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Table 1 Univariable meta-regression analyses

From: Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis

Covariate Social-communication difficulties Repetitive behaviors and restricted interests Overall core symptoms
k, n β [95% CI] p R2 (%) k, n β [95% CI] p R2 (%) k, n β [95% CI] p R2 (%)
Intervention Route (ref. not oral) 52, 1497 0 [− 0.205, 0.206] 0.998 0 52, 1492 − 0.166 [− 0.391, 0.059] 0.148 8.13 45, 1063 − 0.042 [− 0.301, 0.217] 0.749 0
Experimental intervention (ref. dietary supplement) 52, 1497 − 0.082 [− 0.229, 0.064] 0.268 2.61 52, 1492 − 0.081 − 0.262, 0.1] 0.382 0 45, 1063 − 0.023 [− 0.228, 0.181] 0.822 0
Dose schedule (ref. fixed)** 51, 1491 − 0.095 [− 0.229, 0.038] 0.163 2.57 51, 1486 − 0.195 [− 0.351, − 0.038] 0.015 27.03 44, 1057 − 0.044 [− 0.276, 0.189] 0.713 0
Study design Publication year 52, 1497 0.016 [0.003, 0.03] 0.017 31.53 52, 1492 − 0.006 [− 0.022, 0.009] 0.416 0 45, 1063 − 0.004 [− 0.021, 0.013] 0.607 0
Country (ref. outside US/mixed) 52, 1497 − 0.002 [− 0.139, 0.135] 0.973 0 52, 1492 − 0.024 [− 0.194, 0.145] 0.778 0 45, 1063 − 0.054 [− 0.257, 0.148] 0.598 0.03
Sponsorship (ref. no) 50, 1469 0.078 [− 0.054, 0.21] 0.246 2.89 51, 1470 0.002 [− 0.172, 0.175] 0.984 0 43, 996 0.057 [− 0.152, 0.266] 0.590 0
No. sites* 48, 1395 − 0.003 [− 0.008, 0.003] 0.295 0 48, 1427 − 0.004 [− 0.011, 0.003] 0.287 0 41, 957 − 0.025 [− 0.045, − 0.005] 0.015 31.62
% academic sites 46, 1340 − 0.196 [− 0.435, 0.044] 0.11 10.66 47, 1383 − 0.08 [− 0.397, 0.236] 0.619 0 41, 957 − 0.117 [− 0.461, 0.227] 0.505 0
No. arms 52, 1497 − − 0.036 [− 0.208, 0.136] 0.684 0 52, 1492 0.035 [− 0.182, 0.252] 0.753 0 Insufficient data
Duration (weeks) 52, 1497 0.002 [− 0.007, 0.012] 0.669 0 52, 1492 − 0.009 [− 0.021, 0.003] 0.124 5.63 45, 1063 0.00 3[− 0.009, 0.015] 0.677 0
Washout (ref. no) 46, 1404 − 0.064 [− 0.204, 0.076] 0.369 0 47, 1339 − 0.006 [− 0.165, 0.153] 0.943 0 39, 995 − 0.021 [− 0.248, 0.205] 0.855 0
Sample size** 52, 1497 0 [− 0.001, 0.001] 0.967 0 52, 1492 − 0.002 [− 0.003, − 0.001] 0.004 29.38 45, 1063 − 0.001 [− 0.004, 0.001] 0.213 9.89
% participants on placebo 52, 1497 0.172 [− 0.625, 0.968] 0.673 0 52, 1492 − 0.333 [− 1.31, 0.643] 0.503 0 45, 1063 0.401 [− 0.981, 1.783] 0.569 0
Rater (ref. clinician)*** 51, 1491 − 0.164 [− 0.315, − 0.012] 0.034 21.48 51, 1483 0.131 [− 0.033, 0.294] 0.117 12.20 43, 1009 − 0.148 [− 0.361, 0.065] 0.174 0
Sequence generation (ref. unclear) 52, 1497 0.147 [− 0.047, 0.34] 0.138 6.46 52, 1492 − 0.043 [− 0.302, 0.216] 0.743 0 45, 1063 0.243[− 0.048, 0.533] 0.102 1.70
Allocation concealment (ref. unclear) 52, 1497 − 0.045 [− 0.228, 0.138] 0.631 0 52, 1492 − 0.012 [− 0.233, 0.208] 0.912 0 45, 1063 − 0.252 [− 0.485, − 0.019] 0.034 17.23
Blinding (ref. unclear/high) 52, 1497 0.083 [− 0.068, 0.235] 0.28 0 52, 1492 0.006 [− 0.191, 0.202] 0.953 0 45, 1063 − 0.019 [− 0.269, 0.231] 0.881 0
Missing outcome (ref. unclear/high) 52, 1497 − 0.141 [− 0.293, 0.01] 0.067 12.03 52, 1492 − 0.052 [− 0.247, 0.143] 0.6 0 45, 1063 − 0.162 [− 0.362, 0.038] 0.111 12.72
Selective reporting (ref. unclear/high) 52, 1497 − 0.014 [− 0.254, 0.227] 0.912 0 52, 1492 − 0.156 [− 0.471, 0.160] 0.333 0.33 Insufficient data
Other bias (ref. unclear/high) 52, 1497 − 0.160 [− 0.299, − 0.021] 0.024 27.38 52, 1492 − 0.091 [− 0.303, 0.120] 0.398 0 45, 1063 − 0.033 [− 0.254, 0.188] 0.768 0
Participant Age group (ref. adults/mixed) 52, 1497 − 0.057 [− 0.27, 0.155] 0.597 0 52, 1492 − 0.107 [− 0.323, 0.109] 0.33 1.55 45, 1063 0.148 [− 0.124, 0.42] 0.287 9.35
Mean age 51, 1478 0.002 [− 0.011, 0.014] 0.809 0 51, 1486 0.003 [− 0.008, 0.014] 0.547 0 45, 1063 − 0.007 [− 0.021, 0.007] 0.297 7.37
% female 50, 1453 0.131 [− 0.65, 0.911] 0.743 0 50, 1482 − 0.282 − 1.114, 0.55] 0.507 0 45, 1063 0.277 [− 0.650, 1.203] 0.559 0
% intellectual disability 17, 620 − 0.328 [− 0.672, 0.017] 0.063 42.21 21, 672 0.128 [− 0.335, 0.59] 0.588 0 14, 316 0.382 [− 0.105, 0.869] 0.124 20.87
% Caucasian or Hispanic 29, 963 0.036 [− 0.351, 0.423] 0.855 0 29, 971 − 0.157 [− 0.715, 0.402] 0.583 0 21, 545 − 0.42 [− 1.204, 0.364] 0.294 0
Associated conditions at baseline (ref. no) 52, 1497 − 0.068 [− 0.212, 0.075] 0.351 3.45 52, 1492 0.111 [− 0.065, 0.287] 0.216 5.83 45, 1063 − 0.012 [− 0.242, 0.218] 0.919 0
Baseline mean BMI 12, 445 − 0.063 [− 0.156, 0.029] 0.179 19.01 12, 461 − 0.02 [− 0.132, 0.091] 0.720 0 8, 254 − 0.033 [− 0.122, 0.057] 0.476 0
Baseline mean CGI− S 26, 917 − 0.042 [− 0.25, 0.167] 0.694 0 26, 925 0.033 [− 0.227, 0.292] 0.805 0 17, 513 − 0.077 [− 0.442, 0.288] 0.678 0
Baseline mean ABC− Irritability 31, 917 − 0.017 [-0.028, − 0.006] 0.002 100 30, 884 − 0.005 [− 0.022, 0.013] 0.608 0 17, 340 − 0.006 [− 0.035, 0.023] 0.68 0
Minimum threshold of core symptoms for inclusion (ref. no)** 52, 1497 0.085 [− 0.094, 0.264] 0.358 0.88 52, 1492 − 0.346 [− 0.516, − 0.175] < 0.001 53.85 Insufficient data
  1. A negative coefficient represent an increase of placebo response. For dichotomous covariates, the reference level is mentioned. Meta-regression with dichotomous covariates were not performed when there were less than five data points for a level of the covariate (e.g., placebo lead-in or number of medications). For continuous covariates, the covariate refer to a change of 1 point of the variable, e.g., per year for publication year: decrease of placebo response in social-communication difficulties by 0.016 per year, % percentage of intellectual disability: increase of placebo response in social-communication difficulties by − 0.328 from 0 to 1 (100%) of the participants had intellectual disability. *The effect of number of sites on placebo response in overall core symptoms was not significant (k = 40, coefficient 0.0182 [− 0.268, 0.0631], p = 0.4287), when one outlier study with 26 sites was excluded (Bolognani 2019). **Placebo response in repetitive behaviors was not found to be predicted by sample size (k = 49, coefficient − 0.001 [− 0.002, 0.000], p = 0.052), flexible-dosing (k = 48, coefficient − 0.073 [− 0.189, 0.043], p = 0.218) and using a minimum threshold of core symptoms (k = 49, coefficient − 0.083 [− 0.24, 0.073], p = 0.2950), when three antidepressant trials (Herscu 2019, King 2009, and Reddihough 2019) were excluded. ***In the meta-regression of type of rater, Niederhofer 2003 was not included in social-communication difficulties (aggregated caregiver/teacher rating of ABC-L/SW), Saad 2015 was not included in overall core symptoms (it was not clear if CARS was rated only by parents or also filled by clinicians), and Anagnostou_2012 was not included in overall core symptoms and repetitive behaviors (SRS and RBS-R might have been rated as self-reports)
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Molecular Autism

ISSN: 2040-2392