Implementation and effectiveness of non-specialist mediated interventions for children with Autism Spectrum Disorder: A systematic review and meta-analysis.

INTRODUCTION: In recent years, several non-specialist mediated interventions have been developed and tested to address problematic symptoms associated with autism. These can be implemented with a fraction of cost required for specialist delivered interventions. This review represents a robust evidence of clinical effectiveness of these interventions in improving the social, motor and communication deficits among children with autism.
METHODS: An electronic search was conducted in eight academic databases from their inception to 31st December 2018. A total of 31 randomized controlled trials were published post-2010 while only 2 were published prior to it. Outcomes pertaining to communication, social skills and caregiver-child relationship were meta-analyzed when reported in > 2 studies.
RESULTS: A significant improvement was noted in child distress (SMD = 0.55), communication (SMD = 0.23), expressive language (SMD = 0.47), joint engagement (SMD = 0.63), motor skills (SMD = 0.25), parental distress (SMD = 0.33) parental self-efficacy (SMD = 0.42) parent-child relationship (SMD = 0.67) repetitive behaviors (SMD = 0.33), self-regulation (SMD = 0.54), social skills (SMD = 0.53) symptom severity (SMD = 0.44) and visual reception (SMD = 0.29).
CONCLUSION: Non-specialist mediated interventions for autism spectrum disorder demonstrate effectiveness across a range of outcomes for children with autism and their caregivers.

Introduction

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by challenges in social communication and interaction and repetitive stereotypical behaviors, generally detectable in the first 2 years of life [1]. Although there are no definitive pharmacological treatments for the core deficits in ASD, several psychological interventions are used to address the communication and social skill deficits among children with the condition. Such interventions, if delivered in the early developmental period, can have long lasting positive impact on the lives of patients with ASD as well as their caregivers [1].

The Global Burden of Disease study was amongst the first to highlight the global prevalence of ASD, estimated at 52 million–a prevalence rate of 7.6 per 1000 –and disability adjusted life years estimated at 58 per 100,000 population [2,3]. The cost associated with interventions delivered by specialist mental health professionals is high, ranging from USD 40,000 to 80,000 per year, which is not feasible for low resource settings [4]. Therefore, the treatment gap associated with ASD is very high, especially in in low and middle countries (LMIC). For instance, a recent report from 14 African countries highlighted the lack of ASD services throughout Africa [5]. These statistics highlight the need for improved access to ASD services in LMIC as a priority from both public health as well as human rights perspectives.

To bridge these inequities in provision of treatment services for ASD, ‘task sharing’ strategies have been proposed to redistribute mental health services from specialists to non-specialist health workers [6]. In this context, there has been a recent focus on interventions that are delivered or mediated through non-specialists–parents, teachers, caregivers, and peers–that aim to improve developmental, educational, or behavioral outcomes among children with ASD. There are several advantages of non-specialist delivered interventions. For instance, parents, caregivers, and peers are part of the environment of children with ASD, thus providing ample opportunities for incidental therapeutic contacts that, if effective, can lead to a positive impact. The involvement of these stakeholders, including parents, teachers, caregivers, and peers, can be key to making these interventions acceptable and accessible for individuals with ASD [7].

A recent systematic review of single case studies highlighted several non-specialist mediated treatment programs such as the SENSE Theater, LEAP intervention, Pivotal response treatment (PRT), Social Stories TM, and video modelling [8]. These interventions focus mainly on improving behavioral patterns, deficits in vocabulary and expressive language and social communication among children with ASD. The costs associated with these treatments is significantly lower than that of specialist delivered interventions, for instance, one effective program, the play project home consultation program, cost 3500 to 4500 USD per year per child compared to 40,000 to 80,000 USD per year for treatments delivered by specialists [9].

While the aforementioned treatment programs differ in their content, all aimed to improve one or more core deficits of ASD. For instance, Social Stories TM are stories written in first person from the perspective of the target individual engaged in a particular social situation, and explaining the behavior expected in it [8]. Peer mediation trains children with autism and their peers to interact during social engagement, and hence, improve social skills, joint attention and engagement and communication [10]. SENSE Theater involves children with autism and their peers in theaters aiding in an understanding of socially expected behaviors. Video modelling involves videos depicting individuals demonstrating expected behavior to the children with autism [11]. And pivotal response treatment (PRT) trains children in pivotal behaviors required for daily functioning, such as social initiations and responsivity, self-efficacy, and motivation [12].

There is a paucity of comprehensive systematic reviews and meta-analysis of randomized controlled trials detailing content of different interventions, their effectiveness across different outcomes and quality of available evidence. Therefore, the present review was designed to, a) assess the effectiveness of non-specialist delivered or mediated interventions in ASD; b) systematically evaluate relevant implementation processes involved in these non-specialists delivered interventions for ASD, and c) and to rate the quality of evidence across different outcomes using the World Health Organization’s recommended Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (described below).

Methods

This review was conducted as per the updated PRISMA guidelines [13] (S1 File), and the protocol registered in PROSPERO (CRD42017066009).

Search process & selection criteria

An academic search was conducted in eight electronic databases including PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine, PsycINFO, Psycharticles, and CINAHL, from their inception to 31st December 2018, using following search terms (S2 File):

((“autism spectrum disorder” OR Asperger OR autis* OR “pervasive developmental disorder” OR "childhood disintegrative disorder”) AND (intervention OR treatment OR RCT OR trial) AND (parent-mediated OR parent-delivered OR "non-specialist mediated" OR "non-specialist delivered" OR teacher-mediated OR "teacher delivered" OR "aide delivered" OR "aide mediated" OR "peer delivered" OR "peer mediated")). No restrictions or database filters regarding language, time period or publication year were applied.

Three independent reviewers screened the aforementioned databases for eligible studies based on their titles and abstracts, followed by screening of full texts. All discrepancies among reviewers were resolved through discussion between reviewers and senior authors. All studies were assessed for eligibility against following criteria:

Individuals with a clinical diagnosis of ASD, screened for ASD using questionnaires or clinician diagnosis, Asperger's syndrome, and childhood disintegrative disorder were included.

Only studies assessing the efficacy through randomized controlled trials were included.

No restriction to age, gender, language, country, socioeconomic status or time period was applied.

Studies focusing on the parent, caregiver, peer, teacher or any other non-specialist mediated or delivered interventions were included.

Overlapping data sets reporting results from same study.

Studies which are not randomized controlled trials will be excluded.

Books, conference papers, theses, editorials, case reports, case series, reviews and articles without available full text will be excluded.

Specialist-delivered Interventions.

Non-original articles (reviews and analyses)

In Vitro studies and non-human trials.

Interventions conducted among adults with ASD were excluded.

Data extraction, risk of bias assessment & GRADE evidence

All data were extracted independently by three teams of reviewers using manualized data extraction forms and any disagreements among the reviewers, were resolved through discussion in conjunction with a senior author.

Data pertaining to participant characteristics, study setting, nature of intervention and outcomes will be extracted. For outcomes, an apriori decision was taken to include all types of psychometric testing whether conducted by specialists, teachers or parents. A variety of psychometric scales used for measurement of symptoms of autism are reported in the literature. We conducted a thorough audit of included studies to identify the psychometric scales used and categorized them under a unifying category. For instance, total symptom severity comprised of several scales such as Autism Diagnostic Observation Schedule; Autism Behaviour Checklist; Vineland Adaptive Behaviour Scale and Childhood Autism Rating Scale among others.

If there was a trial with more than one publication, preference was given to the primary publication. A US board certified child psychiatrist also devised a taxonomy form for active ingredients of interventions with detailed instructions regarding content, strategies and elements of interventions. Moreover, two authors assessed the quality of the studies without blinding to authorship or journal, using The Cochrane tool for randomized controlled trials, against several matrices: a) sequence generation, b) allocation concealment, c) blinding of participants and personnel, d) blinding of outcome assessment, e) incomplete outcome data, f) selective reporting and g) other bias” [14].

The meta-analytical evidence in present review was assessed for its quality using the recommendations outlined by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group [15]. These recommendations allow for rating of meta-analytical ranging from high to very low based on its study design, risk of bias, inconsistency, indirectness in targeted population and suitability of intervention, imprecision, publication bias and magnitude of effect size [15]. The evidence is judged across outcomes, where each concern in aforementioned matrices is rated as serious or very serious, stepping down the quality of evidence by one or two levels respectively [15].

Data analysis

Descriptive statistics pertaining to characteristics of the study and implementation processes including elements of interventions were explored using Microsoft Excel. Thereafter, using Comprehensive meta-analysis software, a series of meta-analyses were run for similar outcomes assessed post-intervention or primary time points [16]. Only those outcomes were introduced in the meta-analysis that were reported in ≥ 2 studies. Studies reporting similar outcomes were pooled together, weighted by employing inverse variance method, thus, estimating pooled effect sizes expressed as standardized mean differences with 95% confidence intervals (CI) [16]. Depending on the extent of heterogeneity, data were pooled together using either the fixed or random effects. Heterogeneity was considered significant at a cut off value ≥ 40%. However, we applied random effects analysis for all of the outcomes because of heterogeneity in assessment of outcomes across included studies [17]. Sensitivity analyses was conducted by excluding individual studies individually to ascertain their effects on the pooled effect size. When ≥ 5 studies reported an outcome, publication bias was assessed for asymmetry by visualizing the Begg’s funnel plot and Egger’s regression statistics (P ≤ 0.10) [18]. Pooled effect sizes were then adjusted for publication bias using Duvall & Tweedie’s Trim and Fill method [19]. To ensure an appropriate statistical power, when there were ≥4 studies reporting an outcome among different groups, subgroup analyses were conducted. Lastly, an outcome reported in ≥ 10 studies allowed meta-regression analyses to identify potential moderators of intervention effects among children with autism [20].

Results

Searching of academic databases yielded a total of 659 non-duplicate references to be screened based on their titles and abstracts. Out of these, 596 citations were excluded, retaining 63 full texts. Thereafter, 33 randomized controlled trials were deemed eligible after screening of these full texts against inclusion and exclusion criteria. Detailed results have been presented in PRISMA flowchart (Fig 1). S3 File presents effect sizes, means (SD) and subgroups for individual studies.

Fig 1

PRISMA flow diagram demonstrating study selection process.

Study characteristics

A total of 31 studies were published post-2010 while only 2 were published prior to it [21,22]. Only 2 studies was conducted in a low and middle income country [6] (Divan, 2018) while others were conducted in high income countries including USA (n = 21), Australia (n = 3), UK (n = 2), Canada (n = 2) and 1 each in Belgium, Norway, and Netherlands. Only two of the studies was a cluster randomized control trial while rest were individual RCTs [23] (Morgan et al, 2018). National Institutes of Health were the major funder of these trials (n = 11). A total of 24 studies were conducted in urban areas and 3 in both rural and urban areas (missing n = 3). Table 1 provides further details on these variables.

Table 1

Intervention characteristics.

Study	Country of study	age range of respondents	Study Design	Geographical scope	Setting of intervention
Cook et al, 2017 [27]	AUSTRALIA	4 years to 6 years	RCT	Urban	Griffith University Psychology Clinic
Corbett et al, 2016 [26]	USA	8 years to 14 years	RCT	Urban	School
Corbett et al, 2017 [36]	USA	8 years to 14 years	RCT	Urban,	Theater/ Home
Green et al, 2010 [35]	UK	2 years to 4 years and 11 months	RCT	Urban	premises of local primary care trusts
Ingersoll et al, 2016 [31]	USA	19 months and 3 months	RCT	Urban	Video conference/online
Kasari et al, 2015 [46]	USA	22 months—36 months	RCT	Urban	Community
Kasari et al, 2012 [34]	USA	6 years—11 years	RCt	Urban	School
Rahman et al, 2016 [6]	India & Pakistan	2–9 years	RCT	Urban	One-to-one clinic or home sessions between the health worker and the parent with the child present. All sessions in India were delivered in thehome, and all those in Pakistan in the clinic
Roeyers, 1996 [22]	Belgium	5 and 13 years old.	RCT	NA	Playing sessions took place in a playroom at the school or institution
Schertz, 2013 [30]	U.S.A.	under 30 months	RCT	Rural and urban	Homes
Shire, 2016 [39]	U.S.A.	36 months	RCT	Urban	Community
Siller et al, 2014 [37]	U.S.A.	2–6 years	RCT	Urban	Community
Silva et al, 2011 [25]	U.S.A.	3–6 years	RCT	Urban	Community
Silva et al, 2015 [24]	U.S.A.	2–5 years	RCT	urban	Community
Solomon et al, 2014 [9]	USA	2 yr 8 mo–5 yr 11 mo	RCT	Not Mentioned
Strain et al, 2011 [23]	USA	preschoolers with asd	Cluster RCT	Urban, SEMI URBAN AND RURAL ALL THREE	schools
Venker et al, 2012 [32]	USA	41 MONTHS	RCT	Not Mentioned	Community
Kamps et al, 2015 [41]	USA	kindergarten age group (3 yrs)	RCT	URBAN	School
Thompson et al, 2014 [28]	Australia	3 to 6 years	RCT	Urban	Home
Grahame et al, 2015 [42]	ENGLAND, UK	3 to 7 years	RCT	Urban	Community
Carter et al, 2011 [33]	USA	20.25 months	RCT	Urban	Community clinics
Kaale et al, 2012 [51]	NORWAY	24 to 60 months	RCT	Urban	School
Jocelyn et al, 1998 [21]	CANADA	24 to, 72 months	RCT	Urban	Community
Poslawsky et al, 2015 [29]	NETHERLANDS	childrens' age:16 to 61 months; parents age : 25 to 52 years	RCT	urban	hospital and home
Brian et al, 2017 [47]	Canada	16–30 months	RCT	Urban	Home
Divan et al, 2019 [48]	India	27–105 months	RCT	Rural	Home
Ibanez et al, 2018 [49]	USA	N/A	RCT	Urban	Home
Kuravackel et al, 2017 [50]	USA	3 to 12 years old	RCT	Rural and urban	University, regional health center, clinic
Matthews et al, 2018 [51]	USA	13 to 17 years old	RCT	Urban	Community-based non-profit autism center
Morgan et al, 2018 [52]	USA	Mean age = 6.79 years	cRCT	Urban	School
Parsons et al, 2018 [53]	Australia	2 to 6 years old	RCT	Rural	Home
Vernon et al, 2018; Ko et al, 2018 [54,55]	USA	12 to 17 years	RCT	Urban	School

Intervention characteristics

Most of the interventions took place in the community (n = 9) and educational settings, (n = 10) followed by home (n = 7), healthcare setting (n = 2), videoconferencing (n = 1), and the rest in mixed settings (n = 3). The majority of the interventions (n = 14) had employed the Autism Diagnostic Observation Schedule (ADOS) for screening of children with autism. Other scales such as Childhood Autism Rating Scale (CARS), Modified Checklist for Autism in Toddlers (M-CHAT) and Autism Behavior Checklist (ABC), Checklist for Autism Spectrum Disorder (CASD) were also employed (Fig 2 and Fig 3).

Fig 2

Summary effect sizes for symptom severity.

Fig 3

Summary effect sizes for communication skills.

The children were assessed for inclusion by a variety of professionals including research personnel (n = 13), psychologists/therapists (n = 5), multidisciplinary child and adolescent mental health (CAMH) team (n = 4), teachers (n = 1), certified intervention providers (n = 2); the information was unavailable for 5 studies. Delivery agents of interventions included parents (n = 17), peers (n = 4), and school staff (n = 3). These delivery agents were trained by trained certified interventionists (n = 6), researchers (n = 6), therapists (n = 5), speech pathologists (n = 1), trained graduates and doctoral students (n = 6), massage trainer (n = 1), local specialist health workers (n = 2), multidisciplinary counselors (n = 3), music therapists (n = 1), and this information was missing for two studies. Competency evaluation was performed in 3 studies [24,25]. Fidelity was not rated in 7 of the studies [21,22,26-29]. None of the trials reported provision of any certification or remuneration to the delivery agents except one study [30]. Supervision of delivery agents was done onsite (n = 23), onsite and online (n = 2), onsite and videotaped (n = 3), while this information was not available for one study [31]. A majority of the trials (n = 21) were standalone interventions while rest of them were integrated with school curriculum (n = 1), existing services (n = 3) or speech, language and occupational therapy (n = 1) [22,28,32]. Psychopharmacological treatment was included in one trial [6]. These variables are reported in greater detail in Table 2.

Table 2

Strategies employed in interventions.

Author, year	No. of sessions	Duration (minutes)	Program duration (weeks)	Delivery agent	Training provider	Name of intervention	Theoretical orientation of intervention	Strategies employed
Cook et al, 2017 [27]	9	90	13	Parent	Therapists	CBT	Behavioral	PsychoeducationPreventive Strategies related to environmental and parenting.Development of an exposure hierarchy and graded exposure.Affective education.Emotion regulation skills training.
Corbett et al, 2016 [26]	10	240	10	Peer	Researchers	Social Emotional NeuroScience Endocrinology (SENSE) Theater	Sensory stimulation and creative techniques including theater	Observing, interpreting, and articulating thoughts and feelings;Theatrical techniques such as improvisation, role-playing, scripted interaction, video modeling, and performing; behavioral techniques to address
Corbett et al, 2017 [36]	10	240	8	Peer	NR	Social Emotional NeuroScience Endocrinology (SENSE) Theater	Same as above
Green et al, 2010 [35]	12	120	24	Parent	Speech and language pathologist	Preschool Autism Communication Trial (PACT)	Pragmatic language	Establishing shared attentionSynchronicity and sensitivityFocusing on language inputEstablishing routines and anticipationIncreasing communication
Ingersoll et al, 2016 [31]	48	105	24	Parents/Therapists assisted	Masters' level therapists	ImPACT Online website	Communication/Pragmatic language	Social engagementLanguage developmentSocial imitationPlay
Kasari et al, 2015 [46]	20	60	10	Caregivers/parents.	Trained interventionist	JASPER	Behavioral, pragmatic language	Joint attentionSymbolic playSocial engagementEmotional and behavioral Regulation
Kasari et al, 2012 [34]	12	10	6	Peer	Education psychologists graduates	Peer-mediated (PEER) intervention	Pragmatic language	Social interactionPositive peer modelling
Rahman et al, 2016 [6]	12	60	24	Parent	Local specialist, health worker	PASS (Same as PACT)	Pragmatic language	Establishing shared attentionSynchronicity and sensitivityFocusing on language inputEstablishing routines and anticipationIncreasing communication
Roeyers, 1996 [22]	15	23.33	NR	Peer	NR	Peer mediated intervention	Pragmatic language	Focusing on faces Social reciprocity Initiating Joint attention Responding to joint attention
Schertz, 2013 [30]	16	40	16	Parents	Intervention coordinators	Joint Attention Mediated Learning	Communication/ Pragmatic language	Joint attention/engagement
Shire, 2016 [39]	10	60	10	Parent	Trained clinician	JASPER	Communication/ Pragmatic language	Joint attention/engagement
Siller et al, 2014 [37]	12	90	12	Parent	Trained graduates and post-doctoral students	QST Home Program	Communication/ Pragmatic language	PsychoeducationResponsive parental communication/ Maternal synchronizationResponse to joint attentionCommunicationPlayEliciting imitationEliciting eye contact.
Silva et al, 2011 [25]	7	15	7	Parent	Massage trainer	Qigong massage treatment	Sensory stimulation	Qigong massage
Silva et al, 2015 [24]	20	15	20	Parent	Therapists	Qigong massage treatment	Sensory stimulation	Qigong massage
Solomon et al, 2014 [9]	12	180	48	Parent	Multidisciplinary team	PLAY Project Home Consultation Intervention Program	Communication, behavioral, Pragmatic language	Self regulationSocial EngagementCommunicationShared Meanings and Symbolic PlayEmotional Thinking
Strain et al, 2011 [23]	834	180	182.5	Teacher	Trained staff	LEAP (Learning Experiences and Alternative Program for Preschoolers and Their Parents)	Creative, Pragmatic language, behavioral	Organization and planningCommunication skillsSocial interactionsPositive behavioral guidanceInteractions with children and families
Venker et al, 2012 [32]	21	75	10	Parents	Graduate Students	More Than Words: The Hanen Program for Parents of Children with Autism Spectrum Disorder	Communication/ Pragmatic language	Non-verbal and verbal communication, prompts
Kamps et al, 2015 [41]	97	27.5	24	school staff members	researchers trained school staff members	Peer Networks Intervention Procedures	Communication	Social interactionCommunication
Thompson et al, 2014 [28]	16	35	16	Parents	Music therapists	Family-centred music therapy (FCMT)	Creative (music), Pragmatic language	Social engagement, shared attention, joint attention
Grahame et al, 2015 [42]	8	120	8	Parents	Early Year Professionals	The Managing Repetitive Behaviours Programme (MRBÓ)	Behavioral	Psychoeducation, behavioral
Carter et al, 2011 [33]	NR	NR	NR	Parents	Researchers	Hanen’s ‘More Than Words’	Pragmatic language	Social Interaction
Kaale et al, 2012 [51]	80	20	8	Teachers	Counselors with a degree in special education, psychology or social sciences	Modified JASPER intervention: Preverbal pragmatic languageIntroduction and responsiveness Nonverbal comm.	Pragmatic language	Joint attention/social engagement
Jocelyn et al, 1998 [21]	10	180	12	Parent and child care worker	Autism behavioral specialist, child development counselor, community family services workers	Autism Preschool Program	Behavioral	Behavioral
Poslawsky et al, 2015 [29]	5	75	12	Parents	Researchers	Video-feedback Intervention to promote Positive Parenting adapted to Autism (VIPP-AUTI)	Pragmatic language, behavioral	Mastery motivation and child playParent-child interaction Joint attentionRecognition of children’s affect and emotions
Brian et al., 2017 [47]	13	90	12	Parents	Researchers, clinicians	Social ABCs	Communication, behavioral	The ABCs of learning, enhancing Communication, sharing positive emotion, motivation and arousal, play and the Social ABCs, daily care‐giving activities, managing behavioral challenges, and taking care of yourself
Divan et., 2018 [48]	12	17.5	24	Parents	Researchers	Parent mediated intervention for Autism Spectrum Disorder Plus” (PASS Plus)	Pragmatic language, behavioral, sensory stimulation	Increased parental synchronous responses, increased understanding of child’s verbal and non-verbal responses as part of PASS. Plus module involved psycho-education and assessment of the most disruptive comorbidity for the family. It included strategies for sensory seeking and sensory defensive behaviors. The behavioral challenges focused on identifying reasons for hyperactivity, self-harming, and aggression. Additional strategies targeted sleep problems, bed wetting issues, toileting difficulties, restricted diet, pica, and inflexible routines. Parental well-being was also addressed.
Ibanez et al., 2018 [49]	-	-	18	Parents	Not mentioned	Enhancing Interactions Tutorial	Communication, behavioral	This tutorial educated parents about definition of home routine, their importance, and tips for starting and ending home routines. It also enhanced awareness about challenges for children with ASD and increase their engagement in routine by assessing current level of participation. The parents were taught about using choice boards, first-ten boards, visual schedules, timers, prompting, reinforcement, imitation, and language understanding.
Ko et al., 2018 [55]	20	90	20	Peers	Therapists	Social Tools And Rules for Teens socialization (START) intervention	Communication	Unstructured socialization with peers and facilitators, social immersion, self-management of skills, role play, active discussion and practice, structured games, and developing social goals for next week.
Kuravackel et al., 2018 [50]	8	90	8	Parents	Therapists	COMPASS for Hope (C-Hope)	Pragmatic language, communication	Psychoeducation to parents, assessment of problematic issues, education on principles of behaviors and learning, teaching positive behavioral approaches, importance of environmental support, preparation and review of individual behavioral plan for children.
Matthews et al., 2018 [51]	14	90	14	Peers	Certified PEER providers	PEERS curriculum	Communication	Initiation of peer interactions, behavioral rehearsals, and modeling of appropriate social skills by facilitators.
Morgan et al., 2018 [52]	32	1500 (weekly)	32	Teachers	Certified coaches	Communication, Emotional Regulation, and Transactional Support (SCERTS) Intervention	Communication, behavioral	Assessment of individual’s language stage and selection of goals and objectives. The targeted activities were planned to address these goals through direct teaching as needed, guided practice with feedback, teacher practice and reflection with feedback, and teacher independence.
Parsons et al., 2018 [53]	90	20	12	Parents	Researchers	Therapeutic Outcome By You (TOBY) application	Communication, pragmatic language, and sensory	Selection of activities based on a curriculum tree and uses principles of Applied Behavioral Analysis (ABA) for skill attainment by identifying problems and techniques to change environment.
Vernon et al., 2018 [54]	20	90	20	Parents	Therapists	Social Tools And Rules for Teens socialization (START) intervention	Communication	Unstructured socialization with peers and facilitators, social immersion, self-management of skills, role play, active discussion and practice, structured games, and developing social goals for next week.

Density of dosage

The mean number of sessions was 53.29 (SD = 158.07), ranging from 5 [29] to 834 [23] sessions, while this information was not reported by two studies [33]. Duration of each session was averaged at 130.63 minutes (SD = 281.47) and ranged from 10 minutes (daily) to 1500 minutes per week [26,27], and was not reported by two studies[33]. Mean duration for program was 22.62 weeks (SD = 33.34), lasting a minimum of 6 weeks [34] and maximum of 182.50 weeks [23]. Booster sessions were conducted in a total of six trials [26,27,29,35] (Brian and Matthews). These variables are reported in greater detail in Table 2.

Strategies & elements of interventions

The content of the included interventions differed in their theoretical orientation: Cooka et al (2017) employed cognitive behavioral strategies (CBT) [27]; Social Emotional NeuroScience Endocrinology (SENSE) theater (sensory stimulation and creative techniques including theater) [26,36]; family mediated Preschool Autism Communication Trial (PACT) and Parent-mediated intervention for Autism Spectrum Disorders in South Asia (PASS) program (pragmatic language development) [6,35]; Project Impact (Communication/Pragmatic language) [31]; Peer interventions (Communication/pragmatic language intervention)[31,34]; Qigong Sensory Treatment (QST) home program (Communication/pragmatic language development) [37]; Qigong massage (sensory stimulation) [24,25]; Joint Attention, Symbolic Play, Engagement, and Regulation programme (JASPER) (behavioral/pragmatic language & communication)[38-40]; Play project (behavioural, pragmatic language and communication)[9]; LEAP project i.e. Learning Experiences and Alternative Program for Preschoolers and Their Parents (behavioral, creative, pragmatic language training) [23]; Hanen’s “more than words” intervention program (behavioral, pragmatic language) [32,33]; Peer network intervention procedure (communication) [41]; family centered music therapy (Creative and pragmatic language training)[28]; The Managing Repetitive Behaviours Programme (Behavioural and psychoducational) [42]; psychoeducation program autism preschool program (behavioural & psychoeducation) [21] and the Video-feedback Intervention to promote Positive Parenting (behavioural & pragmatic language intervention) adapted for Autism by Poslawsky et al [29]; Social ABCs (communication, behavioral); PASS plus (pragmatic language, behavioral and sensory stimulation); enhancing interactions tutorial (communication, behavioral); Social Tools And Rules for Teens socialization (START) intervention (communication); COMPASS for Hope (communication); PEERS curriculum (communication); Therapeutic Out-come By You (TOBY) application (communication, pragmatic language and sensory stimulation). These variables are reported in Table 2.

Cook et al., (2017) was the sole RCT reporting the effectiveness of CBT based intervention programs among the children with autism [27]. It focused on psychoeducation, assessment, recognition and understanding of affect and cognitive schema, CBT based coping and relaxation exercises. Corbet et al., (2015, 2016) used SENSE theater technique targeting social skills [26,36]. Green et al (2010) and Rahman et al (2016) employed speech and language therapists in parent-mediated intervention to in elicit an improvement in communication skills among children [6,35]. Ingersoll et al, (2016), in her Project ImPACT used interactive and direct techniques to increase the ability of the child to engage and socially and improve their language skills respectively [31]. Kasari et al (2012), Roeyers (1996) and Kamps et al (2015) tested peer delivered intervention to improve social support, engagement, social interaction, play and conflict resolution skills among children with autism. JASPER model was tested for effectiveness in three studies [38-40]. Thompson et al., focused on family centered music therapy to improve initiation and responsive joint attention among children with autism [20]. Jocelyn (1998) et al delivered psychoeducation [21] and Poslawsky et al (2015) employed video recording of play situations and a mealtime to promote Positive Parenting adapted to autism [29]. Venker et al (2012) and Carter et al (2011) in their Hanen’s “more than words” intervention employed child-oriented interaction promoting and language modelling strategies among children with autism [32, 33]. Grahame et al (2015) improved repetitive behaviors using techniques such as psychoeducation, reinforcement, planning and distraction [42]. Silva et al (2011 and 2015) tested the efficacy of Qigong massage treatment [24, 25], Siller et al (2014) employed QST home program to improve responsive parental behaviors [37]. Several other programs such as Joint Attention Mediated Learning (JAML) by Scher, 2013, encouraging opportunities for social interactions [30]. Strain & Edward (2011) tested a LEAP program (Learning Experiences and Alternative Program for Preschoolers and Their Parents) using a naturalistic approach to learning of social interaction [23]. Solomon et al’s (2014) trained children in shared attention, self-regulation, engagement, initiating simple and complex communication using Coaching, modeling, video-feedback [9].

Outcomes

The included trials revealed a number of outcomes including adaptive behaviors (6 trials, n = 286), child anxiety (2 trials, n = 42), child distress (2 trials, n = 76), communication and language (15 trials, n = 896), joint attention (7 trials, n = 464), joint engagement (4 trials, n = 261), motor skills (5 trials, n = 304), parental distress (7 trials, n = 441), parental self-efficacy (4 trials, n = 166), parent child relationship (6 trials, n = 372), repetitive behaviors (2 trials, n = 195), self-regulation (3 trials, n = 175), social skills (10 trials, n = 545), symptom severity (7 trials, n = 398), visual reception (3 trials, n = 198). A variety of psychometric instruments were utilized in the included studies, posing methodological heterogeneity in measurement of outcomes. The most commonly employed psychometric scales included Vineland Adaptive Behavior Scale, Mullen Scales for Early Learning, Autism Diagnostic Observation Schedule, Social Communication Questionnaire and Autism Behavior Checklist. For the purpose of meta-analysis, we combined effect sizes on all types of outcomes reported by teachers, parents or experts.

A significant improvement was noted in child distress (SMD = 0.55, 95% CI = 0.25 to 0.85, I2 = 0%; Chi2 = 1.76); communication (SMD = 0.23, 95% CI = 0.03 to 0.42 I2 = 37.96%; Chi2 = 17.73); expressive language (SMD = 0.47, 95% CI = 0.22 to 0.72 I2 = 53.59%; Chi2 = 8.62); joint engagement (SMD = 0.63, 95% CI = 0.21 to 1.06 I2 = 75.88%; Chi2 = 24.87); motor skills (SMD = 0.25 95% CI = 0.02 to 0.48 I2 = 0%; Chi2 = 4.18); parental distress (SMD = 0.33, 95% CI = 0.09 to 0.57 I2 = 52.01%; Chi2 = 18.75); parental self-efficacy (SMD = 0.42, 95% CI = 0.23 to 0.62 I2 = 0%; Chi2 = 4.64); parent-child relationship (SMD = 0.67, 95% CI 0.23 to 1.10 I2 = 76.0%; Chi2 = 20.83); repetitive behaviors (SMD = 0.33, 95% CI = 0.05 to 0.62 I2 = 0%; Chi2 = 0.17); self-regulation (SMD = 0.54, 95% CI = 0.06 to 1.03 I2 = 55.91%; Chi2 = 4.36); social skills (SMD = 0.53, 95% CI = 0.34 to 0.73 I2 = 48.59%; Chi2 = 31.12); symptom severity (SMD = 0.44, 95% CI = 0.27 to 0.60 I2 = 0%; Chi2 = 5.42) and visual reception (SMD = 0.29, 95% CI = 0.01 to 0.57 I2 = 0%; Chi2 = 1.22), while no significant improvement was noted in adaptive behaviors (SMD = 0.26, 95% CI = -0.001 to 0.52, I2 = 41.44%; Chi2 = 10.25); receptive language (SMD = 0.16, 95% CI = -0.24 to 0.55 I2 = 53.34%; Chi2 = 7.38); and joint attention (SMD = 0.16, CI = -0.22 to 0.54, I2 = 76.13%; Chi2 = 29.32). Forest plots are presented (Fig 2, Fig 3, Fig 4, Fig 5, Fig 6) and complete dataset has been provided as S3 File.

Fig 4

Summary effect sizes for social skills.

Fig 5

Summary effect sizes for motor skills.

Fig 6

Summary effect sizes for parental outcomes.

Sensitivity analyses revealed that removal of specific trials led to significant effect sizes pertaining to adaptive living (Silva, 2015 and Rahman, 2016), motor skills (Grahame et al; Solomon et al) and visual reception (Parsons et al).

Moderator analyses

Initially, meta-regression analysis was run inclusive for all outcomes. It did not reveal any significant effects of age, year of publication or duration of program and session or number of sessions or quality of trials on the significance of these interventions. Meta-regression plots have been presented as S4 File. Subgroup analyses was run when specific outcomes reported in ≥ four studies. It did not reveal any significant differences among interventions delivered by different agents on outcomes of symptom severity and joint attention. While significant subgroup differences were observed in reporting of joint engagement with parent mediated interventions reporting highest effect sizes (Table 3).

Table 3

Subgroup analysis based on type of delivery agent.

Outcome	Delivery agent	Number of studies	Effect size (95% CI)	I2	Tau2	Q statistic	p
Social skills	Parent	10	0.42 (0.17 to 0.67)	61.36%	0.13	13.42	0.34
	Peers	6	0.75 (0.39 to 1.11)	0%	0
	Teachers	2	0.50 (0.03 to 0.98)	39.17%	0.04
Communication	Parent	10	0.12 (-0.04 to 0.29)	0%	0	6.38	0.04
	Peers	1	0.86 (0.08 o 1.63)	0%	0
	Teachers	2	0.46 (0.16 to 0.75)	72.92%	0.15
Expressive language	Parent	5	0.45 (0.03 to 0.88)	57.66%	0.13	0.08	0.78
	Peers	0	-	-
	Teachers	1	0.32 (-0.52 to 1.15)	0%	0
Receptive language	Parent		0.12 (-0.19 to 0.43)			0	1.0
	Peers	0
	Teachers	0
Motor skills	Parents	5	0.17 (-0.08 to 0.41)	0%	0	2.72	0.10
	Teachers	1	0.69 (0.12 to 1.26)	0%	0
Joint engagement	Parents	2	1.01 (0.61 to 1.41)	66.46%	0.13	8.40	0.02
	Peers	1	-0.002 (-0.65 to 0.65)	0%	0
	Teachers	1	0.18 (-0.61 to 0.96)	0%	0
Joint initiation	Parents	7	0.19 (-0.25 to 0.63)	79.22%	0.27	0.09	0.76
	Peers	0	-	-
	Teachers	1	0 (-0.14 to 1.14)	0%	0
Symptom severity	Parents	9	0.44 (0.26 to 0.61)	0%	0	0.003	0.96
	Peers	1	0.42 (-0.14 to 0.98)	0%	0
	Teachers	0	-	-
Child distress	Parents	3	0.57 (0.20 to 0.94)	0	0	0.04	0.85
	Peers	1	0.51 (0.004 to 1.02)	0	0
	Teachers	0	-	0	-
Adaptive behavior	Parents	5	0.17 (-0.17 to 0.51)	43.85%	0.07	1.56	0.46
	Peers	1	0.77 (-0.13 to 1.67)	0%	0
	Teachers	1	0.34 (-0.25 to 0.90)	0%	0
Self-regulation	Parents	3	0.54 (0.06 to 1.03)
	Peers	-
	Teachers	-
Repetitive behaviours	Parents	3	0.36 (0.12 to 0.60)
	Peers	-
	Teachers	-
Visual reception	Parents	3	0.11 (-0.17 to 0.39)	0%	0	1.90	0.17
	Peers	0	-
	Teachers	1	0.55 (-0.01 to 1.12)	0%	0
Parental distress	Parents	10	0.33 (0.09 to 0.57)
	Peers	0
	Teachers	0
Parental self-efficacy	Parents	8	0.38 (0.18 to 0.58)	0%	0	1.90	0.17
	Peers	1	0.89 (0.19 to 1.59)	0%	0
	Teachers	0	-	0%	0
Parent-child relationship	Parents	6	0.67 (0.23 to 1.10)
	Peers	0	-
	Teachers	0	-

Quality rating & strength of evidence

Significant publication bias was revealed in reporting of social skills and symptom severity outcomes (Eggers statistics, P < 0.1). However, adjusted effect sizes for Social skills SMD = 0.42 (0.30 to 0.55) and symptom severity 0.38 (0.22 to 0.54) remained statistically significant (S4 File).

Cochrane’s tool for risk of bias assessment among the included trials revealed an overall low risk of bias among majority of the studies. Random sequence generation was at a high/unclear risk of bias among 8 trials, allocation concealment (n = 13). Frequency of studies reporting a high risk across other domains of Cochrane risk of bias tool were: Blinding of outcome assessors (n = 14), other sources of bias (n = 9), attrition bias (n = 8), selective reporting (n = 4) and blinding of participants and personnel (n = 0). A total of 11 studies were rated as having as having a high risk of overall bias i.e. ≥ 3 matrices of risk of bias tool were rated as having unclear or high risk of bias for these studies [22,23,26,27,32,41] (Fig 7 and S4 File). Fig 7 presents a clustered bar chart exhibiting frequencies of high, unclear and low risk bias across all matrices of Cochrane risk of bias tool. S4 File presents study wise risk of bias across all matrices of Cochrane risk of bias tool.

Fig 7

Risk of bias summary.

According to the GRADE criteria, evidence for four outcomes was rated as: High for communication skills, expressive language, motor skills, repetitive behaviors, and parental distress. The evidence was moderate for adaptive behaviors, severity of symptoms, receptive language, social skills, and improvement in parent child relationship. It was found to be low for joint engagement, self-efficacy and competence, and very low for joint attention (Table 4).

Table 4

GRADE table for outcomes included in the systematic review.

Certainty assessment							№ of patients		Effect		Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	[intervention]	[comparison]	Relative(95% CI)	Absolute(95% CI)
Adaptive behaviors
7	randomised trials	not serious	not serious	not serious	Serious a	none	268	215	-	SMD 0.26 SD higher(-0.001 lower to 0.52 higher)	⨁⨁⨁◯MODERATE	CRITICAL
Severity of symptoms
10	randomised trials	not serious	not serious	not serious	not serious	publication bias strongly suspected c	322	295	-	SMD 0.44 SD higher(0.27 higher to 0.60 higher)	⨁⨁⨁◯MODERATE	CRITICAL
Social skills
18	randomised trials	not serious	not serious	not serious	not serious	publication bias strongly suspected c	493	465	-	SMD 0.52 SD higher(0.34 higher to 0.71 higher)	⨁⨁⨁◯MODERATE	CRITICAL
Communication skills
13	randomised trials	not serious	not serious	not serious	not serious	none	503	447	-	SMD 0.23 SD higher(0.06 higher to 0.40 higher)	⨁⨁⨁⨁HIGH	CRITICAL
Expressive language
6	randomised trials	Not serious	not serious	not serious	not serious	none	147	146	-	SMD 0.42 SD higher(0.09 higher to 0.75 higher)	⨁⨁⨁⨁HIGH	CRITICAL
Receptive language
5	randomised trials	Not serious	Not serious	Not serious	Serious a	none	151	163		SMD 0.12 SD higher(-0.19 lower to 0.43 higher)	⨁⨁⨁◯MODERATE	CRITICAL
Motor skills
6	randomised trials	not serious	not serious	not serious	not serious	none	178	174	-	SMD 0.21 SD higher(-0.006 higher to 0.42 higher)	⨁⨁⨁⨁HIGH	CRITICAL
Joint attention
8	randomised trials	not serious	serious b	not serious	very serious a	none	255	243	-	SMD 0.16 SD higher(0.22 lower to 0.54 higher)	⨁◯◯◯VERY LOW	CRITICAL
Joint engagement
7	randomised trials	not serious	very serious b	not serious	not serious	none	217	217	-	SMD 0.64 SD higher(0.21 higher to 1.06 higher)	⨁⨁◯◯LOW	CRITICAL
Repetitive behaviors
3	randomised trials	not serious	not serious	not serious	not serious	none	130	127	-	SMD 0.36 SD higher(0.11 higher to 0.60 higher)	⨁⨁⨁⨁HIGH	CRITICAL
Self-regulation
3	randomised trials	not serious	serious b	not serious	serious a	none	96	79	-	SMD 0.544 SD higher(0.06 higher to 1.028 higher)	⨁⨁◯◯LOW	CRITICAL
Parental distress
10	randomised trials	not serious	not serious	not serious	not serious	none	334	306	-	SMD 0.33 SD higher(0.09 higher to 0.57 higher)	⨁⨁⨁⨁HIGH	IMPORTANT
Parent-child relationship
6	randomised trials	not serious	serious b	not serious	not serious	none	199	183	-	SMD 0.67 SD higher(0.23 higher to 1.1 higher)	⨁⨁⨁◯MODERATE	IMPORTANT

CI: Confidence interval; SMD: Standardised mean difference

Explanations

a. Wide confidence intervals

b. Substantial heterogeneity partly explained by differences in content and delivery of interventions.

c. Visualization of funnel plot revealed significant publication bias

Discussion

Summary of results

We identified 33 studies comparing the effects of non-specialist mediated interventions with control groups among children with autism spectrum disorder. The meta-analyses demonstrated the effectiveness of non-specialist mediated interventions across several outcomes pertaining to social skills, motor and communication among children with autism. These were also associated with an improvement in parent-child relationship and parenting stress. The risk of bias among the studies assessed was generally low, albeit the overall strength of evidence varied across outcomes. This means that further research may change the effect estimates for a few of the outcomes reported in this review.

All of the interventions reviewed had varying density of dosage, but meta-regression analyses did not generally reveal any significant effects on the effectiveness of interventions. An outlier intervention program was the LEAP intervention program, run for 2 years spanning 834 sessions of naturalistic and incidental teaching among children with autism [23]. This intervention reported the highest effect sizes, hence, we opine that sustained and long term interventions might achieve long sustaining results.

A total of three outcomes including joint engagement, parent child relationship and joint attention exhibited substantial heterogeneity (I2>70%). Rest of the outcomes presented no to moderate heterogeneity. We opine that this may be because of two main reasons. For the outcome of joint engagement, this substantial heterogeneity is due to differences in intervention content as well as different delivery agents as shown in subgroup analysis (Table 3). The outcomes of parent child relationship and joint attention were only reported in parent mediated interventions. The heterogeneity in these outcomes may be accounted for by use of different rating scale or methods of measurement. The studies reporting these outcomes used varying methods for measurement of both the joint attention and parent child relationship.

Recommendation for task shifting

Autism spectrum disorder is a major global health concern accounting for a large disease burden, health loss, disability adjusted life years (DALYs) and high specialist treatment costs. Moreover, the scarce availability of psychiatrists and psychologists in low- and middle-income countries further aggravate this public health issue. The WHO report on global mental health infrastructure, estimated the number of psychiatrists at less than one and 7.7 mental health nurses for 100,000 people in countries inhabited by 45% of the world’s population [2,43]. In 2009, there was only one registered occupational therapist in Pakistan, highlighting the bleak situation in poorly resourced countries [44].

The proven effectiveness of non-specialized autism care in present review is thus, of particular relevance to low resourced settings, where access to specialist mental health interventionists specializing in autism treatment is poor [45]. However, only one good quality randomized controlled trial conducted jointly in India & Pakistan limits the evidence for clinical and cost-effectiveness of these interventions in the region [6]. One of these studies was an adapted version of the PACT trial developed in Manchester [35] and was tested in a multi-site study conducted in Rawalpindi, Pakistan and Goa, India [6]. While, the second study revised this intervention and added a “plus” module pertaining to psychoeducation and assessment of the most disruptive comorbidity for the family [31]. Therefore, more research is required to ascertain the suitability of these interventions in the context of low- and middle-income countries. Moreover, there are no frameworks for recruitment, role descriptions and financial compensation for non-specialists, which creates a barrier in scale up and sustainability of these interventions [5, 6]. Based on the findings of this systematic review, we cannot recommend one non-specialist mediated therapy for autism. PACT, PASS and PASS plus; JASPER, SENSE and Hanen’s more than words were tested in at least two studies and settings. Therefore, we recommend that future investigators, implementors and policy makers consult these therapy programs for development of interventions suitable for their settings.

Strengths and limitations

This study has several strengths. Firstly, the inclusion of randomized controlled studies ensured the internal validity of results. Previously, review studies had reported evidence for single cases, non-randomized controlled trials, specialist interventions or homogenous interventions based on specific strategies only [7,8,46-51]. Lastly, our study was inclusive of children of all ages, confirmed diagnoses of autism spectrum disorder, psychosocial functioning, languages and time period, thereby, improving the generalizability of the results to this study population. Lastly, the subgroup analysis based on intervention mediators led to meaningful subgroup analyses.

Despite of its strengths, there are several limitations of this review and therefore, these results should be interpreted with caution. For instance, none of the studies had reported standardized outcomes pertaining to the IQ and psychological functioning of the study sample. Meta-regression analysis accounting for IQ of the children is a necessary analysis for studying moderating effects on the intervention effects. The interventions differed in their content and strategies, study settings, and intervention mediators, leading to substantial methodological heterogeneity in the meta-analyses. Several diagnostic methods such as ADOS and different updates of DSM criteria for diagnoses of autism were employed in included RCTs, further adding heterogeneity in the results. Psychological interventions limit the blinding status of participants and personnel as well as outcome assessors that is a serious limitation. The present systematic review was based on searching of a limited number of databases, we encourage investigators to search more databases in future studies. Moreover, investigators should also consider using a more comprehensive search strategy encompassing different terms for RCT. Combining results from diverse measures applied for heterogeneous study samples is another limitation of this systematic review.

Implications for practice and future research

The present review provides an overall good quality evidence of effectiveness of non-specialist mediated interventions among the children with autism. Most of the studies were mediated by parents and caregivers and presented low risk of bias. However, the evidence for peer and teacher mediated interventions was poor due to a limited number of studies. The sample size was low among individual studies and only a few interventions were tested in long term follow-up studies. The economic feasibility and cost-effectiveness were not reported in most of the interventions; an important metric for evaluating their suitability for task shifting and scaling up. The standardized instruments differed in studies, adding to the methodological heterogeneity among studies. Future studies should be designed keeping these limitations in context, emphasizing the introduction of standardized and cross-culturally validated instruments for assessment of symptomatology.

Recommendations

Despite of the aforementioned limitations, a small to moderate improvements in several debilitating symptoms of autism were noticed. These interventions also reduced care-giver stress and improved parent-child relationship. Based on the clinical effectiveness and good quality of evidence for these interventions, we recommend up-scaling of these interventions in high income countries. However, more research is required to ascertain the suitability of these interventions in context of low- and middle-income countries. Based on the findings of this systematic review, we cannot recommend one non-specialist mediated therapy for autism. PACT, PASS and PASS plus; JASPER, SENSE and Hanen’s more than words were tested in at least two studies and settings.

PRISMA checklist.

(DOC)

Click here for additional data file.

Search strategy.

Search strategy for all databases utilized in this study.

(XLSX)

Click here for additional data file.

Dataset for meta-analysis.

Data set used for meta-analysis in CMA format.

(CMA)

Click here for additional data file.

Supplementary figures in the manuscript.

This file has following figures: a) Meta-regression analysis for quality of studies b) Meta-regression analysis for duration of intervention program c) Meta-regression analysis for number of sessions of intervention program d) Funnel plot for social skills e) Funnel plot for severity of symptoms f) Risk of bias for all studies.

(DOCX)

Click here for additional data file.

28 Aug 2019

PONE-D-19-19450

Implementation and effectiveness of non-specialist mediated interventions for children with Autism

Spectrum Disorder: A systematic review and meta-analysis

PLOS ONE

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Reviewer #1: This is an important and interesting paper, but there are numerous grammatical errors, and word omissions. Given the sophistication of your approach and the immense effort involved, it is curious that you chose to use the number of participants as a weighting scheme. Why did you not choose inverse variance or the Hedges & Olkin or Hunter & Schmidt estimators of optimal weights?

When you say that, "Heterogeneity was considered significant at a cut off value of GE 40%," does that mean that you used a fixed-effect approach for those under 40% and random-effects for those greater than or equal to 40%? This should be clarified in the manuscript.

I suspect that a random-effects approach throughout the analysis would yield more realistic estimates of effect size given the differences across studies in measurement instruments, procedures, treatments, and participants.

Reviewer #2: Thank you for the opportunity to review this interesting manuscript. Its subject is an important topic and it makes a helpful contribution to the literature. Although well-written in many parts, it would benefit from a careful edit of the English in places to maximise comprehensibility, and I highlight some issues below which should be clarified before it can be accepted for publication.

ABSTRACT

The final sentence of the Introduction section seems to be more of a conclusion.

It is unclear what 'academic search' means. Specific databases should usually be mentioned in the abstract. On which date was the search completed? Were only randomised controlled trials included? Were self-report and objective assessments of outcomes combined?

The English of this section could be tweaked to enhance its clarity.

INTRODUCTION

This section is clear and well-written.

METHODS

A specific search date would be helpful. The abstract states 'through 2018' but the methods say 'through January 2019'. Outside North America, the term 'through' may not be widely understood in this sense.

This is a relatively truncated set of databases to search. Is there a reason, given the authors' interest in LMICs, that other databases such as Global Health or Embase were not included?

The search terms to specify RCTs are quite limited, not including the word 'randomised'. Can the authors be sure that this strategy did not miss eligible studies? The fact that only 659 non-duplicate results were obtained from the search does suggest that this search strategy was extremely narrow.

The title specifies interventions for children but the Inclusion criteria state that no age restrictions were applied, suggesting that studies of adults were included.

What is meant by 'unreliably extracted' data?

Does 'overlapped data sets' mean papers reporting the same study? This could be clearer.

Data analysis: how similar were outcomes required to be in order to be meta-analysed? Were self-report, parent-report, teacher-reported etc. measures combined?

RESULTS

Please define CAMH.

Density of dosage: is (158.07) intended to indicate the standard deviation? This should be stated.

Did two studies genuinely report sessions lasting 1500 minutes, i.e. 25 hours? Can this really have been continuous? Might such an intervention have caused harm?

Please define (if applicable) the meanings of PACT, PASS, QST, JASPER, HANEN, COMPASS, PEERS acronyms.

It is distracting that the referencing style changes from numerical to naming authors halfway through the results.

Under outcomes, please clarify if self-report and reports by heterogeneous others were combined.

It is confusing that "a significant improvement was noted in child distress (SMD=0.23...)" and also "no significant improvement was noted in child distress (SMD=0.158...)" - is this an error?

p11: "allocation concelment (13), selective reporting (4)..." - what do these numbers mean? Also high/unclear risk of bias?

The terms "risk of bias" and quality are conflated in this paragraph which is confusing.

DISCUSSION

Did every included study use TAU as the comparator?

Please define DALYs

Some mention of the ethical and sustainability issues around non-specialists not seeming to have been paid would enhance the discussion

The authors only briefly mention that two included studies came from LMICs and that one was of good quality. A little more detail on both studies would be of interest, given the focus on task sharing for LMICs.

The statement "This would essentially reduce the treatment gap for children with autism, and ensure mental health for all across the globe" does not clearly refer to something in the previous sentence (the "this" of this sentence) and it is debatable that reducing the treatment gap for children with autism would indeed ensure MH for all across the globe.

IQ may be expected to moderate treatment effects but would it mediate them?

The authors state that cost-effectiveness was not reported in most studies but then conclude that "based on the... cost-effectiveness... we recommend up-scaling of these interventions".

Were some interventions more effective than others? Would the authors advocate up-scaling any models in particular?

FIGURES

The forest plots are very cramped and would benefit from larger sizing and greater separation. Does Total mean N? A column for N/n (intervention vs control sample size) would help.

Acronyms in the forest plot impede understanding, e.g. 'PLS' - using simple language here would help.

It might help to order the forest plots in order of strongest to weakest effect size.

The forest plot pages are divided into primary outcomes and secondary outcomes (although the latter is not labelled) but these distinctions are not clearly drawn in the manuscript. Doing so would be helpful, for clarification and to align the figures with the text.

The risk of bias figure requires a heading and its meaning is not clear. Do percentages refer to the percentage of included papers graded as low, unclear or high risk? It would be more informative to show a table of the included studies and their individual gradings in each column.

Reviewer #3: Dear authors,

I appreciate your manuscript and I do not have any substantial comments on it.

Best regards

The reviewer

Reviewer #4: The manuscript in my opinion is technically sound.

I am not very competent in statistics to comment on the accuracy. A statistical expert may comment.

All data is available for review.

The English is standard and intelligible. The language used is simple for the reader’s understanding. The flow of the text is also fine in my opinion.

Additionally, the topic chosen is relevant as it highlights the difference between the highly technical and the basic non pharmacological interventions in ASD in the backdrop of the cost differences between the two. The study being a meta analysis involving 33 studies is a strength. The limitations are also highlighted giving the reader an idea of possible biases.

Reviewer #5: This meta-analysis has not been registered online. Please add this point in the limitation.

Literature Searches and Search terms are incomplete. This is suboptimal for publication for systematic review. Search terms in each database are different. Please attach search terms that were used in each database as supplement for Data source and search strategies in the manuscript. Please provide details search terms in supplementary documents. Please attach syntax used in each database as supplementary.

Please also include timeline of the literature search in the method section of the abstract.

It will be better to show kappa for the selection and data extraction. Please show the data of kappa of agreement during the systematic searches. How disagreements were solved during the systematic search among independent reviewers?

There is still a considerable heterogeneity as in your limitation. Meta-regression analysis is then strongly recommended.

There is substantive heterogeneity in some outcomes. It also is unclear whether the t-statistic is being used for the degrees of freedom in the random effects analysis (i.e., N-1 d.f. not asymptotic [1.96] value multiplied by tau). Please assure that the t-statistic (or Satterthwaite correction) is being used and add that information to the Methods, when the number of studies is small (e.g., < 10). Apply this principle throughout the author's paper. For reference, the authors can refer the article “IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Medical Research Methodology 2014;14:25.” The issue is the Student t statistic.

Authors should discuss the reason of heterogeneity.

Please make the data for this review publicly available, possibly through the Open Science Framework (osf.io). Items to include: list of excluded studies, commands forstatistical analysis, spreadsheets or data used for the meta-analyses, etc. Making data publicly available will promote the reproducibility of the review and is best practices for systematic reviews and meta-analyses.

Some revision of the English language is needed. There are some parts of the paper where it is quite difficult to make sense of some sentences. English edit will help to improve the quality of the manuscript.

**********

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Reviewer #1: No

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13 Sep 2019

Dear Professor Cheungpasitporn,

We are very grateful to you and the reviewers for such an excellent feedback. This has substantially improved the quality of the manuscript. We have revised our manuscript in line with your suggestions and provide point by point responses to the reviewers below.

Please, do not hesitate to contact us if further revisions are needed. We hope for a favorable decision in due time.

Best wishes,

Dr. Ahmed Waqas

Corresponding author

Reviewer #1

Comment 1:

This is an important and interesting paper, but there are numerous grammatical errors, and word omissions. Given the sophistication of your approach and the immense effort involved, it is curious that you chose to use the number of participants as a weighting scheme. Why did you not choose inverse variance or the Hedges & Olkin or Hunter & Schmidt estimators of optimal weights?

Response

My co-authors & I are very grateful to you for your excellent feedback on the manuscript. We have now thoroughly proof read the paper for grammatical errors and accounted for word omissions in the manuscript.

We have now provided forest plots along with relative weights (random effects) assigned to each study. We had used inverse variance method and this has now been mentioned in the manuscript as well.

Comment 2:

When you say that, "Heterogeneity was considered significant at a cut off value of GE 40%," does that mean that you used a fixed-effect approach for those under 40% and random-effects for those greater than or equal to 40%? This should be clarified in the manuscript. I suspect that a random-effects approach throughout the analysis would yield more realistic estimates of effect size given the differences across studies in measurement instruments, procedures, treatments, and participants.

Response

Thank you for a thoughtful comment. We have now revised this statement which reads as, “Depending on the extent of heterogeneity, data were pooled together using either the fixed or random effects. Heterogeneity was considered significant at a cut off value > 40% in which case random effects analysis was used [17].”

We only employed random effects analysis when I2 > 40%- and I believe our criteria to be more firm when compared with recommendations in Cochrane handbook by Higgins and Green (2011). Moreover, most of the outcomes presented significant heterogeneity and therefore were analyzed using random effects.

Reviewer #2

General feedback

Thank you for the opportunity to review this interesting manuscript. Its subject is an important topic and it makes a helpful contribution to the literature. Although well-written in many parts, it would benefit from a careful edit of the English in places to maximise comprehensibility, and I highlight some issues below which should be clarified before it can be accepted for publication.

Response

Dear Sir/Madam, we are very grateful to you for providing such a thorough feedback on our manuscript. We have carefully proof read and edited the manuscript to avoid any mistakes or errors in use of English. We believe it has significantly improved the comprehensibility and readability of the manuscript.

Comment 1

ABSTRACT

The final sentence of the Introduction section seems to be more of a conclusion.

It is unclear what 'academic search' means. Specific databases should usually be mentioned in the abstract. On which date was the search completed? Were only randomised controlled trials included? Were self-report and objective assessments of outcomes combined?

The English of this section could be tweaked to enhance its clarity.

Response

We have rephrased the first sentence as, “In recent years, several non-specialist mediated interventions have been developed and tested to address problematic symptoms associated with autism. These can be implemented”.

Academic search has been rephrased to electronic search. We have also mentioned dates, inclusion of RCTs and use of objective outcomes.

These sentences now reads as, “An electronic search was conducted in eight academic databases since their inception to 31st December 2018…………”.

“A total of 31 randomized controlled trials were published post-2010 while only 2 were published prior to it”.

We have thoroughly proof read the abstract to improve the use of English in it.

Comment 2

INTRODUCTION

This section is clear and well-written.

Response

We are very grateful to you for your kind feedback.

Comment 3

METHODS

a) A specific search date would be helpful. The abstract states 'through 2018' but the methods say 'through January 2019'. Outside North America, the term 'through' may not be widely understood in this sense.

b) This is a relatively truncated set of databases to search. Is there a reason, given the authors' interest in LMICs, that other databases such as Global Health or Embase were not included?

c) The search terms to specify RCTs are quite limited, not including the word 'randomised'. Can the authors be sure that this strategy did not miss eligible studies? The fact that only 659 non-duplicate results were obtained from the search does suggest that this search strategy was extremely narrow.

d) The title specifies interventions for children but the Inclusion criteria state that no age restrictions were applied, suggesting that studies of adults were included.

e) What is meant by 'unreliably extracted' data?

f) Does 'overlapped data sets' mean papers reporting the same study? This could be clearer.

g) Data analysis: how similar were outcomes required to be in order to be meta-analysed? Were self-report, parent-report, teacher-reported etc. measures combined?

Response

a) We have rephrased this sentence which reads as, “An academic search was conducted in eight electronic databases including PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine, PsycINFO, Psycharticles, and CINAHL, from their inception to 31st December 2018. , using following search terms:”

b) Dear Sir/Madam, this is a very valid comment. We searched eight electronic databases out of which three were major ones. This is in accordance with AMSTAR checklist for appraisal of systematic reviews which recommends atleast 2 major database searches and one grey literature search (Reference: https://amstar.ca/docs/AMSTARguideline.pdf).

Pubmed has one of the largest coverage for medical journals, whereas scopus and web of science both cover medical, social and multidisciplinary journals. Moreover, other minor databases including CINAHL and psychinfo are specialized databases for nursing and psychiatry. And popline and NYAM cover grey literature.

Web of science database also searches other databases such as medline, Scielo and Korean journal databases by default (Reference: https://clarivate.libguides.com/webofscienceplatform/coverage.)

Citation Indexes in Web of Science:

Web of Science Core Collection

BIOSIS Citation Index

Chinese Science Citation Database

Data Citation Index

Russian Science Citation Index

SciELO Citation Index

Subject specialized and regional indexes:

Biological Abstracts, BIOSIS Previews

CABI: CAB Abstracts and Global Health

FSTA—the food science resource

Inspec

KCI—Korean Journal Database

Medline

Zoological Record

c) Although the term randomized or controlled was not used, search term trial should be sensitive enough to pick most of the articles. Adding the terms, randomized would have decreased the number of studies by making them more specific.

d) The statement, No restrictions or database filters regarding language, time period or publication year were applied reflects that we did not use any limiters or filters in the databases. We have now mentioned “database filters” to make it more precise.

e) The terms “unreliably extracted data” has been deleted.

f) Yes, it does! It has now been rephrased to “Overlapping data sets reporting results from same study.”

g) We have now included more information for selection of autism and also provide an example for it. “For outcomes, an apriori decision was taken to include all types of psychometric testing whether conducted by specialists, teachers or parents. A variety of psychometric scales used for measurement of symptoms of autism are reported in the literature. We conducted a thorough audit of included studies to identify the psychometric scales used and categorized them under a unifying category. For instance, total symptom severity comprised of several scales such as Autism Diagnostic Observation Schedule; Autism Behaviour Checklist; Vineland Adaptive Behaviour Scale and Childhood Autism Rating Scale among others.”

Comment 4

RESULTS

a) Please define CAMH.

b) Density of dosage: is (158.07) intended to indicate the standard deviation? This should be stated.

c) Did two studies genuinely report sessions lasting 1500 minutes, i.e. 25 hours? Can this really have been continuous? Might such an intervention have caused harm?

d) Please define (if applicable) the meanings of PACT, PASS, QST, JASPER, HANEN, COMPASS, PEERS acronyms.

e) It is distracting that the referencing style changes from numerical to naming authors halfway through the results.

f) Under outcomes, please clarify if self-report and reports by heterogeneous others were combined.

g) It is confusing that "a significant improvement was noted in child distress (SMD=0.23...)" and also "no significant improvement was noted in child distress (SMD=0.158...)" - is this an error?

h) p11: "allocation concelment (13), selective reporting (4)..." - what do these numbers mean? Also high/unclear risk of bias?

i) The terms "risk of bias" and quality are conflated in this paragraph which is confusing.

Response

a) CAMH has been defined as “multidisciplinary child and adolescent mental health”.

b) Yes, it was standard deviation and has now reported.

c) Only one study mentioned implementation of SCERTS intervention (Morgan, 2016) lasting 1 week for 25 hours (1500 minutes). I have now specified this as “weekly”.

d) All of these abbreviation have now been presented in full form.

e) Numerical references have now been provided for this section.

f) We have included a new statement clarifying this: “For the purpose of meta-analysis, we combined effect sizes on all types of outcomes reported by teachers, parents or experts.”

g) This was indeed an error and has been removed from the revised manuscript.

h) We have now rephrased this sentence to “Frequency of studies reporting a high risk across other domains of Cochrane risk of bias tool were: Blinding of outcome assessors (n=14), other sources of bias (n=9), attrition bias (n=8), selective reporting (n=4) and blinding of participants and personnel (n=0). A total of 11 studies were rated as having low quality > 3 matrices rated as having unclear or high risk of bias [22,23,26,27,32,41] (Figure 4 and Supplementary Figure 6).” Figure 4 presents a clustered bar chart exhibiting frequencies of high, unclear and low risk bias across all matrices of Cochrane risk of bias tool. Supplementary figure 6 presents study wise risk of bias across all matrices of Cochrane risk of bias tool.

i) This has now been rectified. The term “Risk of bias” has now been used throughout the manuscript.

Comments

DISCUSSION

a) Did every included study use TAU as the comparator?

b) Please define DALYs

c) Some mention of the ethical and sustainability issues around non-specialists not seeming to have been paid would enhance the discussion

d) The authors only briefly mention that two included studies came from LMICs and that one was of good quality. A little more detail on both studies would be of interest, given the focus on task sharing for LMICs.

e) The statement "This would essentially reduce the treatment gap for children with autism, and ensure mental health for all across the globe" does not clearly refer to something in the previous sentence (the "this" of this sentence) and it is debatable that reducing the treatment gap for children with autism would indeed ensure MH for all across the globe.

f) IQ may be expected to moderate treatment effects but would it mediate them?

g) The authors state that cost-effectiveness was not reported in most studies but then conclude that "based on the... cost-effectiveness... we recommend up-scaling of these interventions".

h) Were some interventions more effective than others? Would the authors advocate up-scaling any models in particular?

Responses

a) TAU has been replaced with control group.

b) DALYs full form “disability adjusted life years” has now been provided.

c) Following sentence has been added, “Moreover, there are no frameworks for recruitment, role descriptions and financial compensation for non-specialists, which creates a barrier in scale up and sustainability of these interventions [5, 6].”

d) We have now added more information pertaining to these studies: “However, only one good quality randomized controlled trial conducted jointly in India & Pakistan limits the evidence for clinical and cost-effectiveness of these interventions in the region [6]. One of these studies was an adapted version of the PACT trial developed in Manchester [35] and was tested in a multi-site study conducted in Rawalpindi, Pakistan and Goa, India [6]. While, the second study revised this intervention and added a “plus” module pertaining to psycho-education and assessment of the most disruptive comorbidity for the family [31].”

e) This sentence has been revised to “Access to non-specialists would essentially reduce the treatment gap for children with autism, and ensure mental health for all across the globe [45].”

f) The term mediating has now been deleted.

g) The term cost-effectiveness has now been deleted.

h) Based on the findings of this systematic review, we cannot recommend one non-specialist mediated therapy for autism. PACT, PASS and PASS plus; JASPER, SENSE and Hanen’s more than words were tested in at least two studies and settings.

Comments

FIGURES

The forest plots are very cramped and would benefit from larger sizing and greater separation. Does Total mean N? A column for N/n (intervention vs control sample size) would help.

Acronyms in the forest plot impede understanding, e.g. 'PLS' - using simple language here would help.

It might help to order the forest plots in order of strongest to weakest effect size.

The forest plot pages are divided into primary outcomes and secondary outcomes (although the latter is not labelled) but these distinctions are not clearly drawn in the manuscript. Doing so would be helpful, for clarification and to align the figures with the text.

The risk of bias figure requires a heading and its meaning is not clear. Do percentages refer to the percentage of included papers graded as low, unclear or high risk? It would be more informative to show a table of the included studies and their individual gradings in each column.

Response

New forest plots have now been added and classified as communication; symptoms; motor symptoms; symptom severity and parental outcomes.

We have also added two sentence to ease the interpretation of risk of bias tool: “Figure 4 presents a clustered bar chart exhibiting frequencies of high, unclear and low risk bias across all matrices of Cochrane risk of bias tool. Supplementary figure 6 presents study wise risk of bias across all matrices of Cochrane risk of bias tool.” Individual gradings for each study are presented as supplementary figure 6.

Reviewer #3

Dear authors, I appreciate your manuscript and I do not have any substantial comments on it.

Best regards

The reviewer

Response

Dear Sir or Madam, we are very grateful to you for your kind feedback.

Reviewer #4

Comment

The manuscript in my opinion is technically sound.

I am not very competent in statistics to comment on the accuracy. A statistical expert may comment.

All data is available for review.

The English is standard and intelligible. The language used is simple for the reader’s understanding. The flow of the text is also fine in my opinion.

Additionally, the topic chosen is relevant as it highlights the difference between the highly technical and the basic non pharmacological interventions in ASD in the backdrop of the cost differences between the two. The study being a meta analysis involving 33 studies is a strength. The limitations are also highlighted giving the reader an idea of possible biases.

Response

Dear Sir or Madam, we are very grateful to you for your kind review of this manuscript and encouraging feedback.

Reviewer #5

Comment 1

This meta-analysis has not been registered online. Please add this point in the limitation.

Response

The manuscript has been registered online. The protocol registered in PROSPERO is numbered (CRD42017066009). Please, access it using this URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=66009

Comment 2

Literature Searches and Search terms are incomplete. This is suboptimal for publication for systematic review. Search terms in each database are different. Please attach search terms that were used in each database as supplement for Data source and search strategies in the manuscript. Please provide details search terms in supplementary documents. Please attach syntax used in each database as supplementary.

Response

We have now provided search terms adapted for each database and provided as a supplementary file.

Comment 4

Please also include timeline of the literature search in the method section of the abstract.

Response

We have now provided with the timeline of literature search which now reads as, “An academic search was conducted in eight electronic databases including PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine, PsycINFO, Psycharticles, and CINAHL, from their inception to 31st December 2018. , using following search terms:…”

Comment 5

It will be better to show kappa for the selection and data extraction. Please show the data of kappa of agreement during the systematic searches. How disagreements were solved during the systematic search among independent reviewers?

Response

Process of disagreement resolution has now been outlined in the manuscript. It reads as, “All data were extracted independently by three teams of reviewers using manualized data extraction forms and any disagreements among the reviewers, were resolved through discussion in conjunction with a senior author.”

However, we did not calculate cohen’s kappa in this case. According to our understanding, Cohen’s kappa is necessary when extractions are done with fewer personnel. For instance, in cases where, a junior reviewer works with a senior reviewer; and the senior reviewer extracts data for a few articles (say 20% of the total) and then checks inter rater reliability with the junior reviewer. In contrast, in present study three teams of reviewers extracted the data independently, where each article was rated by two reviewers working independently from each other, and in conjunction with senior authors.

Comment 6

There is still a considerable heterogeneity as in your limitation. Meta-regression analysis is then strongly recommended.

There is substantive heterogeneity in some outcomes. It also is unclear whether the t-statistic is being used for the degrees of freedom in the random effects analysis (i.e., N-1 d.f. not asymptotic [1.96] value multiplied by tau). Please assure that the t-statistic (or Satterthwaite correction) is being used and add that information to the Methods, when the number of studies is small (e.g., < 10). Apply this principle throughout the author's paper. For reference, the authors can refer the article “IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Medical Research Methodology 2014;14:25.” The issue is the Student t statistic.

Response

Meta-regression was indeed applied for a number of moderators. These moderators included: age, year of publication or duration of program and session and number of sessions or quality of trials. These have been reported in the manuscript. And scatter plots for all of these variables have been provided as supplementary files.

Moreover, we also conducted subgroup analyses for type of delivery agents (parents, teachers and peers). These have also been reported in the revised manuscript under the heading of moderator analysis. We have also added table 3 presenting subgroup analysis based on delivery agents. Regarding the issue of t-statistic, neither is it calculable in Comprehensive Meta-analysis software nor is it widely/frequently used in meta-analyses. However, we have now provided detailed statistics to account for heterogeneity. We have provided detailed subgroup analyses as well as corresponding I2, Tau2, Q-value and P-value. These are more widely used indicators of heterogeneity and may make better sense for the readers.

Comment 7

Authors should discuss the reason of heterogeneity.

Response

We have now added a paragraph on reasons for heterogeneity in discussion section. It reads as, “A total of three outcomes including joint engagement, parent child relationship and joint attention exhibited substantial heterogeneity (I2>70%). Rest of the outcomes presented no to moderate heterogeneity. We opine that this may be because of two main reasons. For the outcome of joint engagement, this substantial heterogeneity is due to differences in intervention content as well as different delivery agents as shown in subgroup analysis (Table 3). The outcomes of parent child relationship and joint attention were only reported in parent mediated interventions. The heterogeneity in these outcomes may be accounted for by use of different rating scale or methods of measurement. The studies reporting these outcomes used varying methods for measurement of both the joint attention and parent child relationship.:

Comment 8

Please make the data for this review publicly available, possibly through the Open Science Framework (osf.io). Items to include: list of excluded studies, commands for statistical analysis, spreadsheets or data used for the meta-analyses, etc. Making data publicly available will promote the reproducibility of the review and is best practices for systematic reviews and meta-analyses.

Response

We have now provided the data requested as supplementary files. All the data related to characteristics of included studies, summary of risk of bias and detailed risk of bias for individual studies have already been given in the manuscript or as supplementary files.

Comment 8

Some revision of the English language is needed. There are some parts of the paper where it is quite difficult to make sense of some sentences. English edit will help to improve the quality of the manuscript.

Response

We have now thoroughly proof read the revised manuscript for any language errors and omissions.

1 Oct 2019

PONE-D-19-19450R1

Implementation and effectiveness of non-specialist mediated interventions for children with Autism Spectrum Disorder: A systematic review and meta-analysis

PLOS ONE

Dear Ahmed Waqas,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Our expert reviewer(s) have additionally recommended some minor revisions to your revised manuscript. Therefore, I invite you to respond to the reviewer(s)' comments as below and revise your manuscript.

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Kind regards,

Wisit Cheungpasitporn, MD, FACP

University of Mississippi Medical Center

Twitter: @wisit661 Email: wcheungpasitporn@gmail.com

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: I Don't Know

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All of my comments were addressed. I have no further comments.

Reviewer #2: Thank you for your responses to my previous review; the changes made have enhanced the manuscript. Please see some comments below which should be addressed before acceptance for publication.

I agree with Reviewer #1 that random-effects meta-analyses across the publication as a whole would be preferable and clearer to the reader. Would the authors consider following this suggestion?

Methods Comment c) When I suggested including the search term 'randomized' I intended this to refer to an alternative to RCT rather than an additional requirement, so this would not have decreased the number of results. The authors have not addressed my question about the very narrow search. I would suggest that the narrowness of the search and the number of databases be included in the discussion as limitations.

Methods Comment d) The authors have not clarified my query about whether the results represent a study of any interventions for participants of any age or whether in fact only studies of children were included. This needs to be clear throughout the manuscript.

Methods Comment g) I would suggest that combining results from diverse measures applied by heterogeneous individuals be mentioned as a limitation/source of heterogeneity in the discussion.

As by the time of publication, the results will be approaching 1 year old, the study would be enhanced by re-running the search for any new results since 31st December 2018.

Discussion Comment e) I'm afraid I still disagree that "Access to non-specialists would essentially reduce the treatment gap for children with autism, and ensure mental health for all across the globe [45].”

Discussion Comment h) adding the authors' response to this query to the discussion would enhance it.

Reviewer #3: Dear Author, I do not have any further comment on your manuscript. I appreciate it.

Best regards

The reviewer

Reviewer #4: The manuscript in my opinion is technically sound.

I am not very competent in statistics to comment on the accuracy. A statistical expert may comment.

All data is available for review.

The English is standard and intelligible. The language used is simple for the reader’s understanding. The flow of the text is also fine in my opinion.

The paper overall looks organised and good to go to me.

Reviewer #5: All my concerns have been fully elucidated, missing sections and analyses have been completed. Finally, comprehension errors have been corrected.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Roxanne Keynejad

Reviewer #3: Yes: Ladislav Hosak

Reviewer #4: No

Reviewer #5: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Oct 2019

Dear Professor Cheungpasitporn,

My coauthors & I are very grateful to you for kind feedback on the manuscript. We believe the extensive feedback received had greatly improved the quality of the manuscript. We have now considered and responded to all the comments by worthy reviewer and revised our manuscript accordingly.

We look forward to a favorable decision in due time.

Best wishes,

Dr. Ahmed Waqas

Corresponding author

Reviewer #2

General feedback

Thank you for your responses to my previous review; the changes made have enhanced the manuscript. Please see some comments below which should be addressed before acceptance for publication.

Response

We are very grateful to you for the kind feedback which has greatly improved the quality of our work. We have now responded to all of your comments below and also revised our manuscript accordingly.

Comment 1

I agree with Reviewer #1 that random-effects meta-analyses across the publication as a whole would be preferable and clearer to the reader. Would the authors consider following this suggestion?

Response

We have indeed used random effects analyses throughout the manuscript. The relative weights provided in the forest plots are random weights. In this context, we have removed the statement on use of random effects for analyses presenting I2 > 40%.

Following statement has now been added: “Depending on the extent of heterogeneity, data were pooled together using either the fixed or random effects. Heterogeneity was considered significant at a cut off value > 40%. However, we applied random effects analysis for all of the outcomes because of heterogeneity in assessment of outcomes across included studies [17].”

Comment 2

Methods Comment c) When I suggested including the search term 'randomized' I intended this to refer to an alternative to RCT rather than an additional requirement, so this would not have decreased the number of results. The authors have not addressed my question about the very narrow search. I would suggest that the narrowness of the search and the number of databases be included in the discussion as limitations.

Response

The limitations related to narrowness of search and number of databases has been added in the limitations section. We have also added a sentence on using a more comprehensive search strategy encompassing different terms for RCT.’

Following sentences have been added: “The present systematic review was based on searching of a limited number of databases, we encourage investigators to search more databases in future studies. Moreover, investigators should also consider using a more comprehensive search strategy encompassing different terms for RCT.”

Comments

Methods Comment d) The authors have not clarified my query about whether the results represent a study of any interventions for participants of any age or whether in fact only studies of children were included. This needs to be clear throughout the manuscript.

Response

We have now added this as an exclusion criteria: “7. Interventions conducted among adults with ASD were excluded.”

Comment

Methods Comment g) I would suggest that combining results from diverse measures applied by heterogeneous individuals be mentioned as a limitation/source of heterogeneity in the discussion.

Response

We have now added following statement: “Combining results from diverse measures applied for heterogeneous study samples is another limitation of this systematic review.”

Comment

As by the time of publication, the results will be approaching 1 year old, the study would be enhanced by re-running the search for any new results since 31st December 2018.

Response

This is a very valid suggestion. However, due to limitation of resources such as funding and human resource, it would not be possible for us to re-run the searches and conduct more analyses. Hopefully, after publication of this manuscript, we will keep working on improving it.

Comment

Discussion Comment e) I'm afraid I still disagree that "Access to non-specialists would essentially reduce the treatment gap for children with autism, and ensure mental health for all across the globe [45].”

Response

We have now deleted this statement from the manuscript.

Comment

Discussion Comment h) adding the authors' response to this query to the discussion would enhance it.

Response

We have now added following statements: Based on the findings of this systematic review, we cannot recommend one non-specialist mediated therapy for autism. PACT, PASS and PASS plus; JASPER, SENSE and Hanen’s more than words were tested in at least two studies and settings. Therefore, we recommend that future investigators, implementors and policy makers consult these therapy programs for development of interventions suitable for their settings.

14 Oct 2019

Implementation and effectiveness of non-specialist mediated interventions for children with Autism Spectrum Disorder: A systematic review and meta-analysis

PONE-D-19-19450R2

Dear Dr. Ahmed Waqas,

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Wisit Cheungpasitporn, MD, FACP, FASN

University of Mississippi Medical Center

Twitter: @wisit661 Email: wcheungpasitporn@gmail.com

Academic Editor

PLOS ONE

Additional Editor Comments:

Your responses to the reviewer's comments were good and led you to make significant improvements to the paper.

Reviewers' comments:

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Comments to the Author

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Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #5: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #5: Yes

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Best regards

The reviewer

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Reviewer #2: Yes: Dr Roxanne C Keynejad

Reviewer #3: No

Reviewer #5: No

1 Nov 2019

PONE-D-19-19450R2

Implementation and effectiveness of non-specialist mediated interventions for children with Autism Spectrum Disorder: A systematic review and meta-analysis

Dear Dr. Waqas:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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