity and degree of methodological detail is sufficient to closely replicate the proposed study procedures and analysis pipeline and to prevent undisclosed flexibility in the procedures and analyses. This criterion assesses the extent to which the Stage 1 protocol contains sufficient detail to be reproducible and ensure protection against research bias, such as analytic overfitting or vague study procedures. In general, meeting this requirement will require the method section(s) of a Stage 1 protocol to be significantly longer and more detailed than in a regular manuscript, while also being clearly structured and accessible to readers. This criterion also covers the extent to which the protocol specifies precise and exhaustive links between the research question(s), hypotheses (where applicable), sampling plans (where applicable), analysis plans, and contingent interpretation given different outcomes. Authors are strongly encouraged to include a design summary table in their Stage 1 protocols that make these links clear (see Section 2.16 for examples). Note that in some circumstances, authors may wish to propose a more general analysis plan involving a blinded analyst rather than a precise specification of data analyses. Such submissions are acceptable and will meet this criterion provided the blinded analysis procedure is specified in reproducible detail, and provided the blinding procedure itself is sufficiently robust.

I am convinced that the methods are clear.

> 1E. Whether the authors have considered sufficient outcome-neutral conditions (e.g. absence of floor or ceiling effects; positive controls; other quality checks) for ensuring that the obtained results are able to test the stated hypotheses or answer the stated research question(s). This criterion addresses, where applicable, the extent to which the proposal pre-specifies data quality checks that will reveal whether the results are able to answer the research question(s). Such tests come in many forms and, depending on the design or subject area, are not always possible or appropriate. Where they are proposed they must be pre-specified and “outcome-neutral”, meaning that they are designed prior to knowledge of the results and are independent of the main study hypotheses. In experimental studies, such tests often consist of positive controls (also referred to in different fields as “manipulation checks” or tests of “intervention fidelity”). In observational studies they might include parallel measurements to replicate an established fact, thus confirming that the design or instrumentation is sufficiently sensitive to detect the existence of the phenomenon that forms the main focus of the research. This 1993 study which used the Galileo spacecraft to search for signs of life on Earth provides a signature example of a positive control.

I am convinced that the outcome is neutral.

# Umbrella review of ASD animal models: A Stage 1 Registered

[richelbilderbeek: this is the paper by Wilson et al., converted by PDF Candy to text, then
by me to proper markdown. I did not do all the formatting: especially the tables in
the appendix are left as-is]

## Report

Emma Wilson1,2, Gillian Currie1, Malcolm Macleod1, Peter Kind2,3,4, and Emily S Sena1
(1) Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, EH16 4SB UK
(2) Simons Initiative for the Developing Brain, The University of Edinburgh, Edinburgh, EH8 9XD UK
(3) Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, EH8 9XD UK
(4) Patrick Wild Centre for Autism Research, The University of Edinburgh, Edinburgh, EH8 9XD UK


## Corresponding author

Emma Wilson, emma.wilson@ed.ac.uk


## Contributors

EW conceptualised the study and performed preliminary searches. EW and GC refined the search
strategy. EW wrote the original study protocol. Critical insights, review and editing were provided by
GC, MM, PK and ESS. MM, PK and ESS provided supervision.

 

## Funding

EW is funded by a Simons Initiative for the Developing Brain PhD studentship (SFARI #529085).

 

## Conflicts of interests

The authors declare no conflicts of interest.

 

## Ethics approval

This study will only examine data from published systematic reviews, so ethical approval is not
required.

 

## ORCID iDs

Emma Wilson, http://orcid.org/0000-0002-8100-7508
Gillian Currie, https://orcid.org/0000-0003-3052-2929
Malcolm Macleod, https://orcid.org/0000-0001-9187-9839
Peter Kind, http://orcid.org/0000-0002-4256-9639
Emily S Sena, http://orcid.org/0000-0002-3282-8502

 


## Abstract


### Objective

Research using animals to model neurodevelopmental disorders, including autism spectrum
disorders and intellectual disabilities, help us understand the underlying biology and develop
treatments and support tools. To inform the development of a living evidence summary of ASD/ID
research, we plan to conduct an umbrella review (a systematic review of systematic reviews) in this
field. This will help us (1) identify the number of systematic reviews previously conducted, (2)
summarise the focus of these reviews, and (3) assess the quality of reporting of these reviews.

 * [richelbilderbeek: note to self: living evidence summary is described in Elliott et al. 'Living Systematic Reviews: An Emerging Opportunity to Narrow the Evidence-Practice Gap', 2016]

### Search strategy

We will search NCBI PubMed, Ovid Embase, and Web of Science to identify systematic reviews of
animal models which use manipulations of 102 genes for which there is high confidence in a causal
relationship to ASD. We will place no restriction on publication date or language.

 

### Screening and annotation

Two independent reviewers will screen studies based on full text. Included systematic reviews will
be annotated for protocol availability, scope of the review, and inclusion criteria of the review. We
will also assess the reporting of each included review using an adapted version of the PRISMA
checklist.

### Data management and reporting

We will not conduct a meta-analysis. We will present a descriptive summary of data extracted from
each included systematic review and score each included review against the adapted PRISMA
checklist.

## Keywords

Umbrella review; Evidence synthesis; Autism; Intellectual disability; Animal models

## Strengths and limitations of this study

 * To maximise the sensitivity (recall) of our search, we will use broad search terms related to
   ASD or neurodevelopment, in parallel with terms related to individual ASD-related genes,
   and screen studies based on full text to avoid erroneously excluding systematic reviews
   which do not report their inclusion criteria in their abstract.

 * We will use a draft extension of the PRISMA guidelines specifically designed for systematic
   reviews of animal studies, to assess the reporting quality of included systematic reviews.

 * This extension remains in draft, is not yet an official extension to PRISMA and may be subject
   to change.

[richelbilderbeek: I would enjoy to know what happens when this draft is changed during this research?
I assume that the draft is kept as-is during this research and it may only change when
becoming a PRISMA standard]

## Abbreviations

Abbreviation|Full
------|--------------------
ASD   | Autism Spectrum Disorder
ASySD | Automated Systematic Search Deduplicator
DOI   | Digital Object Identifier
ID    | Intellectual Disability
NCBI  | National Center for Biotechnology Information
NDD   | Neurodevelopmental Disorder
PRISMA| Preferred Reporting Items for Systematic reviews and Meta-Analyses
SyRF  | Systematic Review Facility

## Introduction

Neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and intellectual
disability (ID), are lifelong conditions characterised by difficulties with socialisation and
communication and the presence of restrictive and repetitive behaviours and interests. Intellectual
disability is characterised by significantly impaired intellect and is defined by an IQ of less than 70.

Animals can be used to model the genetic causes of NDDs and their associated cellular, circuit and
behavioural traits. Such research plays a vital role in developing our understanding of the biology
underlying NDDs (basic research) and in the testing potential drug treatments (preclinical research).

Researchers have developed numerous genetically modified animal models to study ASD. Such
models allow researchers to understand the function of ASD-related genes during brain
development and allow for the development and testing of therapeutics prior to clinical trials.

However, despite extensive research, successful translation of laboratory findings to the clinic is rare
(Pankevich et al., 2013; Silverman et al., 2022). Many factors may contribute to this lack of success
including target choice, outcome measures insensitive to change, disease stage at which treatment
is initiated, lack of construct validity and high risk of bias in the preclinical 
literature [richelbilderbeek: describe bias here, not below].

[richelbilderbeek: I would enjoy to see alpha values, p values and the number of tests done,
over multiple papers. E.g. if 1 paper find gene X out of 20 to be significant, where
many others don't, we can expect that that paper's result was due to chance]

The successful translation of laboratory findings to clinical trials is a major challenge in many areas of
biomedical research (Ioannidis, 2006), and is not limited to neurodevelopmental research. Poor
methodological quality and high risks of bias – such as lack of randomisation of animals or lack of
blinded outcome assessment – can also contribute to this translational barrier by compromising the
internal validity of a study (Krauth et al., 2013). Bias describes a systematic error within a study,
caused by a variable other than the intervention of interest, that influences the measured outcome [richelbilderbeek: describe bias above, not here].

By ensuring that a study is internally valid, we can be more confident that – apart from random error
– findings from the study reflect a true cause-and-effect relationship between the intervention of
interest and the measured outcome in that experimental setting.

Systematic review provides a well-developed method for identifying areas of poor methodological
quality or high risk of bias within a research literature. Systematic review is a research method used
to summarise and appraise all available evidence related to a pre-specified topic (Egger et al., 2001),
and can identify areas for improvements which might increase internal validity and research rigour
and reproducibility. Clinicians have used systematic reviews to inform evidence-based healthcare since the 1980s.

Findings from such reviews have led to considerable improvements in the way clinical trials are
conducted and reported (Plint et al., 2006). Over the last two decades, researchers have adopted
systematic review methods to summarise and appraise evidence from laboratory animal studies (de
Vries et al., 2014) and have achieved similar success in research improvement (McCann et al., 2016;
Ramirez et al., 2017).

However, the fundamental differences [richelbilderbeek: which fundamental differences?
I would enjoy to at least read the most important for this study. Or give a reference]
between clinical and animal studies means that systematic
review methodologies must be appropriately adapted. The development of several tools has been
instrumental in supporting researchers conducting systematic reviews and meta-analyses of animal
studies, including checklists for assessing the risk of bias (Hooijmans et al., 2014) and reporting
quality (Macleod et al., 2004) of laboratory animal studies, and a protocol template for systematic
reviews of animal intervention studies (de Vries et al., 2015). Despite this, reporting quality of animal
systematic reviews is low (Mueller et al., 2014; Hunniford et al., 2021).

This umbrella review aims to understand (1) how many systematic reviews have been conducted in
the area of ASD animal research, (2) the aims of these reviews, and (3) the reporting quality of these
reviews. As a secondary output, this research will help inform the creation of a living evidence
summary (Hair et al., 2022) [richelbilderbeek: I feel the reference to Hair et al., 2022 
is invalid. It is 'Elliott, Julian H., et al. "Living systematic reviews: an emerging opportunity to narrow the evidence-practice gap." PLoS medicine 11.2 (2014): e1001603.'
that describes the term 'living evidence summary' (which is cited by Hair et al.)]
of animal research modelling ASD which might inform future systematic
reviews, by ensuring that such a tool is fit for purpose and provides the appropriate resources to
allow researchers to conduct high quality systematic reviews. We chose to focus on systematic
reviews summarising research using genetic animal models of any of the 102 ASD-related genes
identified through large-scale exome sequencing by Satterstrom et al. (2020), as these are all genes
where there is high confidence in their clinical relevance [richelbilderbeek: reference?].

## Methods

To date, we have completed preliminary searches and optimised our search strategy to inform the
development of this protocol.

## Research question

This systematic review of systematic reviews seeks to investigate (1) how many systematic reviews
have been conducted in this area, (2) what is the aim of each review and what research question
does it seek to ask, and (3) and what is the quality of reporting of these reviews.

## Bibliographic search

We will conduct systematic literature search on three electronic databases: PubMed (accessed via
NCBI), Embase (accessed via Ovid), and Web of Science Core Collection.

Our search strategy includes three components: (1) broad terms related to autism,
neurodevelopment, or ASD-related genes; (2) terms related to animal models, and (3) terms related
systematic reviews or meta-analyses. Terms used to identify animal models were taken from van der
Mierden et al. (2022) and terms used to identify systematic reviews and meta-analyses were taken
from Langendam et al. (2021). Full search terms are given in Appendix 1.

We will not restrict searches by publication date or language. If we include studies without an
English language full-text, we will use Google Translate to translate the full-text into English. Where
citations appear in multiple databases, we will remove duplicate versions of the citation using the
ASySD tool (Hair et al., 2021).

## Screening

We will upload our search results, with duplicate citations removed, to the Systematic Review
Facility (SyRF) platform (Bahor et al., 2021) for screening. Two independent reviewers will screen
each publication for inclusion and any disagreements will be reconciled by a third independent
reviewer. We plan one round of screening, where we will screen the full-texts of all studies retrieved
from our searches against our inclusion and exclusion criteria, to avoid potentially excluding
systematic reviews where the decision for inclusion rests on information contained in the full text
but not in the abstract (Wilson et al., 2022).

We will retrieve full text PDF files using the automated find full text feature in EndNote 20 or via
handsearching. If we cannot access the full text using our institutional subscriptions, we will request
the full text via interlibrary loan.


### Inclusion and exclusion criteria

Studies will be screened according to the criteria outlined below:

 * Inclusion criteria:
   * Study design – systematic reviews or meta-analyses that include animal studies,
     either as a review limited to animal studies or one which includes them alongside
     other study types.
   * Animal models – systematic reviews or meta-analyses which include studies
     investigating a genetic animal model based on at least one of the 102 ASD-related
     genes identified by Satterstrom et al. (2020).
   * Other criteria – conference abstracts and preprints.

 * Exclusion criteria:
   * Study design – systematic reviews of meta-analyses which do not include animal
     studies, or systematic reviews which do not search at least two bibliographic
     databases [richelbilderbeek: I would enjoy to hear why this is an exclusion criterium]. Other publication types such as non-systematic reviews, letters,
     editorials, or opinion pieces.
   * Animal models – systematic reviews or meta-analyses which do not include animal
     models, or where the animals are not models of at least one of the 102 genes
     identified by Satterstrom et al., (2020).
   * Other criteria – publications where we cannot access the full-text.

We will place no restriction on publication date or language.

## Data extraction

Two independent reviewers will conduct data extraction. Discrepancies between reviewer decisions
will be reconciled by a third independent reviewer. We will carry out data extraction using the SyRF
platform, and will collect the following information:
 * Bibliographic data
 * Systematic review aims and research question
 * Reporting quality


## Bibliographic data

We will extract names of first authors, year of publication, title, and DOI of each included study.

### Systematic review aims and research question

To understand the purpose and scope of each included systematic review, we will extract the aim of
each systematic review and the primary research question each review seeks to ask. Additionally, we
will extract:

 * Whether the review only included animal studies, or also included clinical or in vitro studies
 * Which animal models the review included
 * The total number of studies included in the systematic review
 * The total number of studies investigating relevant animal models


## Reporting quality

We will assess the reporting quality of each included systematic review using the 46-point checklist developed by Hunniford et al. (2021). The checklist is adapted from the PRISMA guidelines for
systematic reviews and is more specific to systematic review of animal studies. However, the
checklist is not currently an official extension to PRISMA. Although it is not recommended to use the
general PRISMA guidelines to assess in vivo systematic review reporting 
quality [richelbilderbeek: I would enjoy a reference to this statement :-) ], the adapted
checklist for preclinical systematic reviews has been designed for this purpose.

The checklist items are written in full in Appendix 2.

## Data synthesis

We will not conduct a meta-analysis. However, we will present a descriptive summary of data
extracted from each included systematic review.

We will present bibliographic details of each included systematic review and provide a narrative
review of each review’s research question and aim [richelbilderbeek: I enjoy the enthusiasm
here, but I see no reason why to provide this narrative. I would enjoy to see why this narrative
is provided, especially as the checklist already contain quite some 'describe X' items]. 
We will then score each included systematic
review using the PRISMA modified reporting checklist and provide a summary table detailing which
items of the checklist each review met. 
Additionally, the checklist will allow us to assess which tools
are currently being used to conduct systematic reviews in this field, including the tools used to
screen studies (Checklist Item 6a), extract numerical data (Checklist Item 17a), and measure study
quality or risk of bias (Checklist Item 19).

 * [richelbilderbeek: I would enjoy to see some example table here, like:

Study          |Narrative
---------------|--------------
A et al., 1234 |Focuses on fish
B et al., 2020 |Focus on tools used
.              |.

and

Study          |Checklist item|Follows item?
---------------|--------------|-------------
A et al., 1234 |             1|Yes
A et al., 1234 |             2|No
.              |             .|.

]

## Data availability

This protocol will be shared under a Creative Commons by Attribution (CC-BY) license. Analysis code
and data generated from this umbrella review will be shared online under a Creative Commons by
Attribution (CC-BY) license, and the final manuscript will be published open access.

## Appendices


### Appendix 1: Final full search terms

Animal models search terms are taken from van der Mierden et al. (2022) and systematic review
search terms are taken from Langendam et al., (2021).

#### NCBI PubMed search strategy

Index|Search terms
-----|----------------------
1    |Autism Spectrum Disorder[MeSH] OR ASD[TiAb] OR autis*[TiAb] OR neurodevelop*[TiAb] OR neurodevelop* delay*[TiAb]
2    |"CHD8"[TiAb] OR "SCN2A"[TiAb] OR "SYNGAP1"[TiAb] OR "ADNP"[TiAb] OR "FOXP1"[TiAb] OR "POGZ"[TiAb] OR "ARID1B"[TiAb] OR "SUV420H1"[TiAb] OR "DYRK1A"[TiAb] OR "SLC6A1"[TiAb] OR "GRIN2B"[TiAb] OR "PTEN"[TiAb] OR "SHANK3"[TiAb] OR "MED13L"[TiAb] OR "GIGYF1"[TiAb] OR "CHD2"[TiAb] OR "ANKRD11"[TiAb] OR "ANK2"[TiAb] OR "ASH1L"[TiAb] OR "TLK2"[TiAb] OR "DNMT3A"[TiAb] OR "DEAF1"[TiAb] OR "CTNNB1"[TiAb] OR "KDM6B"[TiAb] OR "DSCAM"[TiAb] OR "SETD5"[TiAb] OR "KCNQ3"[TiAb] OR "SRPR"[TiAb] OR "KDM5B"[TiAb] OR "WAC"[TiAb] OR "SHANK2"[TiAb] OR "NRXN1"[TiAb] OR "TBL1XR1"[TiAb] OR "MYT1L"[TiAb] OR "BCL11A"[TiAb] OR "RORB"[TiAb] OR "RAI1"[TiAb] OR "DYNC1H1"[TiAb] OR "DPYSL2"[TiAb] OR "AP2S1"[TiAb] OR "KMT2C"[TiAb] OR "PAX5"[TiAb] OR "MKX"[TiAb] OR "GABRB3"[TiAb] OR "SIN3A"[TiAb] OR "MBD5"[TiAb] OR "MAP1A"[TiAb] OR "STXBP1"[TiAb] OR "CELF4"[TiAb] OR "PHF12"[TiAb] OR "TBR1"[TiAb] OR "PPP2R5D"[TiAb] OR "TM9SF4"[TiAb] OR "PHF21A"[TiAb] OR "PRR12"[TiAb] OR "SKI"[TiAb] OR "ASXL3"[TiAb] OR "SPAST"[TiAb] OR "SMARCC2"[TiAb] OR "TRIP12"[TiAb] OR "CREBBP"[TiAb] OR "TCF4"[TiAb] OR "CACNA1E"[TiAb] OR "GNAI1"[TiAb] OR "TCF20"[TiAb] OR "FOXP2"[TiAb] OR "NSD1"[TiAb] OR "TCF7L2"[TiAb] OR "LDB1"[TiAb] OR "EIF3G"[TiAb] OR "PHF2"[TiAb] OR "KIAA0232"[TiAb] OR "VEZF1"[TiAb] OR "GFAP"[TiAb] OR "IRF2BPL"[TiAb] OR "ZMYND8"[TiAb] OR "SATB1"[TiAb] OR "RFX3"[TiAb] OR "SCN1A"[TiAb] OR "PPP5C"[TiAb] OR "TRIM23"[TiAb] OR "TRAF7"[TiAb] OR "ELAVL3"[TiAb] OR "GRIA2"[TiAb] OR "LRRC4C"[TiAb] OR "CACNA2D3"[TiAb] OR "NUP155"[TiAb] OR "KMT2E"[TiAb] OR "NR3C2"[TiAb] OR "NACC1"[TiAb] OR "PTK7"[TiAb] OR "PPP1R9B"[TiAb] OR "GABRB2"[TiAb] OR "HDLBP"[TiAb] OR "TAOK1"[TiAb] OR "UBR1"[TiAb] OR "TEK"[TiAb] OR "KCNMA1"[TiAb] OR "CORO1A"[TiAb] OR "HECTD4"[TiAb] OR "NCOA1"[TiAb] OR "DIP2A"[TiAb]
3    |#1 OR #2
4    |(animal experimentation[MeSH] OR models, animal[MeSH] OR Animals[Mesh:noexp] OR
animal population groups [MeSH] OR chordata[MeSH Terms:noexp] OR vertebrates[MeSH
Terms:noexp] OR amphibians[MeSH] OR birds[MeSH] OR fishes[MeSH] OR reptiles[MeSH]
OR mammals[MeSH Terms:noexp] OR primates[MeSH Terms:noexp] OR eutheria[MeSH
Terms:noexp] OR artiodactyla[MeSH] OR carnivore[MeSH] OR cephalopoda[MeSH] OR
cetacea[MeSH] OR chiroptera[MeSH] OR elephants[MeSH] OR hyraxes[MeSH] OR
insectivora[MeSH] OR lagomorpha[MeSH] OR marsupialia[MeSH] OR monotremata[MeSH]
OR perissodactyla[MeSH] OR Proboscidea Mammal[MeSH Terms:noexp] OR
rodentia[MeSH] OR scandentia[MeSH] OR sirenia[MeSH] OR cingulata[MeSH] OR
haplorhini[MeSH Terms:noexp] OR strepsirhini[MeSH] OR platyrrhini[MeSH] OR
tarsii[MeSH] OR catarrhini[MeSH Terms:noexp] OR cercopithecidae[MeSH] OR
hylobatidae[MeSH] OR hominidae[MeSH Terms:noexp] OR gorilla gorilla[MeSH] OR pan
paniscus[MeSH] OR pan troglodytes[MeSH] OR pongo[MeSH]) OR ((rat[tiab] OR rats[tiab]
OR animal[tiab] OR animals[tiab] OR mice[tiab] OR in vivo[tiab] OR mouse[tiab] OR
rabbit[tiab] OR rabbits[tiab] OR murine[tiab] OR pig[tiab] OR pigs[tiab] OR dog[tiab] OR
dogs[tiab] OR bovine[tiab] OR fish[tiab] OR vertebrate[tiab] OR vertebrates[tiab] OR
cat[tiab] OR cats[tiab] OR rodent[tiab] OR rodents[tiab] OR mammal[tiab] OR
mammals[tiab] OR chicken[tiab] OR chickens[tiab] OR monkey[tiab] OR monkeys[tiab] OR
sheep[tiab] OR canine[tiab] OR canines[tiab] OR porcine[tiab] OR cattle[tiab] OR bird[tiab]
OR birds[tiab] OR hamster[tiab] OR hamsters[tiab] OR primate[tiab] OR primates[tiab] OR
cow[tiab] OR cows[tiab] OR chick[tiab] OR horse[tiab] OR horses[tiab] OR avian[tiab] OR
avians[tiab] OR calf[tiab] OR swine[tiab] OR swines[tiab] OR xenopus[tiab] OR turkeys[tiab]
OR bear[tiab] OR bears[tiab] OR frog[tiab] OR frogs[tiab] OR zebrafish[tiab] OR goat[tiab]
OR goats[tiab] OR equine[tiab] OR calves[tiab] OR poultry[tiab] OR macaque[tiab] OR
macaques[tiab] OR mole[tiab] OR moles[tiab] OR ovine[tiab] OR lamb[tiab] OR lambs[tiab]
OR fishes[tiab] OR diptera[tiab] OR amphibian[tiab] OR amphibians[tiab] OR snake[tiab] OR
snakes[tiab] OR ruminant[tiab] OR ruminants[tiab] OR hen[tiab] OR hens[tiab] OR
piglet[tiab] OR piglets[tiab] OR feline[tiab] OR felines[tiab] OR simian[tiab] OR simians[tiab]
OR laevis[tiab] OR trout[tiab] OR trouts[tiab] OR teleost[tiab] OR teleosts[tiab] OR
salmon[tiab] OR salmons[tiab] OR seal[tiab] OR seals[tiab] OR bull[tiab] OR bulls[tiab]OR
ewe[tiab] OR ewes[tiab] OR hedgehog[tiab] OR hedgehogs[tiab] OR macaca[tiab] OR
macacas[tiab] OR proteus[tiab] OR pigeon[tiab] OR pigeons[tiab] OR bat[tiab] OR bats[tiab]
OR duck[tiab] OR ducks[tiab] OR chimpanzee[tiab] OR chimpanzees[tiab] OR baboon[tiab]
OR baboons[tiab] OR deer[tiab] OR rana[tiab] OR ranas[tiab] OR carp[tiab] OR carps[tiab]
OR heifer[tiab] OR swallow[tiab] OR swallows[tiab] OR lizard[tiab] OR lizards[tiab] OR
canis[tiab] OR sow[tiab] OR sows[tiab] OR cynomolgus[tiab] OR quail[tiab] OR quails[tiab]
OR reptile[tiab] OR reptiles[tiab] OR turtle[tiab] OR turtles[tiab] OR buffalo[tiab] OR
gerbil[tiab] OR gerbils[tiab] OR boar[tiab] OR boars[tiab] OR squirrel[tiab] OR squirrels[tiab]
OR oncorhynchus[tiab] OR mus[tiab] OR toad[tiab] OR toads[tiab] OR fowl[tiab] OR
fowls[tiab] OR rerio[tiab] OR danio[tiab] OR ara[tiab] OR aras[tiab] OR musculus[tiab] OR
tadpole[tiab] OR tadpoles[tiab] OR mulatta[tiab] OR salmo[tiab] OR ram[tiab] OR eagle[tiab]
OR eagles[tiab] OR ferret[tiab] OR ferrets[tiab] OR goldfish[tiab] OR catfish[tiab] OR
whale[tiab] OR whales[tiab] OR fox[tiab] OR foxes[tiab] OR ape[tiab] OR apes[tiab] OR
elephant[tiab] OR elephants[tiab] OR bos[tiab] OR marmoset[tiab] OR marmosets[tiab] OR
cod[tiab] OR cods[tiab] OR shark[tiab] OR sharks[tiab] OR wolf[tiab] OR eel[tiab] OR
eels[tiab] OR auratus[tiab] OR rattus[tiab] OR zebra[tiab] OR zebras[tiab] OR tilapia[tiab] OR
tilapias[tiab] OR gilt[tiab] OR camel[tiab] OR camels[tiab] OR squid[tiab] OR gallus[tiab] OR
marsupial[tiab] OR marsupials[tiab] OR vole[tiab] OR voles[tiab] OR fascicularis[tiab] OR
ovis[tiab] OR salmonid[tiab] OR salmonids[tiab] OR tiger[tiab] OR tigers[tiab] OR
dolphin[tiab] OR dolphins[tiab] OR robin[tiab] OR robins[tiab] OR carpio[tiab] OR
opossum[tiab] OR opossums[tiab] OR cyprinus[tiab] OR salamander[tiab] OR
salamanders[tiab] OR felis[tiab]OR mink[tiab] OR minks[tiab] OR swan[tiab] OR swans[tiab]
OR norvegicus[tiab] OR bufo[tiab] OR torpedo[tiab] OR bass[tiab] OR lamprey[tiab] OR
lampreys[tiab] OR sus[tiab] OR python[tiab] OR pythons[tiab] OR tetrapod[tiab] OR
tetrapods[tiab] OR shrew[tiab]OR shrews[tiab] OR lion[tiab] OR lions[tiab] OR hog[tiab] OR
hogs[tiab] OR songbird[tiab] OR songbirds[tiab] OR oreochromis[tiab] OR starling[tiab] OR
starlings[tiab] OR caprine[tiab] OR carassius[tiab] OR owl[tiab] OR owls[tiab] OR newt[tiab]
OR newts[tiab] OR papio[tiab] OR scrofa[tiab] OR hare[tiab] OR hares[tiab] OR gorilla[tiab]
OR gorillas[tiab] OR flounder[tiab] OR flounders[tiab] OR goose[tiab] OR herring[tiab] OR
herrings[tiab] OR therian[tiab] OR buffaloes[tiab] OR canary[tiab] OR sparrow[tiab] OR
sparrows[tiab] OR microtus[tiab] OR octopus[tiab] OR troglodytes[tiab] OR tuna[tiab] OR
amphibia[tiab] OR chinchilla[tiab] OR chinchillas[tiab] OR ide[tiab] OR oryzias[tiab] OR
cervus[tiab] OR kangaroo[tiab] OR kangaroos[tiab] OR armadillo[tiab] OR armadillos[tiab]
OR callithrix[tiab] OR pan troglodytes[tiab] OR saimiri[tiab] OR cichlid[tiab] OR cichlids[tiab]
OR donkey[tiab] OR donkeys[tiab] OR bream[tiab] OR char[tiab] OR chars[tiab] OR
finch[tiab] OR raccoon[tiab] OR raccoons[tiab] OR bothrops[tiab] OR anguilla[tiab] OR
perch[tiab] OR cricetus[tiab] OR seabird[tiab] OR seabirds[tiab] OR buck[tiab] OR
bucks[tiab] OR naja[tiab] OR coturnix[tiab] OR salmonids[tiab] OR geese[tiab] OR
minnow[tiab] OR minnows[tiab] OR raptor[tiab] OR raptors[tiab] OR merione[tiab] OR
meriones[tiab] OR rodentia[tiab] OR elaphus[tiab] OR amniote[tiab] OR amniotes[tiab] OR
elasmobranch[tiab] OR emu[tiab] OR emus[tiab] OR peromyscus[tiab] OR hominid[tiab] OR
hominids[tiab] OR bubalus[tiab] OR crotalus[tiab] OR gull[tiab] OR gulls[tiab] OR anas[tiab]
OR anura[tiab] OR lemur[tiab] OR lemurs[tiab] OR crow[tiab] OR crows[tiab] OR
camelus[tiab] OR gibbon[tiab] OR gibbons[tiab] OR waterfowl[tiab] OR parrot[tiab] OR
parrots[tiab] OR eels[tiab] OR cob[tiab] OR stickleback[tiab] OR sticklebacks[tiab] OR
columba[tiab] OR mesocricetus[tiab] OR ambystoma[tiab] OR raven[tiab] OR ravens[tiab]
OR gadus[tiab] OR penguin[tiab] OR penguins[tiab] OR orangutan[tiab] OR orangutans[tiab]
OR sturgeon[tiab] OR sturgeons[tiab] OR cuniculus[tiab] OR aves[tiab] OR virginianus[tiab]
OR cephalopod[tiab] OR cephalopods[tiab] OR cebus[tiab] OR sparus[tiab] OR tortoise[tiab]
OR tortoises[tiab] OR guttata[tiab] OR morhua[tiab] OR unguiculatus[tiab] OR dogfish[tiab]
OR vulpes[tiab] OR mallard[tiab] OR mallards[tiab] OR apodemus[tiab] OR alligator[tiab] OR
alligators[tiab] OR oryctolagus[tiab] OR llama[tiab] OR llamas[tiab] OR reindeer[tiab] OR
mustela[tiab] OR duckling[tiab] OR ducklings[tiab] OR wolves[tiab] OR sander[tiab] OR
amazona[tiab] OR zebu[tiab] OR badger[tiab] OR badgers[tiab] OR dove[tiab] OR
doves[tiab] OR ictalurus[tiab] OR capra[tiab] OR capras[tiab] OR equus[tiab] OR
camelid[tiab] OR camelids[tiab] OR poecilia[tiab] OR mule[tiab] OR mules[tiab] OR
perciformes[tiab] OR salvelinus[tiab] OR labrax[tiab] OR cyprinidae[tiab] OR ariidae[tiab] OR
crocodile[tiab] OR crocodiles[tiab] OR fundulus[tiab] OR dicentrarchus[tiab] OR clarias[tiab]
OR cercopithecus[tiab] OR chiroptera[tiab] OR alpaca[tiab] OR alpacas[tiab] OR pike[tiab]
OR pikes[tiab] OR paralichthys[tiab] OR puma[tiab] OR pumas[tiab] OR didelphis[tiab] OR
pisces[tiab] OR macropus[tiab] OR triturus[tiab] OR bison[tiab] OR bisons[tiab] OR
epinephelus[tiab] OR gasterosteus[tiab] OR panthera[tiab] OR acipenser[tiab] OR
mackerel[tiab] OR mackerels[tiab] OR tamarin[tiab] OR tamarins[tiab] OR ostrich[tiab] OR
anolis[tiab] OR vervet[tiab] OR vervets[tiab] OR wallaby[tiab] OR glareolus[tiab] OR
beaver[tiab] OR beavers[tiab] OR dromedary[tiab] OR catus[tiab] OR killifish[tiab] OR
pimephales[tiab] OR promelas[tiab] OR aotus[tiab] OR phoca[tiab] OR panda[tiab] OR
pandas[tiab] OR porpoise[tiab] OR porpoises[tiab] OR myotis[tiab] OR yak[tiab] OR
yaks[tiab] OR agkistrodon[tiab] OR vipera[tiab] OR otter[tiab] OR otters[tiab] OR
turbot[tiab] OR turbots[tiab] OR squamate[tiab] OR carnivora[tiab] OR mullet[tiab] OR
mullets[tiab] OR hawk[tiab] OR hawks[tiab] OR taeniopygia[tiab] OR seahorse[tiab] OR
seahorses[tiab] OR poecilia reticulata[tiab] OR falcon[tiab] OR falcons[tiab] OR
prosimian[tiab] OR prosimians[tiab] OR parus[tiab] OR perca[tiab] OR fingerling[tiab] OR
fingerlings[tiab] OR antelope[tiab] OR antelopes[tiab] OR tupaia[tiab] OR
passeriformes[tiab] OR sepia[tiab] OR saguinus[tiab] OR coyote[tiab] OR coyotes[tiab] OR
pongo[tiab] OR meleagris[tiab] OR reptilia[tiab] OR lepus[tiab] OR psittacine[tiab] OR
hagfish[tiab] OR warbler[tiab] OR warblers[tiab] OR russell's viper[tiab] OR russell's
vipers[tiab] OR smolt[tiab] OR smolts[tiab] OR budgerigar[tiab] OR sardine[tiab] OR
sardines[tiab] OR cavia[tiab] OR cavias[tiab] OR hyla[tiab] OR pleurodeles[tiab] OR
siluriformes[tiab] OR great tit[tiab] OR great tits[tiab] OR guppy[tiab] OR bonobo[tiab] OR
bonobos[tiab] OR rutilus[tiab] OR trichosurus[tiab] OR muridae[tiab] OR phodopus[tiab] OR
channa[tiab] OR squalus[tiab] OR lynx[tiab] OR sturnus[tiab] OR petromyzon[tiab] OR
vitulina[tiab] OR monodelphis[tiab] OR cuttlefish[tiab] OR adder[tiab] OR adders[tiab] OR
lepomis[tiab] OR canaria[tiab] OR gambusia[tiab] OR guppies[tiab] OR xiphophorus[tiab] OR
flatfish[tiab] OR koala[tiab] OR koalas[tiab] OR labeo[tiab] OR stingray[tiab] OR
stingrays[tiab] OR chelonia[tiab] OR lampetra[tiab] OR spermophilus[tiab] OR
crocodilian[tiab] OR passer domesticus[tiab] OR sciurus[tiab] OR artiodactyla[tiab] OR
ranidae[tiab] OR corvus[tiab] OR necturus[tiab] OR platypus[tiab] OR canaries[tiab] OR
bovid[tiab] OR lagopus[tiab] OR trimeresurus[tiab] OR gariepinus[tiab] OR marten[tiab] OR
martens[tiab] OR drosophilidae[tiab] OR mugil[tiab] OR sunfish[tiab] OR porcellus[tiab] OR
cypriniformes[tiab] OR alouatta[tiab] OR scophthalmus[tiab] OR anser[tiab] OR
electrophorus[tiab] OR putorius[tiab] OR iguana[tiab] OR iguanas[tiab] OR lama[tiab] OR
lamas[tiab] OR takifugu[tiab] OR circus[tiab] OR eptesicus[tiab] OR flycatcher[tiab] OR
galago[tiab] OR galagos[tiab] OR trachemys[tiab] OR lungfish[tiab] OR characiformes[tiab]
OR shorebird[tiab] OR shorebirds[tiab] OR giraffe[tiab] OR giraffes[tiab] OR
micropterus[tiab] OR scyliorhinus[tiab] OR cichlidae[tiab] OR loligo[tiab] OR porcupine[tiab]
OR porcupines[tiab] OR chub[tiab] OR chubs[tiab] OR solea[tiab] OR pleuronectes[tiab] OR
hylidae[tiab] OR viperidae[tiab] OR echis[tiab] OR sorex[tiab] OR anchovy[tiab] OR
lagomorph[tiab] OR ostriches[tiab] OR vulture[tiab] OR vultures[tiab] OR whitefish[tiab] OR
araneus[tiab] OR jird[tiab] OR jirds[tiab] OR tern[tiab] OR esox[tiab] OR drake[tiab] OR
drakes[tiab] OR elapidae[tiab] OR gallopavo[tiab] OR chordata[tiab] OR myodes[tiab] OR
caretta[tiab] OR serinus[tiab] OR grouse[tiab] OR misgurnus[tiab] OR meles[tiab] OR
blackbird[tiab]OR blackbirds[tiab] OR coregonus[tiab] OR bobwhite[tiab] OR
bobwhites[tiab] OR heteropneustes[tiab] OR mammoth[tiab] OR mammoths[tiab] OR
turdus[tiab] OR rhinella[tiab] OR ateles[tiab] OR characidae[tiab] OR clupea[tiab] OR
bungarus [tiab] OR brill[tiab] OR struthio camelus[tiab] OR sloth[tiab] OR sloths[tiab] OR
pteropus[tiab] OR sculpin[tiab] OR anthropoids[tiab] OR pollock[tiab] OR pollocks[tiab] OR
morone[tiab] OR pan paniscus[tiab] OR litoria[tiab] OR chipmunk[tiab] OR chipmunks[tiab]
OR balaenoptera[tiab] OR marmota[tiab] OR melopsittacus[tiab] OR hyrax[tiab] OR
lemming[tiab] OR lemmings[tiab] OR halibut[tiab] OR hylobates[tiab] OR lates[tiab] OR
caiman[tiab] OR caimans[tiab] OR sigmodon[tiab] OR stenella[tiab] OR barbel[tiab] OR
barbels[tiab] OR sterna[tiab] OR parakeet[tiab] OR parakeets[tiab] OR phocoena[tiab] OR
leptodactylus[tiab] OR canidae[tiab] OR buteo[tiab] OR harengus[tiab] OR gopher[tiab] OR
gophers[tiab] OR marmot[tiab] OR marmots[tiab] OR gosling[tiab] OR goslings[tiab] OR
platichthys[tiab] OR gar[tiab] OR gars[tiab] OR sebastes[tiab] OR marsupialia[tiab] OR
notophthalmus[tiab] OR gazelle[tiab] OR gazelles[tiab] OR insectivora[tiab] OR paridae[tiab]
OR felidae[tiab] OR russula[tiab] OR galliformes[tiab] OR bombina[tiab] OR colobus [tiab]
OR echidna[tiab] OR echidnas[tiab] OR seabass[tiab] OR syncerus[tiab] OR plaice[tiab] OR
blue tit[tiab] OR blue tits[tiab] OR pagrus[tiab] OR catfishes[tiab] OR cetacea[tiab] OR
barbus[tiab] OR cygnus[tiab] OR ficedula[tiab] OR chamois[tiab] OR colubridae[tiab] OR
perches[tiab] OR coelacanth[tiab] OR fitch[tiab] OR urodela[tiab] OR cynops[tiab] OR
martes[tiab] OR halichoerus[tiab] OR aix[tiab] OR salmonidae[tiab] OR leuciscus[tiab] OR
magpie[tiab] OR magpies[tiab] OR silurus[tiab] OR whiting[tiab] OR whitings[tiab] OR
anseriformes[tiab] OR colinus[tiab] OR rhea[tiab] OR chlorocebus[tiab] OR octodon[tiab] OR
acinonyx[tiab] OR mouflon[tiab] OR mouflons[tiab] OR ibex[tiab] OR tetraodon[tiab] OR
bufonidae[tiab] OR equidae[tiab] OR jackal[tiab] OR cephalopoda[tiab] OR
dendroaspis[tiab] OR glama[tiab] OR muskrat[tiab] OR muskrats[tiab] OR sable[tiab] OR
sables[tiab] OR wildebeest[tiab] OR streptopelia[tiab] OR albifrons[tiab] OR
vespertilionidae[tiab] OR woodpecker[tiab] OR woodpeckers[tiab] OR muntjac[tiab] OR
muntjacs[tiab] OR archosaur[tiab] OR branta[tiab] OR cricetulus[tiab] OR
megalobrama[tiab] OR poeciliidae[tiab] OR desmodus[tiab] OR snakehead[tiab] OR
snakeheads[tiab] OR tench[tiab] OR teal[tiab] OR teals[tiab] OR bandicoot[tiab] OR
bandicoots[tiab] OR apteronotus[tiab] OR phyllostomidae[tiab] OR crocidura[tiab] OR
buzzard[tiab] OR buzzards[tiab] OR larimichthys[tiab] OR cercocebus[tiab] OR
pipistrellus[tiab] OR erithacus[tiab] OR impala[tiab] OR impalas[tiab] OR rousettus[tiab] OR
haddock[tiab] OR haddocks[tiab] OR tinca[tiab] OR ratite[tiab] OR calidris[tiab] OR
cynoglossus[tiab] OR hypophthalmichthys[tiab] OR bullock[tiab] OR bullocks[tiab] OR
dromedaries[tiab] OR alectoris[tiab] OR filly[tiab] OR salamandra[tiab] OR cingulata[tiab]
OR bitis[tiab] OR grus[tiab] OR ammodytes[tiab] OR macaw[tiab] OR macaws[tiab] OR
hypoleuca[tiab] OR sapajus[tiab] OR cyprinodontiformes[tiab] OR hippopotamus[tiab] OR
pelophylax[tiab] OR capybara[tiab] OR capybaras[tiab] OR weasel[tiab] OR weasels[tiab] OR
cairina[tiab] OR cynomys[tiab] OR lutra[tiab] OR cockatoo[tiab] OR cockatoos[tiab] OR
lachesis[tiab] OR lagomorpha[tiab] OR rupicapra[tiab] OR daboia[tiab] OR orang utan[tiab]
OR orang utans[tiab] OR platyrrhini[tiab] OR charadriiformes[tiab] OR micrurus[tiab] OR
psittaciformes[tiab] OR spalax[tiab] OR loris[tiab] OR mustelidae[tiab] OR sylvilagus[tiab] OR
vitticeps[tiab] OR cockatiel[tiab] OR mustelus[tiab] OR
cottus[tiab] OR erythrocebus[tiab] OR dipodomys[tiab] OR platessa[tiab] OR callicebus[tiab]
OR loricariidae[tiab] OR catostomus[tiab] OR cuneata[tiab] OR cyanistes[tiab] OR
cyprinodon[tiab] OR sigmodontinae[tiab] OR elasmobranchii[tiab] OR trichechus[tiab] OR
sauropsid[tiab] OR xenarthra[tiab] OR dormouse[tiab] OR perissodactyla[tiab] OR
nautilus[tiab] OR cirrhinus[tiab] OR gulo[tiab] OR tragelaphus[tiab] OR merula[tiab] OR
numida[tiab] OR sciaenidae[tiab] OR cerastes[tiab] OR sciuridae[tiab] OR gibbosus[tiab] OR
octopuses[tiab] OR eland[tiab] OR elands[tiab] OR phyllomedusa[tiab] OR pogona[tiab] OR
walrus[tiab] OR agamidae[tiab] OR leptodactylidae[tiab] OR ridibundus[tiab] OR
leontopithecus[tiab] OR anteater[tiab] OR anteaters[tiab] OR pelodiscus[tiab] OR
cebidae[tiab] OR columbianus[tiab] OR pelteobagrus fulvidraco[tiab] OR hominoidea[tiab]
OR mandrillus[tiab] OR zonotrichia leucophrys[tiab] OR agama[tiab] OR gobiocypris[tiab] OR
bearded dragon[tiab] OR bearded dragons[tiab] OR sarotherodon[tiab] OR talpa[tiab] OR
discoglossus[tiab] OR hagfishes[tiab] OR sphenodon[tiab] OR gudgeon[tiab] OR
amphiuma[tiab] OR aythya[tiab] OR tenrec[tiab] OR tenrec[tiab] OR hominidae[tiab] OR
risoria[tiab] OR salamandridae[tiab] OR camelidae[tiab] OR columbiformes[tiab] OR
latimeria[tiab] OR plover[tiab] OR plovers[tiab] OR afrotheria[tiab] OR falco sparverius[tiab]
OR polecat[tiab] OR polecats[tiab] OR crotalinae[tiab] OR salvadora[tiab] OR tarsier[tiab] OR
lucioperca[tiab] OR anchovies[tiab] OR lungfishes[tiab] OR terrapin[tiab] OR dromaius
novaehollandiae[tiab] OR lateolabrax[tiab] OR eigenmannia[tiab] OR pelamis[tiab] OR
theropithecus[tiab] OR murinae[tiab] OR gander[tiab] OR gymnotus[tiab] OR
pseudacris[tiab] OR gymnophiona[tiab] OR gymnotiformes[tiab] OR laticauda[tiab] OR
falconiformes[tiab] OR dugong[tiab] OR dugongs[tiab] OR pintail[tiab] OR pintails[tiab] OR
rook[tiab] OR rooks[tiab] ORl asiurus[tiab] OR catshark[tiab] OR catsharks[tiab] OR
micropogonias[tiab] OR red junglefowl[tiab] OR paddlefish[tiab] OR ophiophagus[tiab] OR
hollandicus[tiab] OR nymphicus[tiab] OR pimelodidae[tiab] OR aepyceros[tiab] OR
cobitidae[tiab] OR strigiformes[tiab] OR cobitis[tiab] OR dormice[tiab] OR alytes[tiab] OR
calloselasma[tiab] OR guanaco[tiab] OR phasianidae[tiab] OR round goby[tiab] OR
trichogaster[tiab] OR catarrhini[tiab] OR eelpout[tiab] OR eelpouts[tiab] OR galaxias[tiab]
OR gaur[tiab] OR pungitius[tiab] OR suslik[tiab] OR susliks[tiab] OR flatfishes[tiab] OR
percidae[tiab] OR caprinae[tiab] OR todarodes[tiab] OR osmerus[tiab] OR ameiurus[tiab] OR
anthropoidea[tiab] OR castor canadensis[tiab] OR pouting[tiab] OR poutings[tiab] OR
tetraodontiformes[tiab] OR arvicolinae[tiab] OR siamang[tiab] OR siamangs[tiab] OR castor
fiber[tiab] OR nomascus[tiab] OR red knot[tiab] OR red knots[tiab] OR syngnathidae[tiab]
OR iguanidae[tiab] OR eretmochelys[tiab] OR ursidae[tiab] OR callimico[tiab] OR
columbidae[tiab] OR microhylidae[tiab] OR anaxyrus[tiab] OR menidia[tiab] OR
pipistrelle[tiab] OR greylag[tiab] OR pipidae[tiab] OR scandentia[tiab] OR bowfin[tiab] OR
bowfins[tiab] OR dendrobatidae[tiab] OR zenaida[tiab] OR bushbaby[tiab] OR harrier[tiab]
OR harriers[tiab] OR macropodidae[tiab] OR pygerythrus[tiab] OR clupeidae[tiab] OR
odorrana[tiab] OR corvidae[tiab] OR jerboa[tiab] OR jerboas[tiab] OR canutus[tiab] OR
hylobatidae[tiab] OR clupeiformes[tiab] OR great cormorant[tiab] OR great
cormorants[tiab] OR scorpaeniformes[tiab] OR chondrostean[tiab] OR garfish[tiab] OR
proboscidea[tiab] OR psetta[tiab] OR diapsid[tiab] OR serotinus[tiab] OR tetrao[tiab] OR
walruses[tiab] OR carcharhiniformes[tiab] OR leucoraja[tiab] OR pumpkinseed[tiab] OR
dosidicus[tiab] OR acipenseriformes[tiab] OR daubentonii[tiab] OR emberizidae[tiab] OR
gadiformes[tiab] OR hyraxes[tiab] OR stizostedion[tiab] OR wolverine[tiab] OR
wolverines[tiab] OR lissotriton[tiab] OR acanthurus[tiab] OR centrarchidae[tiab] OR
gloydius[tiab] OR laurasiatheria[tiab] OR limosa[tiab] OR psittacula[tiab] OR leporidae[tiab]
OR proteidae[tiab] OR zander[tiab] OR zanders[tiab] OR arapaima[tiab] OR bagridae[tiab]
OR cyprinodontidae[tiab] OR mithun[tiab] OR pandion[tiab] OR jackdaw[tiab] OR
jackdaws[tiab] OR procyonidae[tiab] OR carus[tiab] OR jaculus[tiab] OR salmoniformes[tiab]
OR common sole[tiab] OR common soles[tiab] OR protobothrops[tiab] OR calamita[tiab] OR
brachyteles[tiab] OR trionyx[tiab] OR turdidae[tiab] OR boidae[tiab] OR luscinia[tiab] OR
pugnax[tiab] OR euarchontoglires[tiab] OR saithe[tiab] OR saithes[tiab] OR
symphalangus[tiab] OR aardvark[tiab] OR aardvarks[tiab] OR oystercatcher[tiab] OR
oystercatchers[tiab] OR arius[tiab] OR corydoras[tiab] OR poacher[tiab] OR poachers[tiab]
OR aurochs[tiab] OR cebuella[tiab] OR crecca[tiab] OR lemuridae[tiab] OR sirenia[tiab] OR
lemmus[tiab] OR perdix[tiab] OR glires[tiab] OR lepidosaur[tiab] OR muskox[tiab] OR
deinagkistrodon[tiab] OR pholidota[tiab] OR holocephali[tiab] OR cercopithecinae[tiab] OR
clariidae[tiab] OR agapornis[tiab] OR doryteuthis[tiab] OR tyrannidae[tiab] OR
dicroglossidae[tiab] OR godwit[tiab] OR godwits[tiab] OR monedula[tiab] OR pongidae[tiab]
OR atheriniformes[tiab] OR colobinae[tiab] OR lophocebus[tiab] OR atelidae[tiab] OR
cottidae[tiab] OR leucopsis[tiab] OR acanthuridae[tiab] OR didelphimorphia[tiab] OR
elver[tiab] OR elvers[tiab] OR lapponica[tiab] OR dermoptera[tiab] OR european hake[tiab]
OR european hakes[tiab] OR gerbillinae[tiab] OR banteng[tiab] OR hartebeest[tiab] OR
hartebeests[tiab]OR hogget[tiab] OR haematopus[tiab] OR anguis fragilis[tiab] OR grey
heron[tiab] OR grey herons[tiab] OR blue whiting[tiab] OR blue whitings[tiab] OR
furnariidae[tiab] OR macrovipera[tiab] OR esocidae[tiab] OR lapwing[tiab] OR
lapwings[tiab] OR mylopharyngodon[tiab] OR wallabia[tiab] OR beloniformes[tiab] OR
potoroo[tiab] OR potoroos[tiab] OR athene noctua[tiab] OR pleuronectidae[tiab] OR
bushbabies[tiab] OR muscicapidae[tiab] OR alligatoridae[tiab] OR fuligula[tiab] OR bush
baby[tiab] OR guineafowl[tiab] OR spoonbill[tiab] OR spoonbills[tiab] OR viverridae[tiab] OR
catostomidae[tiab] OR zebrafishes[tiab] OR ibexes[tiab] OR vendace[tiab] OR
estrildidae[tiab] OR monotremata[tiab] OR sepiella[tiab] OR ambystomatidae[tiab] OR
shelduck[tiab] OR shelducks[tiab] OR treeshrew[tiab] OR treeshrews[tiab] OR
hoplobatrachus[tiab] OR pochard[tiab] OR hoolock[tiab] OR hoolocks[tiab] OR lynxes[tiab]
OR antilope[tiab] OR antilopes[tiab] OR blackbuck[tiab] OR blackbucks[tiab] OR
cricetinae[tiab] OR paramisgurnus[tiab] OR skylark[tiab] OR skylarks[tiab] OR soleidae[tiab]
OR allobates[tiab] OR northern wheatear[tiab] OR northern wheatears[tiab] OR
pitheciidae[tiab] OR takin[tiab] OR theria[tiab] OR vanellus[tiab] OR galaxiidae[tiab] OR
lorisidae[tiab] OR ostralegus[tiab] OR palaeognathae[tiab] OR stone loach[tiab] OR
alauda[tiab] OR callitrichinae[tiab] OR caniformia[tiab] OR duttaphrynus[tiab] OR
ictaluridae[tiab] OR osteoglossiformes[tiab] OR poultries[tiab] OR curema[tiab] OR ruddy
turnstone[tiab] OR ruddy turnstones[tiab] OR sheatfish[tiab] OR sunfishes[tiab] OR
centropomidae[tiab] OR hemachatus[tiab] OR platalea[tiab] OR thamnophilidae[tiab] OR
song thrush[tiab] OR atherinopsidae[tiab] OR siluridae[tiab] OR tadorna[tiab] OR
chroicocephalus[tiab] OR ermine[tiab] OR ermines[tiab] OR gavialis[tiab] OR ruff[tiab] OR
tupaiidae[tiab] OR diprotodontia[tiab] OR hyaenidae[tiab] OR antilopinae[tiab] OR
crocodylidae[tiab] OR herpestidae[tiab] OR hippopotamidae[tiab] OR northern
shoveler[tiab] OR round gobies[tiab] OR cheirogaleidae[tiab] OR indriidae[tiab] OR
fundulidae[tiab] OR pythonidae[tiab] OR rhynchocephalia[tiab] OR
anodorhynchus[tiab] OR red-backed shrike[tiab] OR red-backed shrikes[tiab] OR
triakidae[tiab] OR phalangeridae[tiab] OR aoudad[tiab] OR boreoeutheria[tiab] OR
eurasianjay[tiab] OR eurasian jays[tiab] OR feliformia[tiab] OR haplorhini[tiab] OR
osteoglossidae[tiab] OR paenungulata[tiab] OR struthioniformes[tiab] OR ferina[tiab] OR
sanderling[tiab] OR sanderlings[tiab] OR spheniscidae[tiab] OR cuttlefishes[tiab] OR
cygnet[tiab] OR dasycneme[tiab] OR gadwall[tiab] OR gadwalls[tiab] OR pelobates
fuscus[tiab] OR wryneck[tiab] OR wrynecks[tiab] OR afrosoricida[tiab] OR culaea[tiab] OR
dover sole[tiab] OR dover soles[tiab] OR paralichthyidae[tiab] OR passeridae[tiab] OR
osteolaemus[tiab] OR song thrushes[tiab] OR bluethroat[tiab] OR bluethroats[tiab] OR
hydrophiidae[tiab] OR megrim[tiab] OR mephitidae[tiab] OR strepsirhini[tiab] OR
tomistoma[tiab] OR epidalea[tiab] OR osmeriformes[tiab] OR bush babies[tiab] OR
tarsiiform[tiab] OR atelinae[tiab] OR bufotes[tiab] OR eurasian coot[tiab] OR eurasian
coots[tiab] OR galagidae[tiab] OR geopelia[tiab] OR philomachus[tiab] OR
tubulidentata[tiab] OR bombinatoridae[tiab] OR pelobatidae[tiab] OR tachysurus[tiab] OR
ailuridae[tiab] OR woodlark[tiab] OR woodlarks[tiab] OR alcelaphinae[tiab] OR
redshank[tiab] OR redshanks[tiab] OR salientia[tiab] OR sand smelt[tiab] OR sand
smelts[tiab] OR woodmice[tiab] OR woodmouse[tiab] OR dasyproctidae[tiab] OR eurasian
wigeon[tiab] OR eurasian wigeons[tiab]OR garganey[tiab] OR garganeys[tiab] OR lemon
sole[tiab] OR lemon soles[tiab] OR common dab[tiab] OR common dabs[tiab] OR
graylag[tiab] OR graylags[tiab] OR leucorodia[tiab] OR osphronemidae[tiab] OR
bewickii[tiab] OR common moorhen[tiab] OR common moorhens[tiab] OR
decapodiformes[tiab] OR gobbler[tiab] OR gobblers[tiab] OR odontophoridae[tiab] OR
paddlefishes[tiab] OR eutheria[tiab] OR salmonine[tiab] OR esociformes[tiab] OR eurasian
woodcock[tiab] OR eurasian woodcocks[tiab] OR european smelt[tiab] OR european
smelts[tiab] OR goldfishes[tiab] OR tenches[tiab] OR tyranni[tiab] OR common
chaffinch[tiab] OR common chaffinchs[tiab] OR common redstart[tiab] OR common
redstarts[tiab] OR common roach[tiab] OR common roachs[tiab] OR great knot[tiab] OR
great knots[tiab] OR potoroidae[tiab] OR alytidae[tiab] OR coregonine[tiab] OR
dipteral[tiab] OR leveret[tiab] OR poeciliopsis gracilis[tiab] OR amphiumidae[tiab] OR
batrachoidiformes[tiab] OR bighead goby[tiab] OR heteropneustidae[tiab] OR lullula[tiab]
OR norway pout[tiab] OR norway pouts[tiab] OR sipunculida[tiab] OR dogfishes[tiab] OR
sebastidae[tiab] OR tarsiidae[tiab] OR alethinophidia[tiab] OR common nase[tiab] OR
common nases[tiab] OR common sandpiper[tiab] OR common sandpipers[tiab] OR eurasian
blackcap[tiab] OR eurasian blackcaps[tiab] OR pterocnemia[tiab] OR syngnathiformes[tiab]
OR common chaffinches[tiab] OR eupleridae[tiab] OR octopodiformes[tiab] OR
phascolarctidae[tiab] OR scophthalmidae[tiab] OR starry smooth-hound[tiab] OR starry
smooth-hounds[tiab] OR whitefishes[tiab] OR cuniculidae[tiab] OR european sprat[tiab] OR
european sprats[tiab] OR rosy bitterling[tiab] OR rosy bitterlings[tiab] OR common
dace[tiab] OR common daces[tiab] OR lesser weever[tiab] OR lesser weevers[tiab] OR
scaldfish[tiab] OR water rail[tiab] OR water rails[tiab] OR alouattinae[tiab] OR
centrarchiformes[tiab] OR common whitethroat[tiab] OR common whitethroats[tiab] OR
gavialidae[tiab] OR grey gurnard[tiab] OR grey gurnards[tiab] OR lateolabracidae[tiab] OR
rheiformes[tiab] OR tubgurnard[tiab] OR tub gurnards[tiab] OR common chiffchaff[tiab] OR
common chiffchaffs[tiab] OR garfishes[tiab] OR lesser whitethroat[tiab] OR lesser
whitethroats[tiab] OR myoxidae[tiab] OR seabasses[tiab] OR spariformes[tiab] OR
umbridae[tiab] OR yellow boxfish[tiab] OR anabantiformes[tiab] OR aotidae[tiab] OR
common bleak[tiab] OR common bleaks[tiab] OR common rudd[tiab] OR common
rudds[tiab] OR greater pipefish[tiab] OR hapale[tiab] OR nandiniidae[tiab] OR stone
loaches[tiab] OR whinchat[tiab] OR whinchats[tiab] OR acanthuriformes[tiab] OR brotula
barbata[tiab] OR common ling[tiab] OR common lings[tiab] OR common roaches[tiab] OR
cottonrat[tiab] OR cottonrats[tiab] OR douroucoulis[tiab] OR dromaiidae[tiab] OR
fitches[tiab] OR fitchew[tiab] OR galaxiiformes[tiab] OR laprine[tiab] OR saimiriinae[tiab] OR
solenette[tiab] OR tarsii[tiab] OR tompot blenny[tiab] OR common dragonet[tiab] OR
common dragonets[tiab] OR longspined bullhead[tiab] OR longspined bullheads[tiab] OR
monotremate[tiab] OR monotremates[tiab] OR pempheriformes[tiab] OR perdicinae[tiab]
OR presbytini[tiab] OR smegmamorpha[tiab] OR bighead gobies[tiab] OR carangaria
incertae sedis[tiab] OR coiidae[tiab] OR fivebeard rockling[tiab] OR foulmart[tiab] OR
foumart[tiab] OR grasskeet[tiab] OR greater pipefishes[tiab] OR ibices[tiab] OR
millionfish[tiab] OR muguliformes[tiab] OR norwegian topknot[tiab] OR peewit[tiab] OR red
sea sailfin tang[tiab] OR rupicapras[tiab] OR sheatfishes[tiab] OR tompot blennies[tiab] OR
twait shad[tiab] OR yellow boxfishes[tiab]) NOT medline[sb])
5|3 AND 4
6|((systematic review[tiab] OR systematic reviews[tiab] OR meta-analyses[tiab] OR meta-
analysis[tiab] OR metaanalyses[tiab] OR metaanalysis[tiab] OR systematic literature
review[tiab] OR comprehensive literature review[tiab] OR Systematic survey[tiab] OR
systematic overview[tiab] OR "Syst Rev"[Journal] OR meta-analysis[pt] OR Systematically
review[tiab] OR Systematically searched[tiab] OR Systematic search[tiab] OR systematic-
literature-search*[tiab] OR Meta synthesis[tiab] OR PRISMA[tiab] OR ((electronic-
database*[tiab] OR databases-search*[tiab] OR electronic-search*[tiab] OR comprehensive-
search*[tiab] OR literature review[tiab] OR literature search[tiab] OR literature
searches[tiab] OR literature searching[tiab] OR data collection[tiab]) AND (Pubmed[tiab] OR
Medline[tiab] OR Embase[tiab] OR study-selection[tiab] OR selection-criteri*[tiab] OR Web
of Science[tiab] OR Google[tiab] OR Scopus[tiab] OR BIOSIS[tiab]))) NOT (letter[pt] OR
newspaper article[pt] OR comment[pt]))
7|5 AND 6

#### Ovid Embase search strategy

Index|Search terms
-----|--------------
1    |((ASD OR autis* OR neurodevelop* OR neurodevelop* delay*).ti,ab,kw.)
2    |((CHD8 OR SCN2A OR SYNGAP1 OR ADNP OR FOXP1 OR POGZ OR ARID1B OR SUV420H1 OR
DYRK1A OR SLC6A1 OR GRIN2B OR PTEN OR SHANK3 OR MED13L OR GIGYF1 OR CHD2 OR
ANKRD11 OR ANK2 OR ASH1L OR TLK2 OR DNMT3A OR DEAF1 OR CTNNB1 OR KDM6B OR
DSCAM OR SETD5 OR KCNQ3 OR SRPR OR KDM5B OR WAC OR SHANK2 OR NRXN1 OR
TBL1XR1 OR MYT1L OR BCL11A OR RORB OR RAI1 OR DYNC1H1 OR DPYSL2 OR AP2S1 OR
KMT2C OR PAX5 OR MKX OR GABRB3 OR SIN3A OR MBD5 OR MAP1A OR STXBP1 OR CELF4
OR PHF12 OR TBR1 OR PPP2R5D OR TM9SF4 OR PHF21A OR PRR12 OR SKI OR ASXL3 OR
SPAST OR SMARCC2 OR TRIP12 OR CREBBP OR TCF4 OR CACNA1E OR GNAI1 OR TCF20 OR
FOXP2 OR NSD1 OR TCF7L2 OR LDB1 OR EIF3G OR PHF2 OR KIAA0232 OR VEZF1 OR GFAP
OR IRF2BPL OR ZMYND8 OR SATB1 OR RFX3 OR SCN1A OR PPP5C OR TRIM23 OR TRAF7 OR
ELAVL3 OR GRIA2 OR LRRC4C OR CACNA2D3 OR NUP155 OR KMT2E OR NR3C2 OR NACC1
OR PTK7 OR PPP1R9B OR GABRB2 OR HDLBP OR TAOK1 OR UBR1 OR TEK OR KCNMA1 OR
CORO1A OR HECTD4 OR NCOA1 OR DIP2A).ti,ab,kw.)
3|1 OR 2
4|(exp animal experiment/ OR exp animal model/ OR exp experimental animal/ OR exp
transgenic animal/ OR exp male animal/ OR exp female animal/ OR exp juvenile animal/ OR
animal/ OR chordata/ OR vertebrate/ OR tetrapod/ OR exp fish/ OR amniote/ OR exp
amphibia/ OR mammal/ OR exp reptile/ OR exp sauropsid/ OR therian/ OR exp monotreme/
OR placental mammal/ OR exp marsupial/ OR Euarchontoglires/ OR exp Afrotheria/ OR exp
Boreoeutheria/ OR exp Laurasiatheria/ OR exp Xenarthra/ OR primate/ OR exp
Dermoptera/ OR expGlires/ OR exp Scandentia/ OR Haplorhini/ OR exp prosimian/ OR
simian/ OR exp tarsiiform/ OR Catarrhini/ OR exp Platyrrhini/ OR ape/ OR exp
Cercopithecidae/ OR hominid/ OR exp hylobatidae/ OR exp chimpanzee/ OR exp gorilla/ OR
exp orang utan/ OR exp cephalopod/) OR (rat OR rats OR animal OR animals OR mice OR "in
vivo" OR mouse OR rabbit OR rabbits OR murine OR pig OR pigs OR dog OR dogs OR bovine
OR fish OR vertebrate OR vertebrates OR cat OR cats OR rodent OR rodents OR mammal OR
mammals OR chicken OR chickens OR monkey OR monkeys OR sheep OR canine OR canines
OR porcine OR cattle OR bird OR birds OR hamster OR hamsters OR primate OR primates
OR cow OR cows OR chick OR horse OR horses OR avian OR avians OR calf OR swine OR
swines OR xenopus OR turkeys OR bear OR bears OR frog OR frogs OR zebrafish OR goat OR
goats OR equine OR calves OR poultry OR macaque OR macaques OR mole OR moles OR
ovine OR lamb OR lambs OR fishes OR diptera OR amphibian OR amphibians OR snake OR
snakes OR ruminant OR ruminants OR henOR hens OR piglet OR piglets OR feline OR felines
OR simian OR simians OR laevis OR trout OR trouts OR teleost OR teleosts OR salmon OR
salmons OR seal OR seals OR bull OR bulls OR ewe OR ewes OR hedgehog OR hedgehogs OR
macaca OR macacas OR proteus OR pigeon OR pigeons OR bat OR bats OR duck OR ducks
OR chimpanzee OR chimpanzees OR baboon OR baboons OR deer OR deers OR rana OR
ranas OR carp OR carps OR heifer OR swallow OR swallows OR lizard OR lizards OR canis OR
sow OR sows OR cynomolgus OR quail OR quails OR reptile OR reptiles OR turtle OR turtles
OR buffalo OR gerbil OR gerbils OR boar OR boars OR squirrel OR squirrels OR oncorhynchus
OR mus OR toad OR toads OR fowl OR fowls OR rerio OR danio OR ara OR aras OR musculus
OR tadpole OR tadpoles OR mulatta OR salmo OR ram OR eagle OR eagles OR ferret OR
ferrets OR goldfish OR catfish OR whale OR whales OR fox OR foxes OR ape OR apes OR
elephant OR elephants OR bos OR marmoset OR marmosets OR cod OR cods OR shark OR
sharks OR wolf OR eel OR eels OR auratus OR rattus OR zebra OR zebras OR tilapia OR
tilapias OR gilt OR camel OR camels OR squid OR gallus OR marsupial OR marsupials OR vole
OR voles OR fascicularis OR ovis OR salmonid OR salmonids OR tiger OR tigers OR dolphin
OR dolphins OR robin OR robins OR carpio OR opossum OR opossums OR cyprinus OR
salamander OR salamanders OR felis OR mink OR minks OR swan OR swans OR norvegicus
OR bufo OR torpedo OR bass OR lamprey OR lampreys OR sus OR python OR pythons OR
tetrapod OR tetrapods OR shrew OR shrews OR lionOR lions OR hog OR hogs OR songbird
OR songbirds OR oreochromis OR starling OR starlings OR caprine OR carassius OR owl OR
owls OR newt OR newts OR papio OR scrofa OR hare OR hares OR gorilla OR gorillas OR
flounder OR flounders OR goose OR herring OR herrings OR therian OR buffaloes OR canary
OR sparrow OR sparrows OR microtus OR octopus OR troglodytes OR tuna OR amphibia OR
chinchilla OR chinchillas OR ide OR oryzias OR cervus OR kangaroo OR kangaroos OR
armadillo OR armadillos OR callithrix OR "pan troglodytes" OR saimiri OR cichlid OR cichlids
OR donkey OR donkeys OR bream OR char OR chars OR finch OR raccoon OR raccoons OR
bothrops OR anguilla OR perch OR cricetus OR seabird OR seabirds OR buck OR bucks OR
naja OR coturnix OR salmonids OR geese OR minnow OR minnows OR raptor OR raptors OR
merione OR meriones OR rodentia OR elaphus OR amniote OR amniotes OR elasmobranch
OR emu OR emus OR peromyscus OR hominid OR hominids OR bubalus OR crotalus OR gull
OR gulls OR anas OR anura OR lemur OR lemurs OR crow OR crows OR camelus OR gibbon
OR gibbons OR waterfowl OR parrot OR parrots OR eels OR cob OR stickleback OR
sticklebacks OR columba OR mesocricetus OR ambystoma OR raven OR ravens OR gadus OR
penguin OR penguins OR orangutan OR orangutans OR sturgeon OR sturgeons OR cuniculus
OR aves OR virginianus OR cephalopod OR cephalopods OR cebus OR sparus OR tortoise OR
tortoises OR guttata OR morhua OR unguiculatus OR dogfish OR vulpes OR mallard OR
mallards OR apodemus OR alligator OR alligators OR oryctolagus OR llama OR llamas OR
reindeer OR mustela OR duckling OR ducklings OR wolves OR sander OR amazona OR zebu
OR badger OR badgers OR dove OR doves OR ictalurus OR capra OR capras OR equus OR
camelid OR camelids OR poecilia OR mule OR mules OR perciformes OR salvelinus OR labrax
OR cyprinidae OR ariidae OR crocodile OR crocodiles OR fundulus OR dicentrarchus OR
clarias OR cercopithecus OR chiroptera OR alpaca OR alpacas OR pike OR pikes OR
paralichthys OR puma OR pumas OR didelphis OR pisces OR macropus OR triturusOR bison
OR bisons OR epinephelus OR gasterosteus OR panthera OR acipenser OR mackerel OR
mackerels OR tamarin OR tamarins OR ostrich OR anolis OR vervet OR vervets OR wallaby
OR glareolus OR beaver OR beavers OR dromedary OR catus OR killifish OR pimephales OR
promelas OR aotus OR phoca OR panda OR pandas OR porpoise OR porpoises OR myotis OR
yak OR yaks OR agkistrodon OR vipera OR otter OR otters OR turbot OR turbots OR
squamate OR carnivora OR mullet OR mullets OR hawk OR hawks OR taeniopygia OR
seahorse OR seahorses OR "poecilia reticulata" OR falcon OR falcons OR prosimian OR
prosimians OR parus OR perca OR fingerling OR fingerlings OR antelope OR antelopes OR
tupaia OR passeriformes OR sepia OR saguinus OR coyote OR coyotes OR pongo OR
meleagris OR reptilia OR lepus OR psittacine OR hagfish OR warbler OR warblers OR "russell
s viper" OR "russell s vipers" OR smolt OR smolts OR budgerigar OR sardine OR sardines OR
cavia OR cavias OR hyla OR pleurodeles OR siluriformes OR "great tit" OR "great tits" OR
guppy OR bonobo OR bonobos OR rutilus OR trichosurus OR muridae OR phodopus OR
channa OR squalus OR lynx OR sturnus OR petromyzon OR vitulina OR monodelphis OR
cuttlefish OR adder OR adders OR lepomis OR canaria OR gambusia OR guppies
OR xiphophorus OR flatfish OR koala OR koalas OR labeo OR stingray OR stingrays OR
chelonia OR lampetra OR spermophilus OR crocodilian OR "passer domesticus" OR sciurus
OR artiodactyla OR ranidae OR corvus OR necturus OR platypus OR canaries OR bovid OR
lagopus OR trimeresurus OR gariepinus OR marten OR martens OR drosophilidae OR mugil
OR sunfish OR porcellus OR cypriniformes OR alouatta OR scophthalmus OR anser OR
electrophorus OR putorius OR iguana OR iguanas OR lama OR lamas OR takifugu OR circus
OR eptesicus OR flycatcher OR galago OR galagos OR trachemys OR lungfish OR
characiformes OR shorebird OR shorebirds OR giraffe OR giraffes OR micropterus OR
scyliorhinus OR cichlidae OR loligo OR porcupine OR porcupines OR chub OR chubs OR solea
OR pleuronectes OR hylidae OR viperidae OR echis OR sorex OR anchovy OR lagomorph OR
ostriches OR vulture OR vultures OR whitefish OR araneus OR jird OR jirds OR tern OR esox
OR drake OR drakes OR elapidae OR gallopavo OR chordata OR myodes OR caretta OR
serinus OR grouse OR misgurnus OR meles OR blackbird OR blackbirds OR coregonus OR
bobwhite OR bobwhites OR heteropneustes OR mammoth OR mammoths OR turdus OR
rhinella OR ateles OR characidae OR clupea OR bungarus OR brill OR "struthio camelus" OR
sloth OR sloths OR pteropus OR sculpin OR anthropoids OR pollock OR pollocks OR morone
OR "pan paniscus" OR litoria OR chipmunk OR chipmunks OR balaenoptera OR marmota OR
melopsittacus OR hyrax OR lemming OR lemmings OR halibut OR hylobates OR lates OR
caiman OR caimans OR sigmodon OR stenella OR barbel OR barbels OR sterna OR parakeet
OR parakeets OR phocoena OR leptodactylus OR canidae OR buteo OR harengus OR gopher
OR gophers OR marmot OR marmots OR gosling OR goslings OR platichthys OR gar OR gars
OR sebastes OR marsupialia OR notophthalmus OR gazelle OR gazelles OR insectivora OR
paridae OR felidae OR russula OR galliformes OR bombina OR colobus OR echidna OR
echidnas OR seabass OR syncerus OR plaice OR "blue tit" OR "blue tits" OR pagrus OR
catfishes OR cetacea OR barbus OR cygnus OR ficedula OR chamois OR colubridae OR
perches OR coelacanth OR fitch OR urodela OR cynops OR martes OR halichoerus OR aix OR
salmonidae OR leuciscus OR magpie OR magpies OR silurus OR whiting OR whitings OR
anseriformes OR colinus OR rhea OR chlorocebus OR octodon OR acinonyx OR mouflon OR
mouflons OR ibex OR tetraodon OR bufonidae OR equidae OR jackal OR cephalopoda OR
dendroaspis OR glama OR muskrat OR muskrats OR sable OR sables OR wildebeest OR
streptopelia OR albifrons OR vespertilionidae OR woodpecker OR woodpeckers OR muntjac
OR muntjacs OR archosaur OR branta OR cricetulus OR megalobrama OR poeciliidae OR
desmodus OR snakehead OR snakeheads OR tench OR teal OR teals OR bandicoot OR
bandicoots OR apteronotus OR phyllostomidae OR crocidura OR buzzard OR buzzards OR
larimichthys OR cercocebus OR pipistrellus OR erithacus OR impala OR impalas OR
rousettus OR haddock OR haddocks OR tinca OR ratite OR calidris OR cynoglossus OR
hypophthalmichthys OR bullock OR bullocks OR dromedaries OR alectoris OR filly OR
salamandra OR cingulata OR bitis OR grus OR ammodytes OR macaw OR macaws OR
hypoleuca OR sapajus OR cyprinodontiformes OR hippopotamus OR pelophylax OR
capybara OR capybaras OR weasel OR weasels OR cairina OR cynomys OR lutra OR cockatoo
OR cockatoos OR lachesis OR lagomorpha OR rupicapra OR daboia OR "orang utan" OR
"orang utans" OR platyrrhini OR charadriiformes OR micrurus OR psittaciformes OR spalax OR loris OR mustelidae OR sylvilagus OR vitticeps OR cockatiel OR mustelus OR cottus OR
erythrocebus OR dipodomys OR platessa OR callicebus OR loricariidae OR catostomus OR
cuneata OR cyanistes OR cyprinodon OR sigmodontinae OR elasmobranchii OR trichechus
OR sauropsid OR xenarthra OR dormouse OR perissodactyla OR nautilus OR cirrhinus OR
gulo OR gulos OR tragelaphus OR merula OR numida OR sciaenidae OR cerastes OR
sciuridae OR gibbosus OR octopuses OR eland OR elands OR phyllomedusa OR pogona OR
walrus OR agamidae OR leptodactylidae OR ridibundus OR leontopithecus OR anteater OR
anteaters OR pelodiscus OR cebidae OR columbianus OR "pelteobagrus fulvidraco" OR
hominoidea OR mandrillus OR "zonotrichia leucophrys" OR agama OR gobiocypris OR
"bearded dragon" OR "bearded dragons" OR sarotherodon OR talpa OR discoglossus OR
hagfishes OR sphenodon OR gudgeon OR amphiuma OR aythya OR tenrec OR tenrec OR
hominidae OR risoria OR salamandridae OR camelidae OR columbiformes OR latimeria OR
plover OR plovers OR afrotheria OR "falco sparverius" OR polecat OR polecats OR crotalinae
OR salvadora OR tarsier OR lucioperca OR anchovies OR lungfishes OR terrapin OR
"dromaius novaehollandiae" OR lateolabrax OR eigenmannia OR pelamis OR theropithecus
OR murinae OR gander OR gymnotus OR pseudacris OR gymnophiona OR gymnotiformes
OR laticauda OR falconiformes OR dugong OR dugongs OR pintail OR pintails OR rook OR
rooks OR lasiurus OR catshark OR catsharks OR micropogonias OR "red junglefowl" OR
paddlefish OR ophiophagus OR hollandicus OR nymphicus OR pimelodidae OR aepyceros OR
cobitidae OR strigiformes OR cobitis OR dormice OR alytes OR calloselasma OR guanaco OR
guanacos OR phasianidae OR "round goby" OR trichogaster OR catarrhini OR eelpout OR
eelpouts OR galaxias OR gaur OR pungitius OR suslik OR susliks OR flatfishes OR percidae OR
caprinae OR todarodes OR osmerus OR ameiurus OR anthropoidea OR"castor canadensis"
OR pouting OR poutings OR tetraodontiformes OR arvicolinae OR siamang OR siamangs OR
"castor fiber" OR nomascus OR "red knot" OR "red knots" OR syngnathidae OR iguanidae OR eretmochelys OR ursidae OR callimico OR columbidae OR microhylidae OR anaxyrus OR
menidia OR pipistrelle OR greylag OR pipidae OR scandentia OR bowfin OR bowfins OR
dendrobatidae OR zenaida OR bushbaby OR harrier OR harriers OR macropodidae OR
pygerythrus OR clupeidae OR odorrana OR corvidae OR jerboa OR jerboas OR canutus OR
hylobatidae OR clupeiformes OR "great cormorant" OR "great cormorants" OR
scorpaeniformes OR chondrostean OR garfish OR proboscidea OR psetta OR diapsid OR
serotinus OR tetrao OR walruses OR carcharhiniformes OR leucoraja OR pumpkinseed OR
dosidicus OR acipenseriformes OR daubentonii OR emberizidae OR gadiformes OR hyraxes
OR stizostedion OR wolverine OR wolverines OR lissotriton OR acanthurus OR centrarchidae
OR gloydius OR laurasiatheria OR limosa OR psittacula OR leporidae OR proteidae OR
zander OR zanders OR arapaima OR bagridae OR cyprinodontidae OR mithun OR pandion
OR jackdaw OR jackdaws OR procyonidae OR carus OR jaculus OR salmoniformes OR
"common sole" OR "common soles" OR protobothrops OR calamita OR brachyteles OR
trionyx OR turdidae ORboidae OR luscinia OR pugnax OR euarchontoglires OR saithe OR
saithes OR symphalangus OR aardvark OR aardvarks OR oystercatcher OR oystercatchers OR
arius OR corydoras OR poacher OR poachers OR aurochs OR cebuella OR crecca OR
lemuridae OR sirenia OR lemmus OR perdix OR glires OR lepidosaur OR muskox OR
deinagkistrodon OR pholidota OR holocephali OR cercopithecinae OR clariidae OR agapornis
OR doryteuthis OR tyrannidae OR dicroglossidae OR godwit OR godwits OR monedula OR
pongidae OR atheriniformes OR colobinae OR lophocebus OR atelidae OR cottidae OR
leucopsis OR acanthuridae OR didelphimorphia OR elver OR elvers OR lapponica OR
dermoptera OR "european hake" OR "european hakes" OR gerbillinae OR banteng OR
hartebeest OR hartebeests OR hogget OR haematopus OR "anguis fragilis" OR "grey heron"
OR "grey herons" OR "blue whiting" OR "blue whitings" OR furnariidae OR macrovipera OR
esocidae OR lapwing OR lapwings OR mylopharyngodon OR wallabia OR beloniformes OR
potoroo OR potoroos OR "athene noctua" OR pleuronectidae OR bushbabies OR
muscicapidae OR alligatoridae OR fuligula OR "bush baby" OR guineafowl OR spoonbill OR
spoonbills OR viverridae OR catostomidae OR zebrafishes OR ibexes OR vendace OR
estrildidae OR monotremata OR sepiella OR ambystomatidae OR shelduck OR shelducks OR
treeshrew OR treeshrews OR hoplobatrachus OR pochard OR hoolock OR hoolocks OR
lynxes OR antilope OR antilopes OR blackbuck OR blackbucks OR cricetinae OR
paramisgurnus OR skylark OR skylarks OR soleidae OR allobates OR "northern wheatear" OR
"northern wheatears" OR pitheciidae OR takin OR theria OR vanellus OR galaxiidae OR
lorisidae OR ostralegus OR palaeognathae OR "stone loach" OR alauda OR callitrichinae OR
caniformia OR duttaphrynus OR ictaluridae OR osteoglossiformes OR poultries OR curema
OR "ruddy turnstone" OR "ruddy turnstones" OR sheatfish OR sunfishes OR centropomidae
OR hemachatus OR platalea OR thamnophilidae OR "song thrush" OR atherinopsidae OR
siluridae OR tadorna OR chroicocephalus OR ermine OR ermines OR gavialis OR ruff OR
tupaiidae OR diprotodontia OR hyaenidae OR antilopinae OR crocodylidae OR herpestidae
OR hippopotamidae OR "northern shoveler" OR "round gobies" OR cheirogaleidae OR
indriidae OR fundulidae OR pythonidae OR rhynchocephalia OR anodorhynchus OR "red-
backed shrike" OR "red-backed shrikes" OR triakidae OR phalangeridae OR aoudad OR
boreoeutheria OR "eurasian jay" OR "eurasian jays" OR feliformia OR haplorhini OR
osteoglossidae OR paenungulata OR struthioniformes OR ferina OR sanderling OR
sanderlings OR spheniscidae OR cuttlefishes OR cygnet OR dasycneme OR gadwall OR
gadwalls OR "pelobates fuscus" OR wryneck OR wrynecks OR afrosoricida OR culaea OR
"dover sole" OR "dover soles" OR paralichthyidae OR passeridae OR osteolaemus OR "song thrushes" OR bluethroat OR bluethroats OR hydrophiidae OR megrim OR mephitidae OR
strepsirhini OR tomistoma OR epidalea OR osmeriformes OR "bush babies" OR tarsiiform
OR atelinae OR bufotes OR "eurasian coot" OR "eurasian coots" OR galagidae OR geopelia
OR philomachus OR tubulidentata OR bombinatoridae OR pelobatidae OR tachysurus OR
ailuridae OR woodlark OR woodlarks OR alcelaphinae OR redshank OR redshanks OR
salientia OR "sand smelt" OR "sand smelts" OR woodmice OR woodmouse OR
dasyproctidae OR "eurasian wigeon" OR "eurasianwigeons" OR garganey OR garganeys OR
"lemon sole" OR "lemon soles" OR "common dab" OR "common dabs" OR graylag OR
graylags OR leucorodia OR osphronemidae OR bewickii OR "common moorhen" OR
"common moorhens" OR decapodiformes OR gobbler OR gobblers OR odontophoridae OR
paddlefishes OR eutheria OR salmonine OR esociformes OR "eurasian woodcock" OR
"eurasian woodcocks" OR "european smelt" OR "european smelts" OR goldfishes OR
tenches OR tyranni OR "common chaffinch" OR "common chaffinchs" OR "common
redstart"OR "common redstarts" OR "common roach" OR "common roachs" OR "great knot" OR "great knots" OR potoroidae OR alytidae OR coregonine OR dipteral OR leveret OR
"poeciliopsis gracilis" OR amphiumidae OR batrachoidiformes OR "bighead goby" OR
heteropneustidaeOR lullula OR "norway pout" OR "norway pouts" OR sipunculida OR
dogfishes OR sebastidae OR tarsiidae OR alethinophidia OR "common nase" OR "common
nases" OR "common sandpiper" OR "common sandpipers" OR "eurasian blackcap" OR
"eurasian blackcaps" OR pterocnemia OR syngnathiformes OR "common chaffinches" OR
eupleridae OR octopodiformes OR phascolarctidae OR scophthalmidae OR "starry smooth-
hound" OR "starry smooth-hounds" OR whitefishes OR cuniculidae OR "european sprat" OR
"european sprats" OR "rosy bitterling" OR "rosy bitterlings" OR "common dace" OR
"common daces" OR "lesser weever" OR "lesser weevers" OR scaldfish OR "water rail" OR
"water rails" OR alouattinae OR centrarchiformes OR "common whitethroat" OR "common
whitethroats" OR gavialidae OR "grey gurnard" OR "grey gurnards" OR lateolabracidae OR
rheiformes OR "tub gurnard" OR "tub gurnards" OR "common chiffchaff" OR "common chiffchaffs" OR garfishes OR "lesser whitethroat" OR "lesser whitethroats" OR myoxidae OR
seabasses OR spariformes OR umbridae OR "yellow boxfish" OR anabantiformes OR aotidae
OR "common bleak" OR "common bleaks" OR "common rudd" OR "common rudds" OR
"greater pipefish" OR hapale OR nandiniidae OR "stone loaches" OR whinchat OR whinchats
OR acanthuriformes OR "brotula barbata" OR "common ling" OR "common lings" OR
"common roaches" OR cottonrat OR cottonrats OR douroucoulis OR dromaiidae OR fitches
OR fitchew OR galaxiiformes OR laprine OR saimiriinae OR solenette OR tarsii OR "tompot
blenny" OR "common dragonet" OR "common dragonets"OR "longspined bullhead" OR
"longspined bullheads" OR monotremate OR monotremates OR pempheriformes OR
perdicinae OR presbytini OR smegmamorpha OR "bighead gobies" OR "carangaria incertae
sedis" OR coiidae OR "fivebeard rockling" OR foulmart OR foumart ORgrasskeet OR "greater
pipefishes" OR ibices OR millionfish OR muguliformes OR "norwegian topknot" OR peewit
OR "red sea sailfin tang" OR rupicapras OR sheatfishes OR "tompot blennies" OR "twait shad" OR "yellow boxfishes").ti,ab,kw.
5|3 AND 4
6|(("systematic review" OR "meta-analysis" OR metaanalysis).ti. OR (((meta-analyses OR
meta-analysis OR metaanalyses OR metaanalysis OR "systematic overview").ti,ab,de. OR
"systematic reviews".jt. OR "meta analysis".jt. OR "Meta synthesis".ti,ab,de. OR
(Systematic* adj2 (Review OR literature OR Reviews OR survey OR search*)).ti,ab,de.) and
("Data collection" OR "Data extraction" OR "Inclusion Criteria" OR "Exclusion criteria" OR
Search* OR Literature OR Pubmed OR Medline OR Embase OR selection OR Web of Science
OR Google OR Scopus OR BIOSIS).ti,ab,de.))
7|5 AND 6


#### Web of Science search strategy

Index|Search terms
-----|---------------------
1    |(TS=(ASD OR autis* OR neurodevelop* OR neurodevelop* delay*))
2    |(TS=( CHD8 OR SCN2A OR SYNGAP1 OR ADNP OR FOXP1 OR POGZ OR ARID1B OR SUV420H1
OR DYRK1A OR SLC6A1 OR GRIN2B OR PTEN OR SHANK3 OR MED13L OR GIGYF1 OR CHD2
OR ANKRD11 OR ANK2 OR ASH1L OR TLK2 OR DNMT3A OR DEAF1 OR CTNNB1 OR KDM6B
OR DSCAM OR SETD5 OR KCNQ3 OR SRPR OR KDM5B OR WAC OR SHANK2 OR NRXN1 OR
TBL1XR1 OR MYT1L OR BCL11A OR RORB OR RAI1 OR DYNC1H1 OR DPYSL2 OR AP2S1 OR
KMT2C OR PAX5 OR MKX OR GABRB3 OR SIN3A OR MBD5 OR MAP1A OR STXBP1 OR CELF4
OR PHF12 OR TBR1 OR PPP2R5D OR TM9SF4 OR PHF21A OR PRR12 OR SKI OR ASXL3 OR
SPAST OR SMARCC2 OR TRIP12 OR CREBBP OR TCF4 OR CACNA1E OR GNAI1 OR TCF20 OR
FOXP2 OR NSD1 OR TCF7L2 OR LDB1 OR EIF3G OR PHF2 OR KIAA0232 OR VEZF1 OR GFAP
OR IRF2BPL OR ZMYND8 OR SATB1 OR RFX3 OR SCN1A OR PPP5C OR TRIM23 OR TRAF7 OR
ELAVL3 OR GRIA2 OR LRRC4C OR CACNA2D3 OR NUP155 OR KMT2E OR NR3C2 OR NACC1
OR PTK7 OR PPP1R9B OR GABRB2 OR HDLBP OR TAOK1 OR UBR1 OR TEK OR KCNMA1 OR
CORO1A OR HECTD4 OR NCOA1 OR DIP2A))
3    |1 OR 2
4    |TS=(rat OR rats OR animal OR animals OR mice OR "in vivo" OR mouse OR rabbit OR rabbits
OR murine OR pig OR pigs OR dog OR dogs OR bovine OR fish OR vertebrate OR
vertebrates OR cat OR cats OR rodent OR rodents OR mammal OR mammals OR
chicken OR chickens OR monkey OR monkeys OR sheep OR canine OR canines OR porcine
OR cattle OR bird OR birds OR hamster OR hamsters OR primate OR primates OR cow
OR cows OR chick OR horse OR horses OR avian OR avians OR calf OR swine OR
swines OR xenopus OR turkeys OR bear OR bears OR frog OR frogs OR zebrafish OR
goat OR goats OR equine OR calves OR poultry OR macaque OR macaques OR mole OR
moles OR ovine OR lamb OR lambs OR fishes OR diptera OR amphibian OR amphibians
OR snake OR snakes OR ruminant OR ruminants OR hen OR hens OR piglet OR
piglets OR feline OR felines OR simian OR simians OR laevis OR trout OR trouts OR
teleost OR teleosts OR salmon OR salmons OR seal OR seals OR bull OR bulls OR
ewe OR ewes OR hedgehog OR hedgehogs OR macaca OR macacas OR proteus OR
pigeon ORpigeons OR bat OR bats OR duck OR ducks OR chimpanzee OR chimpanzees OR
baboon OR baboons OR deer OR rana OR ranas OR carp OR carps OR heifer OR swallow OR
swallows OR lizard OR lizards OR canis OR sow OR sows OR cynomolgus OR quail OR quails
OR reptile OR reptiles OR turtle OR turtles OR buffalo OR gerbil OR gerbils OR boar OR boars
OR squirrel OR squirrels OR oncorhynchus OR mus OR toad OR toads OR fowl OR fowls OR
rerio OR danio OR ara OR aras OR musculus OR tadpole OR tadpoles OR mulatta OR
salmo OR ram OR eagle OR eagles OR ferret OR ferrets OR goldfish OR catfish OR
whale OR whales OR fox OR foxes OR ape OR apes OR elephant OR elephants OR bos OR
marmoset OR marmosets OR cod OR cods OR shark OR sharks OR wolf OR eel OR eels OR
auratus OR rattus OR zebra OR zebras OR tilapia OR tilapias OR gilt OR camel OR camels
OR squid OR gallus OR marsupial OR marsupials OR vole OR voles OR fascicularis OR
ovis OR salmonid OR salmonids OR tiger OR tigers OR dolphin OR dolphins OR robin OR
robins OR carpio OR opossumOR opossums OR cyprinus OR salamander OR
salamanders OR felis OR mink OR minks OR swan OR swans OR norvegicus OR bufo
OR torpedo OR bass OR lamprey OR lampreys OR sus OR python OR pythons OR tetrapod
OR tetrapods OR shrew OR shrews OR lion OR lions OR hogOR hogs OR songbird OR
songbirds OR oreochromis OR starling OR starlings OR caprine OR carassius OR owl OR owls
OR newt OR newts OR papio OR scrofa OR hare OR hares OR gorilla OR gorillas OR flounder
OR flounders OR goose OR herring OR herrings OR therianOR buffaloes OR canary OR
sparrow OR sparrows OR microtus OR octopus OR troglodytes OR tuna OR amphibia
OR chinchilla OR chinchillas OR ide OR oryzias OR cervus OR kangaroo OR kangaroos
OR armadillo OR armadillos OR callithrix OR "pan troglodytes" OR saimiri OR cichlid OR
cichlids OR donkey OR donkeys OR bream OR char OR chars OR finch OR raccoon OR
raccoons OR bothrops OR anguilla OR perch OR cricetus OR seabird OR seabirds OR buck OR
bucks OR naja OR coturnix OR salmonids OR geese OR minnow OR minnows ORraptor OR
raptors OR merione OR meriones OR rodentia OR elaphus OR amniote OR amniotes
OR elasmobranch OR emu OR emus OR peromyscus OR hominid OR hominids OR bubalus
OR crotalus OR gull OR gulls OR anas OR anura OR lemur OR lemurs OR crow OR crows
OR camelus OR gibbon OR gibbons OR waterfowl OR parrot OR parrots OR eels OR
cob OR stickleback OR sticklebacks OR columba OR mesocricetus OR ambystoma OR
raven OR ravens OR gadus OR penguin OR penguins OR orangutan OR orangutans OR
sturgeon OR sturgeons OR cuniculus OR aves OR virginianus OR cephalopod OR
cephalopods OR cebus OR sparus OR tortoise OR tortoises OR guttata OR morhua OR
unguiculatus OR dogfish OR vulpes OR mallard OR mallards OR apodemus OR alligator
OR alligators OR oryctolagus OR llama OR llamas OR reindeer OR mustela OR duckling
OR ducklings OR wolves OR sander OR amazona OR zebu OR badger OR badgers OR dove
OR doves OR ictalurus OR capra OR capras OR equus OR camelid OR camelids OR
poecilia OR mule OR mules OR perciformes OR salvelinus OR labrax OR cyprinidae OR
ariidae OR crocodile OR crocodiles OR fundulus OR dicentrarchus OR clarias OR
cercopithecus OR chiroptera OR alpaca OR alpacas OR pike OR pikes OR paralichthys OR
puma OR pumas OR didelphis OR pisces OR macropus OR triturus OR bison OR bisons OR
epinephelus OR gasterosteus OR panthera OR acipenser OR mackerel OR mackerels OR
tamarin OR tamarins OR ostrich OR anolis OR vervet OR vervets OR wallaby OR
glareolus OR beaver OR beavers OR dromedary OR catus OR killifish OR pimephales
OR promelas OR aotus OR phoca OR panda OR pandas OR porpoise OR porpoises OR
myotis OR yak OR yaks OR agkistrodon OR vipera OR otter OR otters OR turbot OR turbots
OR squamate OR carnivora OR mullet OR mullets OR hawk OR hawks OR taeniopygia OR
seahorse OR seahorses OR "poecilia reticulata" OR falcon OR falcons OR prosimian OR
prosimians OR parus OR perca OR fingerling OR fingerlings OR antelope OR antelopes
OR tupaia OR passeriformes OR sepia OR saguinus OR coyote OR coyotes OR pongo OR
meleagris OR reptilia OR lepus OR psittacine OR hagfish OR warbler OR warblers OR "russell
s viper" OR "russell s vipers" OR smolt OR smolts OR budgerigar OR sardine OR sardines OR
cavia OR cavias OR hyla OR pleurodeles OR siluriformes OR "great tit" OR "great tits" OR
guppy OR bonobo OR bonobos OR rutilus OR trichosurus OR muridae OR phodopus OR
channa OR squalus OR lynx OR sturnus OR petromyzon OR vitulina OR monodelphis OR
cuttlefish OR adder OR adders OR lepomis OR canaria OR gambusia OR guppies OR
xiphophorus OR flatfish OR koala ORkoalas OR labeo OR stingray OR stingrays OR
chelonia OR lampetra OR spermophilus OR crocodilian OR "passer domesticus" OR
sciurus OR artiodactyla OR ranidae OR corvus OR necturus OR platypus OR canaries
OR bovid OR lagopus OR trimeresurus OR gariepinus ORmarten OR martens OR
drosophilidae OR mugil OR sunfish OR porcellus OR cypriniformes OR alouatta OR
scophthalmus OR anser OR electrophorus OR putorius OR iguana OR iguanas OR lama OR
lamas OR takifugu OR circus OR eptesicus OR flycatcher OR galago OR galagos OR trachemys
OR lungfish OR characiformes OR shorebird OR shorebirds OR giraffe OR giraffes OR
micropterus OR scyliorhinus OR cichlidae OR loligo OR porcupine OR porcupines OR chub
OR chubs OR solea OR pleuronectes OR hylidae OR viperidae OR echis OR sorex OR anchovy
OR lagomorph OR ostriches OR vulture OR vultures OR whitefish OR araneus OR jird OR jirds
OR tern OR esox OR drake OR drakes OR elapidae OR gallopavo OR chordata OR myodes OR
caretta OR serinus OR grouse OR misgurnus OR meles OR blackbird OR blackbirds OR
coregonus OR bobwhite OR bobwhites OR heteropneustes OR
mammoth OR mammoths OR turdus OR rhinella OR ateles OR characidae OR clupea
OR bungarus OR brill OR "struthio camelus" OR sloth OR sloths OR pteropus OR sculpin
OR anthropoids OR pollock OR pollocks OR morone OR "pan paniscus" OR litoria OR
chipmunk OR chipmunks OR balaenoptera OR marmota OR melopsittacus OR hyrax OR
lemming OR lemmings OR halibut OR hylobates OR lates OR caiman OR caimans OR
sigmodon OR stenella OR barbel OR barbels ORsterna OR parakeet OR parakeets OR
phocoena OR leptodactylus OR canidae OR buteo OR harengus OR gopher OR
gophers OR marmot OR marmots OR gosling OR goslings OR platichthys OR gar OR gars OR
sebastes OR marsupialia OR notophthalmus OR gazelle OR gazelles OR insectivora OR
paridae OR felidae OR russula OR galliformes OR bombina OR colobus OR echidna OR
echidnas OR seabass OR syncerus OR plaice OR "blue tit" OR "blue tits" OR pagrus OR
catfishes OR cetacea OR barbus OR cygnus OR ficedula OR chamois OR colubridae OR
perches OR coelacanth OR fitch OR urodela OR cynops OR martes OR halichoerus OR aix OR
salmonidae OR leuciscus OR magpie OR magpies OR silurus OR whiting OR whitings OR
anseriformes OR colinus OR rhea OR chlorocebus OR octodon OR acinonyx OR mouflon OR
mouflons OR ibex OR tetraodon OR bufonidae OR equidae OR jackal OR cephalopoda OR
dendroaspis OR glama OR muskrat OR muskrats OR sable OR sables OR wildebeest OR
streptopelia OR albifrons OR vespertilionidae OR woodpecker OR woodpeckers OR muntjac
OR muntjacs OR archosaur OR branta OR cricetulus OR megalobrama OR poeciliidae OR
desmodus OR snakehead OR snakeheads OR tench OR teal OR teals OR bandicoot OR
bandicoots OR apteronotus OR phyllostomidae OR crocidura OR buzzard OR buzzards OR
larimichthys OR cercocebus OR pipistrellus OR erithacus OR impala OR impalas OR
rousettus OR haddock OR haddocks OR tinca OR ratite OR calidris OR cynoglossus OR
hypophthalmichthys OR bullock OR bullocks OR dromedaries OR alectoris OR filly OR
salamandra OR cingulata OR bitis OR grus OR ammodytes OR macaw OR macaws OR
hypoleuca OR sapajus OR cyprinodontiformes OR hippopotamus OR pelophylax OR
capybara OR capybaras OR weasel OR weasels OR cairina OR cynomys OR lutra OR
cockatoo OR cockatoos OR lachesis OR lagomorpha OR rupicapra OR daboia OR
"orang utan" OR "orang utans" OR platyrrhini OR charadriiformes OR micrurus OR
psittaciformes OR spalax OR loris OR mustelidae OR sylvilagus OR vitticeps OR
cockatiel OR mustelus OR cottus OR erythrocebus OR dipodomys OR platessa OR
callicebus OR loricariidae OR catostomus OR cuneata OR cyanistes OR cyprinodon OR
sigmodontinae OR elasmobranchii OR trichechus OR sauropsid OR xenarthra OR
dormouse OR perissodactyla OR nautilus OR cirrhinus OR gulo OR gulos OR tragelaphus OR
merula OR numidaOR sciaenidae OR cerastes OR sciuridae OR gibbosus OR
octopuses OR eland OR elands OR phyllomedusa OR pogona OR walrus OR
agamidae OR leptodactylidae OR ridibundus OR leontopithecus OR anteater OR
anteaters OR pelodiscus OR cebidae OR columbianus OR "pelteobagrus fulvidraco" OR
hominoidea OR mandrillus OR "zonotrichia leucophrys" OR agama OR gobiocypris OR
"bearded dragon" OR "bearded dragons" OR sarotherodon OR talpa OR discoglossus OR
hagfishes OR sphenodon OR gudgeon OR amphiuma OR aythya OR tenrec OR tenrec OR
hominidae OR risoria OR salamandridae OR camelidae OR columbiformes OR latimeria
OR plover OR plovers OR afrotheria OR "falco sparverius" OR polecat OR polecats OR
crotalinae OR salvadora OR tarsier OR lucioperca OR anchovies OR lungfishes OR
terrapin OR "dromaius novaehollandiae" OR lateolabrax OR eigenmannia OR pelamis
OR theropithecus OR murinae OR gander OR gymnotus OR pseudacris OR
gymnophiona OR gymnotiformes OR laticauda OR falconiformes OR dugong OR
dugongs OR pintail OR pintails OR rook ORrooks OR lasiurus OR catshark OR
catsharks OR micropogonias OR "red junglefowl" OR paddlefish OR eutheria OR
ophiophagus OR hollandicus OR nymphicus OR pimelodidae OR aepyceros OR
cobitidae OR strigiformes OR cobitis OR dormice OR alytes OR calloselasma OR
guanaco OR guanacos OR phasianidae OR "round goby" OR trichogaster OR catarrhini OR
eelpout OR eelpouts OR galaxias OR gaur OR pungitius OR suslik OR susliks OR flatfishes OR
percidae OR caprinae OR todarodes OR osmerus OR ameiurus OR anthropoidea OR "castor
canadensis" OR pouting OR poutings OR tetraodontiformes OR arvicolinae OR siamang OR
siamangs OR "castor fiber" OR nomascus OR "red knot" OR "red knots" OR syngnathidae OR iguanidae OR eretmochelys OR ursidae OR callimico OR columbidae OR
microhylidaeOR anaxyrus OR menidia OR pipistrelle OR greylag OR pipidae OR
scandentia OR bowfin OR bowfins OR dendrobatidae OR zenaida OR bushbaby OR
harrier OR harriers OR macropodidae OR pygerythrus OR clupeidae OR odorrana OR
corvidae OR jerboa OR jerboas OR canutus OR hylobatidae OR clupeiformes OR "great
cormorant" OR "great cormorants" OR scorpaeniformes OR chondrostean OR garfish OR
proboscidea OR psetta OR diapsid OR serotinus OR tetrao OR walruses OR
carcharhiniformes OR leucoraja OR pumpkinseed OR dosidicus OR acipenseriformes OR
daubentonii OR emberizidae OR gadiformes OR hyraxes OR stizostedion OR wolverine
OR wolverines OR lissotriton OR acanthurus OR centrarchidae OR gloydius OR
laurasiatheria OR limosa OR psittacula OR leporidae OR proteidae OR zander ORzanders OR
arapaima OR bagridae OR cyprinodontidae OR mithun OR pandion OR jackdaw OR jackdaws
OR procyonidae OR carus OR jaculus OR salmoniformes OR "common sole" OR "common
soles" OR protobothrops OR calamita OR brachyteles OR trionyx OR turdidae OR boidae OR
luscinia OR pugnax OR euarchontoglires OR saithe OR saithes OR symphalangus OR
aardvark OR aardvarks OR oystercatcher OR oystercatchers OR arius OR corydoras OR
poacher OR poachers OR aurochs OR cebuella OR crecca OR lemuridae OR sirenia OR
lemmus OR perdix OR glires OR lepidosaur OR muskox OR deinagkistrodon OR pholidota OR
holocephali OR cercopithecinae OR clariidae OR agapornis OR doryteuthis OR tyrannidae OR
dicroglossidae OR godwit OR godwits OR monedula OR pongidae OR atheriniformes OR
colobinae OR lophocebus OR atelidae OR cottidae OR leucopsis OR acanthuridae OR
didelphimorphia OR elver OR elvers OR lapponica OR dermoptera OR "european
hake" OR "european hakes" OR gerbillinae OR banteng OR hartebeest OR hartebeests OR
hogget OR haematopus OR "anguis fragilis" OR "grey heron" OR "grey herons" OR "blue whiting" OR "blue whitings" OR furnariidae OR macrovipera OR esocidae OR lapwing
OR lapwings OR mylopharyngodon OR wallabia OR beloniformes OR potoroo OR potoroos
OR "athene noctua" OR pleuronectidae OR bushbabies OR muscicapidae OR
alligatoridae OR fuligula OR "bush baby" OR guineafowl OR spoonbill OR spoonbills
OR viverridae OR catostomidae OR zebrafishes OR ibexes OR vendace OR estrildidae
OR monotremata OR sepiella OR ambystomatidae OR shelduck OR shelducks OR
treeshrew OR treeshrews OR hoplobatrachus OR pochard OR hoolock OR hoolocks OR
lynxes OR antilope OR antilopes OR blackbuck OR blackbucks OR cricetinae OR
paramisgurnus OR skylark OR skylarks OR soleidae OR allobates OR "northern wheatear" OR
"northern wheatears" OR pitheciidae OR takin OR theria OR vanellus OR galaxiidae OR
lorisidae OR ostralegus OR palaeognathae OR "stone loach" OR alauda OR callitrichinae OR
caniformia OR duttaphrynus OR ictaluridae OR osteoglossiformes OR poultries OR
curema OR "ruddy turnstone" OR
"ruddy turnstones" OR sheatfish OR sunfishes OR centropomidae OR hemachatus OR
platalea OR thamnophilidae OR "song thrush" OR atherinopsidae OR siluridae OR
tadorna OR chroicocephalus OR ermine OR ermines OR gavialis OR ruffe OR tupaiidae
OR diprotodontia OR hyaenidae OR antilopinae OR crocodylidae OR herpestidae OR
hippopotamidae OR "northern shoveler" OR "round gobies" OR cheirogaleidae OR
indriidae OR fundulidae OR pythonidae OR rhynchocephalia OR anodorhynchus OR "red-
backed shrike" OR "red-backed shrikes" OR triakidae OR phalangeridae OR aoudad OR
boreoeutheria OR "eurasian jay" OR "eurasian jays" OR feliformia OR haplorhini OR
osteoglossidae OR paenungulata OR struthioniformes OR ferina OR sanderling OR
sanderlings OR spheniscidae OR cuttlefishes OR cygnet OR dasycneme OR gadwall OR
gadwalls OR "pelobates fuscus" OR wryneck OR wrynecks OR afrosoricida OR culaea OR
"dover sole" OR "dover soles" OR paralichthyidae OR passeridae OR osteolaemus OR "song thrushes" OR bluethroat OR bluethroats OR hydrophiidae OR megrim OR
mephitidae OR strepsirhini OR tomistoma OR epidalea OR osmeriformes OR "bush babies"
OR tarsiiform OR atelinae OR bufotes OR "eurasian coot" OR "eurasian coots" OR
galagidae OR geopelia OR philomachus OR tubulidentata OR bombinatoridae OR
pelobatidae OR tachysurus OR ailuridae OR woodlark OR woodlarks OR alcelaphinae OR
redshank OR redshanks OR salientia OR "sand smelt" OR "sand smelts" OR woodmice OR
woodmouse OR dasyproctidae OR "eurasian wigeon" OR "eurasian wigeons" OR garganey
OR garganeys OR "lemon sole" OR "lemon soles" OR "common dab" OR "common dabs" OR
graylag OR graylags OR leucorodia OR osphronemidae OR bewickii OR "common moorhen"
OR "common moorhens" OR decapodiformes OR gobbler OR gobblers OR
odontophoridae OR paddlefishes OR salmonine OR esociformes OR "eurasian woodcock"
OR "eurasian woodcocks" OR "european smelt" OR "european smelts" OR goldfishes OR
tenches OR tyranni OR "common chaffinch" OR "common chaffinchs" OR "common
redstart" OR "common redstarts" OR "common roach" OR "common roachs" OR "great knot" OR "great knots" OR potoroidae OR alytidae OR coregonine OR dipteral OR leveret
OR "poeciliopsis gracilis" OR amphiumidae OR batrachoidiformes OR "bighead
goby" OR heteropneustidae OR lullula OR "norway pout" OR "norway pouts" OR
sipunculida OR dogfishes OR sebastidae OR tarsiidae OR alethinophidia OR "common
nase" OR "common nases" OR "common sandpiper" OR "common sandpipers" OR
"eurasian blackcap" OR "eurasian blackcaps" OR pterocnemia OR syngnathiformes OR
"common chaffinches" OR eupleridae OR octopodiformes OR phascolarctidae OR
scophthalmidae OR "starry smooth-hound" OR "starry smooth-hounds" OR whitefishes
OR cuniculidae OR "european sprat" OR "european sprats" OR "rosy bitterling" OR
"rosy bitterlings" OR "common dace" OR "common daces" OR "lesser weever" OR "lesser weevers" OR scaldfish OR "water rail" OR "water rails" OR alouattinae OR
centrarchiformes OR "common whitethroat" OR "common whitethroats" OR gavialidae
OR "grey gurnard" OR "greygurnards" OR lateolabracidae OR rheiformes OR "tub gurnard" OR "tub gurnards" OR "common chiffchaff" OR "common chiffchaffs" OR
garfishes OR "lesser whitethroat" OR "lesser whitethroats" OR myoxidae OR seabasses OR spariformes OR umbridae OR "yellow boxfish" OR anabantiformes OR aotidae OR
"common bleak" OR "common bleaks" OR "common rudd" OR "common rudds" OR
"greater pipefish" OR hapale OR nandiniidae OR "stone loaches" OR whinchat OR
whinchats OR acanthuriformes OR "brotula barbata" OR "common ling" OR "common lings" OR "common roaches" OR cottonrat OR cottonrats OR douroucoulis OR dromaiidae
OR fitches OR fitchew OR galaxiiformes OR laprine OR saimiriinae OR solenette OR tarsii
OR "tompot blenny" OR "common dragonet" OR "common dragonets" OR
"longspinedbullhead" OR "longspined bullheads" OR monotremate OR monotremates OR
pempheriformes OR perdicinae OR presbytini OR smegmamorpha OR "bighead gobies"
OR "carangaria incertae sedis" OR coiidae OR "fivebeard rockling" OR foulmart OR
foumart OR grasskeet OR "greater pipefishes" OR ibices OR millionfish OR
muguliformes OR "norwegian topknot" OR peewit OR "red sea sailfin tang" OR
rupicapras OR sheatfishes OR "tompot blennies" OR "twait shad" OR "yellow
boxfishes")
5    |3 AND 4
6    |(TS=(("literature search" OR "literature searches" OR "literature searching" OR "data collection" OR "electronic-database*" OR "databases-search*" OR "electronic-search*" OR
"comprehensive-search*" OR "literature search" OR "literature searches" OR "literature searching" OR "data collection") AND (Pubmed OR Medline OR Embase OR selection OR
Web of Science OR Google OR Scopus OR BIOSIS)))
7    |5 AND 6

## Appendix 2: Checklist to assess the state of reporting within preclinical systematic reviews 

This checklist is taken from Hunniford et al., 2021.

Section|Index|Item
-------|-----|------------------------------------------------
Title  |1    |Identify the report as systematic review in title
.      |2    |Identify that the report contains animal data in title (preclinical, in vivo or synonym)
Intro  |3    |Describe the human condition being modelled (e.g. describe what is already known)
.      |4    |Describe the biological rationale for testing the intervention (e.g. how would the intervention affect the condition)
.      |5    |Provide an explicit statement of the question(s) the review addresses (specify the main objectives of the review, ideally in PICO format)
Methods|6    |Indicate whether a review protocol was registered a priori
.      |a    |Where can the protocol be accessed and indicate the name of the protocol registry OR state that it is not available
.      |b    |Indicate any deviations from the protocol OR that there were no deviations
.      |7    |Eligibility criteria: Describe the animal species to be included in the review (e.g. only mice, vertebrates, large animals)
.      |8    |Eligibility criteria: Describe the animal model to be included in the review (methods of disease induction, age, sex, etc.)
.      |9    |Eligibility criteria: Describe the intervention/exposure of interest
.      |10   |Eligibility criteria: Describe the comparators and/or control population
.      |11   |Eligibility criteria: Describe the primary outcomes of interest (what is being measured/assessed in primary studies)
.      |12   |Eligibility criteria: Describe the timing (prevention vs rescue) of intervention, IF applicable
.      |13   |Indicate where a full search strategy of all data bases OR representative search strategy can be accessed
.      |14   |Describe inclusion limits (years conducted, language, AND publication type)
.      |15   |Describe the study screening/selection process a Report the platform used to screen and select studies (Excel, Access, DistillerSR, SyRF)
.      |16   |State the number of independent screeners
.      |17   |Describe methods for extracting numerical data from reports (e.g. data in bar graph, or non-text presentation), IF applicable * a Report the platform and tools used to extract numerical data (Graph2data, Engauge)
.      |18   |Report number of independent reviewers extracting data
.      |19   |Describe methods and tool used to measure study quality/risk of bias in individual studies (e.g. SYRCLE tool, CAMARADES tool)
.      |20   |Describe methods to assess construct validity in individual studies
.      |21   |Describe methods for assessing publication bias of included studies, IF applicable
.      |22   |Describe methods for synthesizing the quantitative effect measures of included studies (e.g. risk ratio, mean difference), IF applicable *
.      |23   |Describe methods for any data transformation needed to make extracted data suitable for analysis (e.g. only sample size range), IF applicable *
.      |24   |Describe methods for handling shared control groups (common issue in analysis of preclinical studies), IF applicable *
.      |25   |Describe methods for assessing heterogeneity between individual studies, IF applicable *
.      |26   |Describe methods for handling effect sizes over multiple time points (e.g. used all time points or latest time point), IF applicable *
.      |27   |Describe methods for sub-group and sensitivity analysis, IF applicable *
Results|28   |Report the number of included reports (individual references/publication) included in the review
.      |a    |Provides a list or table of individual studies with data or references
.      |29   |Report the number of eligible experiments included in the analysis (eligible animal experiments in individual reports)
.      |30   |Include a PRISMA flow diagram (or equivalent) of study selection process
31
Study characteristics: Report animal species
32
Study characteristics: Report animal model details (e.g. method of disease
induction, age, sex)
33
Study characteristics: Report a measure of the sample size (e.g. total number
or mean number of animals)
34
Study characteristics: Report intervention/exposure details (timing, dose)
35
Study characteristics: Report study design/intention (pharmakinetic,
mechanistic, efficacy)
36
Report the risk of bias of the primary studies (individual studies/across
outcomes)
37
Report the outcome effects of primary studies (forest plot if applicable), IF
applicable *
38
Report the confidence intervals of outcomes for the included studies, IF
applicable *
39
Report any measure of heterogeneity between studies, IF applicable *
40
Report the results of sub-group and sensitivity analysis, IF applicable *
41
Report the results of publication bias, OR report that it was not
possible/done
Discussion 42
Discuss the impact of the risk of bias of the primary studies
43
Discuss the limitations (i.e. limitation of primary studies and/or outcomes
included)
44
Discuss the limitations of the systematic review


Other

45

Include the funding source(s) of the systematic review
46
Report any data sharing, OR that there was no data sharing
* Reporting item is not applicable to systematic reviews that did not perform a quantitative
synthesis. For reviews that did not perform a quantitative synthesis, these items receive an NA.

 

27

## References

Bahor Z, Liao J, Currie G, et al. Development and uptake of an online systematic review platform: the
early years of the CAMARADES Systematic Review Facility (SyRF)BMJ Open Science 2021;5:e100103.

DOI: 10.1136/bmjos-2020-100103
de Vries RBM, Hooijmans CR, Langendam MW, van Luijk J, Leenaars M, Ritskes-Hoitinga M, Wever
KE. A protocol format for the preparation, registration and publication of systematic reviews of
animal intervention studies. Evidence-based Preclinical Medicine. 2015;2: 1-9 e00007. DOI:
10.1002/ebm2.7
de Vries RB, Wever KE, Avey MT, Stephens ML, Sena ES, Leenaars M. The usefulness of systematic
reviews of animal experiments for the design of preclinical and clinical studies. ILAR J. 2014; 55
(3):427–37. DOI: 10.1093/ilar/ilu043
Egger, Matthias, George Davey Smith, and Douglas Altman, eds. Systematic reviews in health care:
meta-analysis in context. John Wiley & Sons, 2008.

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