Hirschtritt et al., Appendices and Supplementary Tables Page 1 of 8

Appendices

Appendix e-1. Inclusion and Exclusion Criteria

Probands were limited to one Tourette syndrome (TS)-affected individual per family. Inclusion criteria for probands were: age ≥6 years old, established TS diagnosis, and availability of living parents for family-based genetic analyses. Exclusion criteria included: intellectual disability and tics caused by neurologic disorders other than TS. For children, parents and children were interviewed jointly or separately, depending on the family’s preference. For adults, parents were interviewed whenever possible to corroborate data. The sample included 283 affected sib-pairs (two or more TS-affected siblings plus parents) and 1,082 trio families (TS-affected individuals plus both parents). The sib-pair families analyzed in our previous study are included in the current study1. Due to the design of the original genetic study, sib-pair families were excluded at the time of enrollment if both parents had chronic tics or OCD. No such exclusions were made for trio families.

Appendix e-2. Clinical Assessments: Tic symptoms

The TSAICG Tic and Comorbid Symptom (TICS) Inventory is a modified version of the Schedule for Tourette Syndrome and other Behavioral Syndromes2and includes an inventory of >80 motor and phonic tics. Participants were asked whether they had experienced each symptom in the past week, past six months, ever, or never. For analyses, the first three response options were collapsed, and dichotomous data (lifetime presence or absence) were analyzed. Tic frequency and severity items on the TICS Inventory were modified from the Yale Global Tic Severity Scale (YGTSS) 3. Tic severity was characterized by frequency, intensity, and interference of symptoms. The highest score resulting from summing the modified severity questions is 15. As the TICS Inventory was modified during the study period to improve response rates, items not present for all participants were excluded from analysis.

Appendix e-3. Clinical Assessments: Co-morbid Psychiatric Diagnoses

Psychiatric diagnoses comorbid with TS were assessed through structured interviews. Adults were administered either the Structured Clinical Interview for DSM4 or the Schedule for Affective Disorders and Schizophrenia-Lifetime Version, Modified for the Study of Anxiety Disorders5. Children were administered the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Lifetime Version6 and Epidemiologic Version7. These data were only collected during the first wave of recruitment and were available for approximately 19% of participants. Following the procedure described previously 8, to arrive at a best-estimate set of diagnoses, two clinicians who were not involved in the interview process used DSM-IV-TR criteria to assign diagnoses using all available data (i.e., TICS Inventory, structured diagnostic interview data, clinical narrative, and medical records). A consensus diagnosis was achieved after discussion of discrepancies. If a consensus could not be reached, a third clinician’s ratings were used to determine diagnostic status.For analyses, psychiatric diagnoses other than TS, OCD, and ADHD were combined into categories; mood (depression and bipolar disorder), anxiety (panic, generalized anxiety, social phobia, and separation anxiety), and disruptive behavior disorders (conduct disorder and oppositional defiant disorder).

References for Appendices

1. Grados MA, Mathews CA, Tourette Syndrome Association International Consortium for Genetics. Latent class analysis of gilles de la tourette syndrome using comorbidities: Clinical and genetic implications. Biol Psychiatry. 2008;64(3):219-225.

2. Pauls DL, Hurst CR, Kruger SD, Leckman JF, Kidd KK, Cohen DJ. Gilles de la tourette's syndrome and attention deficit disorder with hyperactivity. evidence against a genetic relationship. Arch Gen Psychiatry. 1986;43(12):1177-1179.

3. Leckman JF, Riddle MA, Hardin MT, et al. The yale global tic severity scale: Initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry. 1989;28(4):566-573.

4. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I Disorders–Non-patient edition (SCID-I/NP, version 2.0). New York: Biometrics Research Department, New York State Psychiatric Institute; 1995.

5. Fyer A, Endicott J, Mannuzza S, Klein DF. Schedule for affective disorders and schizophrenia-lifetime version, modified for the study of anxiety disorders (SADS-LA). New York: Anxiety Disorders Clinic, New York State Psychiatric Institute; 1985.

6. Kaufman J, Birmaher B, Brent D, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry. 1997;36(7):980-988.

7. Orvaschel H, Thompson WD, Belanger A, Prusoff BA, Kidd KK. Comparison of the family history method to direct interview. factors affecting the diagnosis of depression. J Affect Disord. 1982;4(1):49-59.

8. Leckman JF, Sholomskas D, Thompson WD, Belanger A, Weissman MM. Best estimate of lifetime psychiatric diagnosis: A methodological study. Arch Gen Psychiatry. 1982;39(8):879-883.

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Supplementary Tables

Table e-1. Factor loadings and internal consistency for tic symptoms exploratory factor model

F1
Eye tics / F2
Head/ Facial tics / F3
Body tics / F4
Socially disinhibited tics / F5 Touching tics / F6 Simple vocal tics
Cronbach’s alpha / 0.68 / 0.68 / 0.61 / 0.73 / 0.61 / 0.52
Item
Eye blinking / 0.66 / 0.03 / -0.09 / -0.08 / -0.05 / 0.07
A quick turn of the eyes / 0.62 / 0.06 / -0.03 / 0.10 / 0.15 / -0.21
Rolling of the eyes to one side / 0.59 / 0.04 / -0.03 / 0.11 / 0.14 / -0.24
Squinting / 0.45 / 0.18 / -0.02 / -0.01 / 0.07 / -0.01
Shrugging the shoulders as if to say ''I don’t know'' / 0.44 / -0.07 / 0.31 / 0.03 / -0.03 / 0.22
Touching the chin to shoulder / 0.44 / -0.01 / 0.29 / -0.07 / 0.13 / 0.11
Opening the eyes wide (briefly) / 0.41 / 0.19 / 0.04 / 0.04 / 0.13 / -0.10
Biting the tongue / -0.06 / 0.66 / 0.10 / 0.05 / -0.08 / 0.00
Chewing on lip(s) / -0.02 / 0.61 / -0.14 / -0.03 / 0.07 / 0.15
Flexing or extending the ankle(s) / 0.04 / 0.55 / 0.30 / -0.20 / 0.04 / -0.06
Tensing the buttocks / 0.05 / 0.54 / 0.35 / -0.11 / -0.01 / -0.12
Teeth bearing / 0.12 / 0.53 / 0.03 / 0.14 / 0.03 / 0.08
Licking the lips / -0.02 / 0.50 / -0.27 / 0.05 / 0.16 / 0.27
Broadening the nostrils (as if smelling something) / 0.33 / 0.49 / 0.06 / 0.02 / -0.22 / 0.01
Smiling / 0.19 / 0.46 / -0.06 / 0.23 / -0.01 / -0.09
Nose twitching / 0.31 / 0.44 / -0.02 / 0.02 / -0.21 / 0.03
Deep knee bending / -0.05 / 0.09 / 0.91 / 0.10 / -0.10 / -0.02
Squatting / -0.08 / 0.02 / 0.77 / 0.10 / 0.03 / -0.03
Knee-bending / 0.03 / 0.27 / 0.60 / -0.03 / 0.15 / 0.02
Bending or gyrating (e.g., bending over) / 0.02 / -0.06 / 0.51 / 0.25 / 0.17 / 0.07
Unusual postures (dystonic tics) / 0.08 / -0.06 / 0.46 / 0.25 / 0.09 / 0.11
Rude or obscene words or phrases (coprolalia) / 0.12 / -0.06 / 0.02 / 0.87 / -0.02 / -0.08
Rude or obscene gestures (copropraxia) / 0.09 / 0.01 / 0.08 / 0.77 / -0.09 / -0.09
Repeating what someone else said, either sounds, single words or phrases (e.g., repeating what is said on TV) (echolalia) / -0.02 / -0.03 / -0.04 / 0.62 / 0.32 / 0.12
Words / -0.10 / 0.09 / 0.06 / 0.60 / 0.22 / -0.06
Repeating something s/he said over and over again (palilalia) / 0.01 / 0.01 / -0.05 / 0.59 / 0.35 / 0.01
Syllables / -0.02 / 0.16 / 0.06 / 0.54 / 0.06 / 0.03
Animal or bird noises / -0.03 / 0.11 / 0.05 / 0.46 / -0.04 / 0.29
Touching / 0.13 / -0.03 / 0.08 / 0.03 / 0.76 / -0.05
Tapping / 0.02 / 0.20 / -0.01 / -0.10 / 0.74 / 0.05
Slower movements (e.g., taking a step forward and 2 steps back) / 0.03 / 0.03 / 0.31 / 0.06 / 0.55 / -0.08
Throat clearing / 0.30 / 0.02 / 0.00 / -0.04 / 0.03 / 0.63
Coughing / 0.25 / 0.06 / 0.03 / 0.00 / 0.05 / 0.50
Sniffing / 0.24 / 0.14 / 0.03 / 0.05 / -0.09 / 0.47

Values represent factor loadings associated with each tic (the degree to which a factor explains or affects a variable); for each tic, the bolded factor loading represents the highest and was used to assign each tic to a single factor.

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Table e-2. Fit statistics and class size for LCA solutions
2 Classes / 3 Classes / 4 Classes / 5 Classes
Tic LCAs Probands
Entropy / 0.88 / 0.84 / 0.84 / 0.83
LMR p-value / ≤.001 / .19 / .03 / .65
BIC / 53593 / 53161 / 52792 / 52868
n of LC1 / 409 / 257 / 132 / 60
n of LC2 / 782 / 308 / 292 / 155
n of LC3 / 626 / 253 / 303
n of LC4 / 514 / 216
n of LC5 / 457
Tic LCAs Probands & Family members
Entropy / 0.93 / 0.92 / 0.88 / 0.87
LMR p-value / ≤.001 / ≤.001 / ≤.001 / .61
BIC / 101282 / 96879 / 96047 / 95508
n of LC1 / 1468 / 592 / 789 / 246
n of LC2 / 2026 / 1332 / 1024 / 447
n of LC3 / 1570 / 1406 / 409
n of LC4 / 275 / 1023
n of LC5 / 1369

Abbreviations: BIC = Bayesian Information Criterion; LCA = latent class analysis; LMR = Lo, Mendel, and Rubin parametric likelihood ratio test

Boldedvalues indicate best-fitting solution based on low BIC, significant LMR results, and clinically interpretable classes.

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Figure e-1. Scree plot of exploratory factor analysis among patients (N = 1191)