Literature Search and Study Characteristics
A flow diagram detailing the selection process is presented in Figure 1. We identified 8,725 potentially relevant citations, and 174 full citations were retrieved. Overall, 18 unique citations were deemed eligible for the systematic review and meta-analysis [12, 19, 31-47].
A systematic description of eight between-group studies and ten prepost studies (including 495 nonoverlapping participants with ASD) is provided in Table 1. Three of the ten prepost studies with within-subject designs were natural experiments, and the intervention characteristics were reported by parents. Half of the included studies were postintervention follow-ups and thus had a period of time during which the intervention was not being implemented; the outcomes from these studies were defined as “long-term”. These studies used a wide range of measures to assess autism symptom severity, cognitive and language abilities, and adaptive behavior (Table S2). Most employed standardized measures and researcher-developed interviews, and all the repeatedly measured outcomes were standard scores. Moreover, six studies (33%) received the highest rating (strong), two (11%) received the middle rating (adequate), and ten studies (56%) received the lowest rating (weak; Table S3) based on the assessment of research report rigor.
Table 1. Characteristics of the studies included in the meta-analysis reporting multiple outcomes in children and adolescents with ASD.
|
|
|
Participants
|
|
Intervention characteristicsc
|
|
|
|
Study
|
Region
|
Design
|
Samplea (n, male%)
|
Diagnosis (criteria)
|
Pre-test CAb
(months)
|
Pre-IQ
|
|
Methods (model)
|
Intensity (h/week)
|
Duration (months)
|
agent
|
Post/follow-up CA (months)
|
|
Control group
|
Rigor ratingd
|
Akshoomoff et al
(2010)
|
USA
|
Pre-post
experimental
|
20
90.00%
|
AD
PDD-NOS
(DSM-IV)
|
28.90
(2.70)
|
---
|
|
otherse
|
31.00
|
7.70
(2.20)
|
T+P
|
85.30
(27.80)
|
|
NO
|
Weak
|
Bibby
et al
(2002)
|
UK
|
Pre-post
Observational
|
22
83.33% ⱡ
21f
|
ASD
PDD
|
45.00
(11.20)
|
50.80
(20.60)
|
|
EIBI (UCLA)
|
30.30
(5.50)
|
31.60
(11.90)
33.20f
|
T
|
77.40
(15.00)
78.70f
|
|
NO
|
Weak
|
Clark
et al
(2017)
|
AUS
|
Pre-post
Observational
|
48
75%
|
AD
ASD
(DSM-IV)
|
25.45
(2.12)
|
65.68
(11.87)
|
|
others
|
NR
|
NR
|
T
|
96.50
(6.60)
|
|
NO
|
Weak
|
Cohen
et al
(2006) g
|
USA
|
Between-group
NRT
|
21
85.71%
|
AD
PDD-NOS
|
30.20
(5.80)
|
61.60
(16.40)
|
|
EIBI (UCLA)
|
35-40
|
36.00
|
T+P
|
66.24
(5.76)
|
|
YES
N-R
|
Strong
|
Estes
et al
(2015)
|
USA
|
Between-group
RCT
|
21
|
AD
PDD-NOS
(DSM-IVTR)
|
23.90
(4.00)
|
61.00h
(9.20)
|
|
ESDM
|
31.50
|
24.00
|
T+P
|
72.90
(2.60)
|
|
YES
Random
|
Strong
|
Gabriels
et al
(2001)
|
USA
|
Pre-posti
Observational
|
17
70.59%
|
Autism
PDD-NOS
|
30.60
(7.27)
|
57.81
(25.88)
|
|
others
|
22.63
|
36.00
|
T
|
68.70
(10.11)
|
|
NO
|
Weak
|
Harris
et al
(2000)
|
USA
|
Pre-post
experimental
|
27
85.19%
|
AD
(DSM-III-R)
|
49.00 (31-65)
|
59.33
(23.75)
|
|
EIBI
|
35-45
|
36.00
|
T+P
|
85.00
|
|
NO
|
Weak
|
Howard
et al
(2014)
|
USA
|
Between-group
NRSI
Observational
|
29
86.00%
|
AD
PDD-NOS
(DSM-IV)
|
30.86
(5.16)
|
60.57
(17.48)
|
|
EIBI (IBT)
|
35-40
|
37.90
(2.98)
|
T+P
|
69.24
(5.01)
|
|
Yes
N-R
|
Strong
|
Kovshoff
et al (2011)
|
UK
|
Between-group
NRT
|
23
|
Autism
|
35.70
(4.00)
|
61.43
(16.43)
|
|
EIBI
|
25.60
(4.80)
|
24.00
|
T+P
|
83.70
|
|
Yes
N-R
|
Adequate
|
|
|
|
Participants
|
|
Intervention characteristicsc
|
|
|
|
Study
|
Region
|
Design
|
Samplea (n, male%)
|
Diagnosis (criteria)
|
Pre-test CAb
(months)
|
Pre-IQ
|
|
Methods (model)
|
Intensity (h/week)
|
Duration (months)
|
agent
|
Post-test/
follow-up (months)
|
|
Control group
|
Rigor ratingd
|
Landa
et al
(2012)
|
USA
|
Pre-post
experimental
|
48
81.25%
|
ASD
|
27.20
(2.80)
|
60.10
(11.90)
|
|
others
|
10.00
|
6.00
|
T+P
|
72.60
(17.50)
|
|
No
|
Weak
|
McEachin
et al
(1993)j
|
USA
|
Between-group
NRT
|
19
84.21%
|
Autism
(DSM-III)
|
34.60
|
53.00
(30-82)
|
|
EIBI (UCLA)
|
40.00
|
60.00
|
T+P
|
156.00
(108-228)
|
|
YES
N-R
|
Strong
|
Magiati
et al
(2011)
|
UK
|
Pre-post
experimental
|
36
|
Autism
ASD
|
38.90
(7.10)
|
64.40
(30.00)
|
|
EIBI (UCLA)
|
30.00
|
57.90
(21.20)
|
T
|
123.60
(9.60)
|
|
No
|
Weak
|
|
Perry
et al
(2017)
|
CA
|
Pre-post
experimental
|
21
90.48%
|
AD
PDD-NOS
(DSM-IV)
|
40.92
(12.60)
|
---
|
|
EIBI
|
20-40
|
26.76
(9.84)
|
T
|
192.20
(21.48)
|
|
No
|
Weak
|
Sallows
et al
(2005)
|
USA
|
Between-group
RCT
|
13
84.61%
|
Autism
(DSM-IV)
|
33.23
(3.89)
|
50.85
(10.57)
|
|
EIBI (UCLA)
|
38.60
(2.91)
|
48.00
|
T
|
83.23
(8.92)
|
|
Yes
Random
|
Strong
|
Smith
et al
(2000)
|
USA
|
Between-group
RCT
|
15
80.00%
|
Autism
PDD/NOS
|
36.07
(6.00)
|
50.53
(11.18)
|
|
EIBI (UCLA)
|
24.52
(3.69)
|
33.44
(11.00)
|
T
|
94.07
(13.17)
|
|
Yes
Random
|
Adequate
|
Smith
et al
(2015)
|
USA
|
Pre-post
experimental
|
64
84.51% ⱡ
|
ASD
|
39.12
(7.92)
|
58.80
(13.39)
|
|
EIBI (UCLA)
|
16.66
|
12.00
|
T
|
67.80
(9.72)
|
|
No
|
Weak
|
Vinen
et al
(2017)
|
AUS
|
Between-group
NRSI
|
31
87.10%
|
ASD
(DSM-IV, DSM-V)
|
39.16
(9.91)
|
55.42h
(8.74)
|
|
ESDM
|
≥15
|
22.44
|
T+P
|
79.97
(7.99)
|
|
Yes
N-R
|
Strong
|
Weiss and Delmolino (2006)
|
USA
|
Pre-post
experimental
|
20
95.00%
|
Autism
PDD/NOS
(DSM-IV)
|
41.50
(20-65)
|
---
|
|
EIBI (IBT)
|
40.00
|
48.00
|
T
|
89.5
|
|
No
|
Weak
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Notes: a Total number of subjects at the last measurement for pre-post studies and subjects in the experimental group for between-group studies.
b Chronological age at which the participants entered the study or started the intervention.
c Intervention characteristics for pre-post studies and the experimental group’s features for between-group studies.
d The quality assessment was examined by the Evaluative Method for Determining Evidence-Based Practices in Autism (Reichow, 2011).
e Others (other interventions) refers to the combination of standard interventions, including discrete trial training, incidental teaching, pivotal response training, structured teaching and the picture exchange communication system (e.g., community, inclusive intervention).
f The samples are inconsistent between the two outcomes reported by Bibby et al. (2002).
g Sufficient data were acquired from the figures in Cohen et al. (2006).
h The early learning composite (ELC) from MSEL was used to report cognition function.
i Gabriels et al. (2001) was a retrospective case-control study conducted on one sample receiving the same treatment and examined the influencing factors of the best outcomes.
j Two reports, Lovaas (1987) and McEachin et al. (1993), used the same participants. The McEachin et al. (1993) report was used because it had the longest follow-up.
ⱡ Male% was not reported in follow-up subjects. We used male% at intake to replace it.
ABA, applied behavior analysis; AD, autism disorder; ASD, autism spectrum disorder; AUS, Australia; CA, chronological age; CA, Canada; DSM, The Diagnostic and Statistical Manual of Mental Disorders; EIBI, early intensive behavioral intervention; ESDM, the Early Start Denver Model; IBT, intensive behavioral treatment; IQ, intelligence quotient; PDD/NOS, pervasive developmental disorder not otherwise specified; T, therapist ; T+P, therapist and parents; N-R, non-random; NR, not reported; NRT, non-randomized trial; NRSI, non-randomized study for intervention; RCT, randomized controlled trial; UCLA, University of California, Los Angeles.
Population and Intervention Characteristics
The mean pre-IQ, reported in 15 studies, was 50-64; the mean pretest age was 24-49 months, and the mean age at the last assessment was 66–192 months. Of the 18 studies included, 12 conducted EIBI (seven applied the UCLA model [39]), two used the ESDM, and four used other interventions. Other interventions (e.g., community intervention) include the combination of standard interventions. With regard to the intervention characteristics, eight studies were implemented by therapists and parents. The intervention duration and intensity ranged from 6 to 60 months and from 15 to 40 weekly hours, respectively. Six studies reported that participants were receiving supplemental treatments. Moreover, the comparison conditions in the eight between-group studies, which included 6 EIBI programs and 2 ESDM programs, were treatment as usual (k=5), different implementers (k=2) and active comparison (k=1).
Outcomes and Meta-Analysis I: Longitudinal Change in Mid-Childhood and Adolescence
Although a number of studies evaluated outcomes across multiple domains, others focused on specific areas, such as intellectual abilities, adaptive functioning, language outcomes or autism severity. A summary of reported outcomes is presented in Table 2; generally, positive ESs (gc) suggest that children’s performance improved on average after the preintervention stage in multiple dimensions of functioning (see Figure 2 and Figure 3).
The pooled standardized mean change ES for IQ, covering 420 participants, was 0.85 (95% CI: 0.47-1.22). Only one study [19] had a negative ES for IQ, while ten of the other samples yielded an ES for IQ equal to or greater than 0.50. Five EIBI studies reported data on language skills, four of which reported favorable effects on both expressive and receptive language. The pooled ESs for expressive language and receptive language were 1.12 (95% CI: 0.70-1.53) and 1.11 (95% CI: 0.83-1.40), respectively. Regarding the longitudinal changes in ASD symptom severity, seven studies reported relevant data, and three of them showed a favorable effect. The pooled ES was -0.68 (95% CI: -1.24--0.12). For adaptive functioning, the subdomains showed heterogeneity (Figure 3). A medium ES was found for both communication (ES=0.75, 95% CI: 0.47-1.02) and social (ES=0.55; 95% CI: 0.17-0.92), whereas a trivial ES was found for daily living skills (DLS) (ES=-0.05, 95% CI: -0.49-0.39) and composite score (ES=0.15, 95% CI: -0.28-0.57).
Table 2. Summary of cognitive, language, symptomatic and adaptive functioning outcomes in mid-childhood and adolescence.
Study
|
IQd
|
|
Expressive languagee
|
|
ASD Symptom Severityf
|
|
Adaptation compositeg
|
|
Preintervention
|
Middle childhood
|
|
Preintervention
|
Middle childhood
|
|
Preintervention
|
Middle childhood
|
|
Preintervention
|
Middle childhood
|
Bibby
|
50.80 ± 20.60
|
55.00 ± 22.30
|
|
|
|
|
|
|
|
54.50 ± 13.00
|
63.40 ± 21.90
|
Clarka
|
65.68 ± 11.87
|
102.71 ± 19.55
|
|
|
|
|
6.45 ± 2.08
|
6.20 ± 2.68
|
|
|
|
Cohenb
|
61.60 ± 16.40
|
87.00 ± 25.26
|
|
52.90 ± 14.50
|
78.00 ± 29.91
|
|
|
|
|
69.80 ± 8.10
|
79.00 ± 19.77
|
Estesc
|
61.00 ± 9.20
|
90.52 ± 26.36
|
|
|
|
|
|
|
|
69.50 ± 5.70
|
81.41 ± 17.27
|
Gabriels
|
57.81 ± 25.88
|
62.94 ± 30.79
|
|
|
|
|
|
|
|
|
|
Harris
|
59.33 ± 23.75
|
77.59 ± 28.10
|
|
|
|
|
|
|
|
|
|
Howard
|
60.57 ± 17.48
|
89.43 ± 23.99
|
|
49.73 ± 16.34
|
83.25 ± 29.88
|
|
|
|
|
72.00 ± 7.73
|
76.00 ± 15.94
|
Kovshoff
|
61.43 ± 16.43
|
64.65 ± 33.04
|
|
|
|
|
|
|
|
60.22 ± 5.82
|
55.13 ± 19.40
|
Landa
|
60.10 ± 11.90
|
81.50 ± 24.40
|
|
|
|
|
7.30 ± 2.20
|
7.40 ± 2.00
|
|
|
|
McEachinc
|
53.00 ± 13.00
|
84.50 ± 32.40
|
|
|
|
|
|
|
|
|
|
Magiati
|
64.40 ± 30.00
|
52.60 ± 21.80
|
|
2.60 ± 7.30
|
34.50 ± 37.90
|
|
36.70 ± 7.20
|
32.40 ± 10.00
|
|
58.70 ± 5.90
|
37.20 ± 17.90
|
Perry
|
|
|
|
|
|
|
34.16 ± 5.49
|
26.63 ± 6.40
|
|
63.45 ± 8.95
|
66.85 ± 17.18
|
Sallows
|
50.85 ± 10.57
|
73.08 ± 33.08
|
|
47.92 ± 6.17
|
53.38 ± 31.91
|
|
|
|
|
59.54 ± 5.31
|
69.00 ± 28.04
|
Smith 2000
|
50.53 ± 11.18
|
66.49 ± 24.08
|
|
15.13 ± 0.52
|
44.53 ± 23.48
|
|
|
|
|
63.44 ± 9.35
|
61.19 ± 29.72
|
Smith 2015
|
58.80 ± 13.39
|
64.93 ± 18.01
|
|
|
|
|
8.51 ± 1.76
|
6.45 ± 2.15
|
|
62.68 ± 9.02
|
59.89 ± 14.65
|
Vinen
|
55.42 ± 8.74
|
76.06 ± 20.82
|
|
|
|
|
7.39 ± 2.09
|
7.97 ± 2.60
|
|
|
|
Weiss
|
|
|
|
|
|
|
45.68 ± 5.30
|
26.58 ± 8.60
|
|
49.85 ± 7.84
|
76.05 ± 36.01
|
Note: a Data were acquired from the merging of subgroups in Clark et al. (2017).
b Data were acquired from the figures in Cohen et al. (2006).
c The standard deviation is calculated from the range of the outcomes in Estes et al. (2015) and McEachin et al. (1993).
d IQ was measured by a series of instruments, including WISC, BSID, WPPSI, and so on.
e Language was measured by Reynell, SICD-R, EOWPVT and BPVS-2.
f ASD symptom severity was measured by ADOS, ADI-R, and CARS.
g Adaptation composite was measured by VABS.
Akshoomoff et al. (2010) reported the subdomains of adaptive functioning and non-verbal/verbal IQ, which are not represented in Table 2.
ASD, autism spectrum disorder; IQ, intelligence quotient.
Meta-Analysis II: Effects of EIBI on Outcomes in Mid-childhood and Adolescence Compared to those in the Control Group
As presented in Figure 4, the majority of the SMD ESs (gd) were positive, which indicates that the functioning of children with ASD in the EIBI group was generally better than that in the comparison group in multiple dimensions. In line with the longitudinal change results, EIBI had small to medium effects in terms of improving IQ (ES=0.53, 95% CI: 0.16-0.90), communication (ES=0.38, 95% CI: 0.03-0.73), and social (ES=0.38, 95% CI: 0.03-0.73). The ES for DLS was also nonsignificant in four studies (ES=0.18; 95% CI: -0.16-0.53). However, we failed to find a favorable improvement in expressive and receptive language when the analysis was applied solely to controlled studies (ES=0.46, 0.42; 95% CI: -0.08-1.0, -0.06-0.91, respectively). Additionally, adaptation composite scores were reported in five studies, resulting in a significant effect size of 0.47 (95% CI 0.11 to 0.83).
The controlled ESDM studies and the outcome for ASD symptom severity were discarded from meta-analysis II because of inadequate or isolated data.
Stratified Analyses
The results for the comparison of the three intervention approaches in the stratified analyses of meta-analysis I revealed disparate effects. Notably, the ESDM group had a significantly higher ES for IQ than the EIBI and other interventions groups (gc=1.37, 0.61 and 1.21, respectively; Figure 2). Regarding other outcomes, the number of ESDM studies is insufficient for comparison. Nevertheless, the opposite occurred for symptom outcomes (ASD symptom severity and social adaptive functioning), as the EIBI group had clearly greater symptom improvement than the other interventions group (gc=-1.27, 0.65 vs. gc=-0.03, 0.19). Additionally, stratified analyses could not be conducted in meta-analysis II because of the limitations of the controlled studies.
Sensitivity Analysis
Sensitivity analyses suggested that the estimates were not substantially modified by any single study. There was an exception for the adaptive composite score, as a small effect with a gc of 0.31 (95% CI 0.002 to 0.62) was shown when Magiati [19] was removed in meta-analysis I. The sensitivity analyses did not yield different findings after the data were reanalyzed using a fixed effects model.
Publication Bias
No sign of publication bias was found in the funnel plots and Egger’s test for any outcome.
Meta-regression
Across 9 predictors in univariate meta-regressions (Table 3), four mediators of longitudinal change in mid-childhood and adolescence outcomes emerged: (1) EIBI was more effective in reducing symptom severity than non-EIBI programs, and this explained 64% of the heterogeneity (Coefficient=-1.31, P=0.045). (2) Higher total and social adaptive functioning were associated with longer total hours of the intervention and explained 78% and 100% of the heterogeneity (Coefficient=0.0001, P=0.021; Coefficient=0.0002, P=0.032, respectively). (3) Higher social adaptive functioning was also associated with a higher risk of bias (Adj R2=100.00%, Coefficient=0.78, P=0.026). No potential confounding factors affected the change in DLS. The multivariate meta-regressions demonstrated a clear effect of implementer (therapist or therapist and parents) on IQ after the p-value was adjusted (P=0.028, Table 4). Specifically, the involvement of parents in implementing intervention strategies had a more beneficial effect on IQ enhancement than the involvement of a therapist alone.
Table 3. Results of the univariate meta-regression analyses by adaptation and symptomatic variables.
|
|
ASD SS
|
|
Composited
|
|
DLS
|
|
Social
|
|
|
Coeff
|
P
|
|
Coeff
|
P
|
|
Coeff
|
P
|
|
Coeff
|
P
|
Internal Validity
|
Risk of bias
|
|
1.100
|
0.33
|
|
0.450
|
0.16
|
|
0.019
|
0.97
|
|
0.780
|
0.03*
|
Sample size
|
|
0.020
|
0.41
|
|
-0.014
|
0.15
|
|
-0.037
|
0.63
|
|
-0.033
|
0.62
|
Population Characteristics
|
Pre age
|
|
-0.080
|
0.17
|
|
-0.018
|
0.48
|
|
-0.046
|
0.46
|
|
-0.027
|
0.61
|
Pre IQ
|
|
-0.029
|
0.75
|
|
0.001
|
0.98
|
|
-0.014
|
0.74
|
|
0.011
|
0.83
|
Time intervala
|
|
-0.002
|
0.85
|
|
-0.002
|
0.65
|
|
0.009
|
0.53
|
|
-0.022
|
0.03
|
Post ageb
|
|
-0.005
|
0.64
|
|
-0.001
|
0.89
|
|
0.0006
|
0.98
|
|
-0.039
|
0.05
|
Intervention Characteristics
|
Approachesc
|
|
-1.310
|
<0.05*
|
|
-0.704
|
0.18
|
|
-0.550
|
0.30
|
|
0.330
|
0.47
|
Total treatment hours
|
|
-0.0002
|
0.19
|
|
0.0001
|
0.02*
|
|
-0.0001
|
0.82
|
|
0.0002
|
0.03*
|
Delivery agents
|
|
1.180
|
0.15
|
|
0.097
|
0.77
|
|
0.120
|
0.84
|
|
0.033
|
0.95
|
Notes: a Time interval between postintervention and follow-up.
b Mean age of participants at last (“middle child or adolescent”) assessment.
c Categorical variable, EIBI=1, non-EIBI (ESDM and other interventions)=0.
d Based on the result of sensitivity analysis, Magiati (2011) was removed from the meta-regression analyses.
ASD SS, ASD symptom severity; Coeff, unstandardized meta-regression coefficient; Composite, Vineland adaptive composite score; DLS, Daily living skills; Pre, preintervention.
* p<0.05
ASD symptom severity - Approaches: Adj R2 =64.19%
Vineland adaptive composite score - Total treatment hours: Adj R2 =78.06%
Vineland social adaptive score - Total treatment hours: Adj R2 =100.00%
Vineland social adaptive score - risk of bias: Adj R2 =100.00%
Table 4. Results of the multivariate meta-regression analyses by cognitive function.
|
Coefficient
|
SE
|
95% CI
|
P
|
tau2
|
k
|
Adj R2 (%)
|
Model P
|
Type I errorsa
|
IQ
|
|
|
|
|
|
|
|
|
|
Delivery agentsb
|
0.6756
|
0.2637
|
[0.0881, 1.2632]
|
0.028*
|
|
|
|
|
|
Pre age
|
-0.0289
|
0.0204
|
[-0.0742, 0.0165]
|
0.187
|
0.1294
|
14
|
52.15
|
0.048*
|
not
|
Total treatment hours
|
0.00000184
|
0.000046
|
[-0.0001, 0.0001]
|
0.969
|
|
|
|
|
|
Notes: a Monte Carlo permutation test was applied to correct type I errors for multiple covariate meta-regressions.
b Categorical variable: therapist=1, therapist+parents=2.
CI, confidence interval; Coefficient, unstandardized meta-regression coefficient; CTM, comprehensive treatment model; IQ, intelligence quotient; k, number of studies or "clusters"; Pre, preintervention; SE, standard error.
* p< 0.05