1. Design and Setting
The GAP project will be conducted from March 2023 to September 2024 in three tertiary care hospitals in the province of Barcelona (Sant Joan de Déu Hospital (SJDH), Vall d'Hebron Hospital (VHH), and Parc Taulí Hospital (PTH)) conforming together a territorial expertise network (XUEC-MCC: Xarxa d'Unitats d'expertesa clínica-malalties minoritàries cognitiu conductuals). This network was created and accredited in 2015 to guarantee equal and full access to health and research opportunities regardless of geographic location for children with genetic syndromes that are included in the rare conditions register (ReMin, Registre de Malalties Minoritàries de Catalunya). This is the most exhaustive national registry and is custodied by the National Health System (CatSalut). This registry provides access to a sample that is difficult to ascertain, thereby overcoming the rarity of genetic conditions. The three participating hospitals have multidisciplinary units led by a patient-centered policy that can go beyond institutional or geographical limits.
2. Eligibility criteria
Participating families will be recruited from the three units within each hospital, and patients will fulfil the following criteria:
1. Children aged 3.0–7.11 years at recruitment.
2. Children with genetically determined neurodevelopmental conditions (see Supplementary File 1).
3. For children aged up to 5.11 years:
Withdrawn problems (defined as Child Behavior Checklist (CBCL/1.5-5) scores above the borderline clinical range for the “Withdrawn” domain, T-score ≥ 65)
AND/OR
Pervasive neurodevelopmental problems (defined as CBCL/1.5-5 scores above the borderline clinical range for the “Pervasive developmental problems” domain, T-score ≥ 65)
AND/OR
Socialization problems (defined as Vineland-III scores below 1SD in the socialization subdomains).
4. For children aged over 6 years:
Social problems (defined as CBCL/6–18 scores above the borderline clinical range for the “Social problems” domain, T-score ≥ 65)
AND/OR
Thought problems (defined as CBCL/6–18 scores above the borderline clinical range for the “Though problems” domain, T-score ≥ 65)
AND/OR
Socialization problems (defined as Vineland-III scores below 1SD in the socialization subdomains).
5. Parents/caregivers showing good understanding of Spanish or Catalan language.
6. Parents/caregivers consenting to take part in the study and signing the informed consent.
The following are the exclusion criteria:
1. Children with a previously known diagnosis of ASD.
2. Children scoring above the diagnostic cut-off for ASD in the Autism Diagnostic Observation Schedule (ADOS-2) assessment.
3. Attending another structured parenting program.
4. Children in the care of their local authority.
3. Recruitment and sample size calculation
Parents will be recruited from the specialist units in genetic neurodevelopmental syndromes at the three hospitals. Figure 1 shows the recruitment process that will be followed. Clinicians will present the study to preselected eligible families and will ask them for permission to be contacted by the research assistant, who will then explain the study further. If the family is interested, an appointment to evaluate all the inclusion criteria will be set up and the parents will be asked to sign the informed consent and to complete the pre-intervention assessment (see Eligibility criteria section). Any children excluded from the study at that point due to scoring above diagnostic cut-off for ASD at the ADOS-2, will be referred for a specialized mental health assessment within the public system. Participants will be able to discontinue the treatment sessions or drop out from the control group at any point at their request. The participation or disengagement from the study will not affect their usual treatment.
For the sample size calculation, we used the parental stress outcome, measured through the Parental Stress Index Short Form (PSI-SF) questionnaire [29]. This is a 36-item scale, with a range of 180 points. There is data showing that a decrease of 16.5 points in the total scale stress score can be seen after attending an IY program [30]. Given that this study will be conducted with parents of children presenting neurodevelopmental difficulties, we anticipated that the decrease in the PSI-SF score would be lower. We estimated the necessary sample size considering a power of 80%, α = 0.05, a difference between pre- and post-test of 10 points, and a standard deviation of 20, using a paired-samples t test. We estimated 34 participants needed per arm of the study. Thus, we aim to recruit approximately 68 participants. The dropout rate has not been included when calculating the sample size, considering that a sample of 68 participants is similar than previous studies [26, 31] and in line with recommendations by the National Institute of Health Research [32]. Using the public registry for rare diseases (ReMin: Registre de Malalties Minoritàries) we have identified a minimum number of 184 patients within the age interval and confirmed genetic syndrome (see inclusion criteria above).
Regarding the sample size for the individual interviews that will be conducted with parents after the intervention, a minimum of two parents of each intervention group will be interviewed. We will aim for a representative sample in terms of children’s diagnosis, age and gender. Parents who drop out from the intervention will also be invited to be interviewed. Data saturation will be used to determine the final sample size.
For the post-intervention individual interviews with clinicians, all clinicians who delivered the intervention will be interviewed after the intervention phase.
4. Randomization
Randomization (intervention or TAU condition on a 1:1 ratio) will take place once all the participating families have completed baseline measures. Once included in the trial, the randomization code will be generated centrally by a statistician using PROC PLAN available in the SAS® version 9.4 statistical program. One list will be generated with blocks of length 4. The seed number will be chosen randomly using RANUNI (function available in SAS), because random numbers are known to follow a uniform distribution. Allocation will be stratified by cognition developmental level depending on the final sample characteristics (Developmental Profile-3 (DP-3) cognition scale below or above 70). An independent researcher will carry out the randomization process, and researchers responsible for recruitment or intervention delivery will not be involved. Due to the pragmatic and clinically focused nature of the study, further blinding procedures will not be possible.
5. Intervention
Clinical psychologists (ME, LM, IS, BM) and child psychiatrists (LV, MLL, GE, SP) working in specialized mental health services for neurodevelopmental disorders within the three hospitals will deliver the intervention.
The IY-ASLD® program [25] encourages positive parent-child relationships to promote children’s social competence, peer relationships, language skills, pre-academic coaching, and emotion and behavior regulation. The intervention encourages parents to play in a child-directed way but with a specific focus on enhancing children’s communication and social engagement. It also focuses on how to use positive discipline to set limits and handle misbehavior. During the coronavirus disease-19 (COVID-19) pandemic, the IY-ASLD® program developers adapted the intervention to be performed online (22 sessions approximately). Each group includes a maximum of 8–10 participants, although the online format recommends keeping the number of participants in the lower range, particularly if children have complex clinical presentations. The intervention includes video modelling, role-playing and discussion activities with parents and emphasizes the importance of practice-based learning in the sessions and at home. Families will be contacted weekly between sessions to encourage home-based practice.
Fidelity to the treatment manual will be ensured in different ways. The intervention will be conducted by experienced psychiatrists and clinical psychologists, officially trained in the IY-ASLD® model and its online adaptation by an accredited trainer. Group leaders will complete weekly fidelity checklists and will receive group supervision by a certified supervisor in two different timepoints throughout the intervention. Due to the pragmatic nature of the study further supervision or accreditation processes will not be possible. The TAU condition involves outpatient appointments with neuropediatricians to monitor children’s developmental level and drug prescription when needed. All children under 5 years of age are also treated in Early Childhood Developmental Centers based in the community, where they receive individual unstructured interventions to foster children’s development. Children aged over 5 years might or might not receive psychological or psychiatric treatment in specialized child and adolescent mental health community centers. Families allocated to the intervention group will also receive TAU.
6. Measures
Table 1 summarizes the study timeline and the measures that will be used.
Baseline and sample descriptors:
At baseline, sociodemographic and children clinical variables will be collected from clinical notes and parent reports. Socioeconomic status will be determined using Hollingdale’s Index of Social Position [33].
The following questionnaires, which have already shown valid and reliable results in children with neurodevelopmental problems, will be administered before the intervention:
-
Social Communication Questionnaire (SCQ) [34]: this screening tool is a 40-item parent report measure, with a yes/no format, based on the Autism Diagnostic Interview-Revised (ADI-R) [35]. The Lifetime version of the questionnaire will be applied to all children, from 3 to 7 years old. Children are likely to be on the autism spectrum when their total scores are 8 or higher.
-
Autism Diagnostic Observation Schedule (ADOS-2) [36]: it is a semi-structured assessment of social interaction, communication and play exposing the child to situations that elicit spontaneous behaviors in standardized contexts. Modules 1 to 3 will be selected in accordance to the children’s language level. To receive an autism spectrum diagnosis by the ADOS-2 algorithm an individual’s score must exceed a total cut-off score.
-
Vineland Adaptive Behavior Scale-III (VABS-III, parent/caregiver report form) [37]: it assesses the adaptive functioning of the child in the family environment. It is composed of the following domains: communication, socialization, daily life skills, and motor skills. It also generates an index of adaptive behavior.
-
Developmental Profile-3 (DP-3) [38]: this is a 180-item parental questionnaire assessing developmental delays in different domains: motor, adaptative, socio-emotional, cognitive, and communication. It also computes an overall general development score.
-
Child Behavior Checklist (CBCL 1.5-5 and 6–18) [39, 40]: this questionnaire is a component of the Achenbach System of Empirically Based Assessment (ASEBA). It is a parent-reported 99-item (CBCL 1.5-5) and 113-item (CBCL 6–18) inventory that measures adaptive functioning and behavioral, emotional and social problems. It is made up of eight syndrome scales, which are grouped into two main categories: internalizing and externalizing. The sum of scores forms a total problem score, and it also includes subdomains. This questionnaire will also be administered after the intervention as an exploratory measure.
Outcome measures:
Primary outcomes (Feasibility):
-
Parents’ engagement with the program and participant retention will be monitored weekly throughout the intervention using an attendance sheet, expecting they will attend at least 15/22 sessions with a minimum of 50% of parents finishing the program.
-
Autism Program Parent Weekly Evaluation [41]: this instrument is part of the IY-ASLD® program materials and will be administered weekly throughout the intervention to collect information regarding parents’ compliance and satisfaction.
-
Autism Program Parent Final Satisfaction Questionnaire [41]: this questionnaire is included within the IY-ASLD® program. It will be used to measure the acceptability and satisfaction with the intervention after the last session.
-
Parents’ overall experiences with the program will be explored by means of individual interviews. These interviews will be conducted after the last session to explore from a qualitative perspective: (1) parents’ acceptability, satisfaction and overall experience with the intervention, and (2) parents’ perceived changes in their parenting skills and parental distress after the intervention.
-
Clinicians’ experiences with the intervention will also be qualitatively assessed by means of individual interviews with all clinicians who delivered the intervention. These interviews will be conducted after the last session.
Secondary outcomes (effectiveness for parental outcomes):
All the following questionnaires will be administered before and after the intervention:
-
Parent Stress Inventory-Short Form (PSI-SF) [29, 42]: 36-item questionnaire to assess parental stress associated with the care of their offspring. It is aimed at parents of children from 1 month to 12 years of age. It has three domains: parental distress, parent-child dysfunctional interaction, and difficult child, which combine to form a total stress scale.
-
Beck Depression Inventory (BDI) [43]: 21-item screening tool assessing the severity of depressive symptoms. It is a standardized and validated questionnaire, often used in adults’ mood disorder assessments.
-
Alabama Parenting Questionnaire-Preschool revision (APQ-Pr) [44]: 32-item parent-reported questionnaire measuring parenting practices associated with disruptive child behaviors. This version has 3 dimensions: positive parenting, inconsistent parenting, and punitive parenting.
-
Autism-Specific Five Minute Speech Sample (ASFMSS) [45]: this is a narrative 5-min interview used to measure parental expressed emotions for children with ASD and related disorders. Parents are asked to speak about their child and the parent-child relationship. Speech samples are audiotaped, transcribed, and coded following six global categories: (a) initial statement, (b) warmth, (c) relationship, (d) emotional over-involvement, (e) critical comments and (f) positive comments. This tool has been translated and validated in Spanish families [46].
Other exploratory measures:
Preliminary effectiveness of the intervention on children’s problems will be explored with the Child Behavior Checklist (CBCL explained above).
Table 1
Overview of the study timeline and measures
Time points
|
|
|
Study period
|
Enrollment
|
Allocation
|
Weekly intervention
(22 sessions)
|
Close-out
|
March to November 2023
|
November 2023
|
November 2023
Session 1
|
June 2024
Session 22
|
June to September 2024
|
Enrollment:
|
|
|
|
|
|
Eligibility screen
|
X
|
|
|
|
|
Informed consent
|
X
|
|
|
|
|
Randomization and allocation
|
|
X
|
|
|
|
Intervention:
|
|
|
|
|
|
IY-ASLD® group
|
X
|
X
|
X
|
X
|
X
|
TAU group
|
X
|
X
|
|
|
X
|
Assessments:
|
|
|
|
|
|
Baseline variables
|
|
|
|
|
|
Sociodemographic variables: Hollingdale’s index of Social Position
|
X
|
|
|
|
|
Social Communication Questionnaire (SCQ)
|
X
|
|
|
|
|
Autism Diagnostic Observation Schedule-2 (ADOS-2)
|
X
|
|
|
|
|
Vineland Adaptive Behavior Scale-III (VABS-III)
|
X
|
|
|
|
|
Developmental Profile-3 (DP-3)
|
X
|
|
|
|
|
Child Behavior Checklist (CBCL)
|
X
|
|
|
|
X
|
Outcome variables and other measures
|
|
|
|
|
|
Autism Program Parent Weekly Evaluation
|
|
|
X
|
X
|
|
Autism Program Parent Final Satisfaction Questionnaire
|
|
|
|
X
|
X
|
Individual interviews with parents
|
|
|
|
|
X
|
Individual interviews with clinicians
|
|
|
|
|
X
|
Parent Stress Inventory-Short Form (PSI-SF)
|
X
|
|
|
|
X
|
Beck Depression Inventory (BDI)
|
X
|
|
|
|
X
|
Alabama Parenting Questionnaire-Preschool version (APQ-Pr)
|
X
|
|
|
|
X
|
Autism-Specific Five Minute Speech Sample (ASFMSS)
|
X
|
|
|
|
X
|
Child Behavior Checklist (CBCL)
|
X
|
|
|
|
X
|
IY-ASLD®: Incredible Years Autism Spectrum and Language Delays program®, TAU: treatment as usual.
|
7. Data collection and data analysis
Quantitative data collection and analysis:
Data will be collected at baseline (before performing randomization) and after finishing the IY-ASLD® intervention. Parents consenting to participate will be offered a hospital appointment with a research assistant to evaluate children inclusion criteria (children questionnaires and ADOS-2). If the child meets inclusion criteria parents will be contacted on the phone to complete the remaining questionnaires (including all children descriptors, effectiveness parental outcome measures and the ASFMFSS voice recording). If both parents agree to participate in the study, they will fill out children measures together by consensus, and parental outcome measures individually.
Descriptive analyses will be used for recruitment, attrition and satisfaction rates of the participants with the program. Differences in baseline and descriptive variables between intervention and TAU conditions will be described and controlled in the main analyses. For effectiveness outcomes, the analysis will follow an intention-to-treat basis. Relevant confounding variables, such as socio-demographic variables, developmental level, or treatment site, will be added as covariates. Statistical analysis will be performed using SPSS (IBM Corp., Armonk, NY). The Wilcoxon test will be used to compare quantitative paired variables between the different evaluations through time. Chi-square test will be used to compare categorical variables with efficacy variables. Spearman’s rank correlation coefficient test will be applied to study the relationship between the quantitative variables (such as clinical scores). We will also estimate 95% confidence intervals and effect sizes.
All statistical analyses will be two-sided and p-values < 0.05 will be considered significant.
Missing data (i.e., missing item responses in questionnaires) will be treated following the instructions stipulated in the questionnaire’s manual. Imputation methods will be considered for full-case missing data.
Qualitative data collection and analysis:
Interviews with parents and clinicians will take place after finishing the intervention. They will be conducted online by a psychologist trained in qualitative methods and will be audio-recorded and transcribed verbatim.
A qualitative thematic analysis will be performed to analyze the data. All transcripts will be coded, analyzed and discussed by at least two independent researchers not involved in the intervention delivery. The coding process will be inductive: themes and associated codes will be generated from the interviews data. The coding process will be supported by the software Atlas.ti.
8. Ethical issues
Signed Informed Consent will be obtained from the parents/caregivers of study participants. The study protocol and consents will be reviewed and approved by the ethics committee of each participating site: Research & Ethics Committee of SJDH, Clinical Research Ethics Committee (CEIm) of VHH, and Committee for Ethical Clinical Investigation of PTH. A copy of the consent will be given to the patient’s parent/caregiver. All data will be anonymized and stored by the research group. The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practices, and applicable regulatory requirements.
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be agreed upon by the research group and approved by the Ethics Committee prior to implementation. It will also be registered at ClinicalTrials.gov.
We used the SPIRIT checklist when writing our report [47] (see Supplementary File 2).
Dissemination plans
The results of the study, regardless of whether they are in favor of the intervention or TAU group, or inconclusive, will be published in a peer-reviewed journal. The investigators will also communicate the trial results to the national and international scientific community and healthcare providers at different conferences.
We do not intend to use professional writers for our publications. Authorship eligibility will be based on the recommendations from the International Comittees of Medical Journal Editors.