Supporting Information: Assessing Hippocampal Development and Language in Early Childhood: Evidence from a New Application of the Automatic Segmentation Adapter Tool
Joshua K. Lee12, Christine W. Nordahl3, David G. Amaral3, Aaron Lee3, Marjorie Solomon3, Simona Ghetti12 University of California, Davis
1
Department of Psychology, University of California, Davis
2
Center for Mind and Brain, University of California, Davis 3
MIND Institute, University of California, Davis
Corresponding Authors: Joshua K Lee,
[email protected], 202 Cousteau Place, Davis, CA 95618, U.S.A. and Simona Ghetti,
[email protected], 202 Cousteau Place, Davis, CA 95618, U.S.A.
To provide a more complete picture of our results, we conducted additional regression analyses using hippocampal volumes generated with the following methods: (1) FreeSurfer without correction using procedures described in Study 1; (2) Manually corrected ASAT volumes obtained using the same algorithms described in Study 1 and subsequently corrected manually by the same trained tracer, AL, who generated the segmentations used in Study 1. These volumes are used as an approximation of manual segmentation. For the reader’s convenience, results using ASAT-10 volumes included in the main manuscript are also reproduced here. Regression Analyses. We examined age and sex related differences in hippocampal volume while accounting for intracranial volume (ICV). Left and right hippocampal volumes from FreeSurfer and from manually corrected volumes were separately regressed on age, sex (male = -1, female = 1), ICV, age X sex, and ICV X age interaction terms. Results of these regression analyses are reported in Supporting Information Table 1 for left hippocampus and in Supporting Information Table 2 for right hippocampus. Using FreeSurfer and manual corrected hippocampal segmentations, we then examined the relation between hippocampal volume and early language development with multiple linear regression, regressing expressive or receptive language scores from the MSEL on age (Z-score), sex (male = -1, female = 1), left or right hippocampal volumes (Z-score), ICV (Z-score), sex X age, age X volume, volume X sex, age X ICV, and volume X ICV. Results for early expressive language ability are reported in Supporting Information Tables 3 for left hippocampus and in Table 4 for right hippocampus. Results for early receptive language ability are reported in Supporting Information Tables 5 for left hippocampus and in Table 6 for right hippocampus. Results from these analyses are largely analogous across methods, with small, unreliable numerical differences in parameter estimates.
While FreeSurfer appeared to produce comparable beta estimates as those produced by demonstrably more accurate methods (i.e. ASAT-10), we caution readers from the implication that FreeSurfer volumes can be relied on to function the same as those generated by those other more accurate methods. In Study 2, the estimated errors of FreeSurfer’s segmentations (i.e. FreeSurfer minus manual corrected volume) are substantial: Left: M = 1209 mm3, SD = 221 mm3; Right: M = 1247 mm3, SD = 120 mm3, adding approximately 49% to the total volume of the manual segmentation. Those stand in contrast to ASAT-10 errors: Left: M = 9.13 mm3, SD = 116 mm3; Right: M = 4.43 mm3, SD = 88 mm3, corresponding to approximately ± 2% difference in total volume of the manual segmentations. Therefore, any biases in how FreeSurfer errors may are distributed over relevant research variables (e.g., age, sex, ICV) would be situated to impact the validity of results. We examined the relation between the volumes of manual corrected segmentations and the volume of segmentation errors produced by FreeSurfer and ASAT-10 (i.e., automated segmentation volume minus manual corrected volume). We found that the volume of manually corrected segmentations positively predicted the volume of FreeSurfer errors in left, r(87) = .29, p = .006, and right, r(87) = .47, p < .001, hippocampus. In contrast, manually corrected volumes were not significantly associated with the magnitude of segmentation errors produced by ASAT-10 in left, r(87) = -.07, p = .56, or right, r(87) = .19, p = .08, hippocampus. These results are important for several reasons. First, given that many factors have been found to predict the size of the hippocampus (e.g., age in typical development, Wierenga et al., 2014; autism spectrum disorder, Schumann, et al., 2004, hypoxic-ischemic injury, Gadian et al., 2000; premature birth, Nosarti et al., 2002), the accuracy of FreeSurfer may differ depending on the kind of population observed and the factors examined. Second, these Free Surfer errors may
not always be linearly related to size. Wenger et al., (2014) conducted similar analyses in 44 middle-aged adults and 47 older-aged adults. Like in the present research, Wenger et al., (2014) reported that FreeSurfer substantially overestimated the magnitude of hippocampal volumes in comparison to manual segmentations across age-groups. Unlike our results, however, Wenger et al., (2014) reported negative correlations between manual volumes and FreeSurfer errors bilaterally in a sample of older adults, while failing to detect reliable correlations between manual volumes and FreeSurfer errors bilaterally in middle-aged adults. Thus, it seems that FreeSurfer errors do not scale with their manually estimated counterparts in the same way across age-groups. Such age-related biases in FreeSurfer’s hippocampal segmentation suggest potential threats to the validity of FreeSurfer’s segmentation as a measure of hippocampal volume in developmental research across the lifespan. Further quantification of these potential biases is warranted in future research.
References Gadian, D. G., Aicardi, J., Watkins, K. E., Porter, D. A., Mishkin, M., & Vargha-Khadem, F. (2000). Developmental amnesia associated with early hypoxic–ischaemic injury. Brain, 123(3), 499-507. Nosarti, C., Al‐Asady, M. H., Frangou, S., Stewart, A. L., Rifkin, L., & Murray, R. M. (2002). Adolescents who were born very preterm have decreased brain volumes. Brain, 125(7), 1616-1623. Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, Amaral, DG (2004): The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci 24:6392–6401. Wenger E, Mårtensson J, Noack H, Bodammer NC, Kühn S, Schaefer S, Lövdén M (2014): Comparing manual and automatic segmentation of hippocampal volumes: Reliability and validity issues in younger and older brains. Hum Brain Map 35: 4236-4248. Wierenga L, Langen M, Ambrosino S, van Dijk S, Oranje B, Durston S (2014): Typical development of basal ganglia, hippocampus, amygdala and cerebellum from age 7 to 24. NeuroImage 96: 67-72.
Table 1 (Supporting Information) Age and Sex Differences in Left Hippocampal Volume Left Hippocampus
Manual Corrections
FreeSurfer β
(Constant)
SE B
t
p
41.51
90.80
