Table 1.
Trigger and Case Definitions and Percent Meeting Trigger and Case Status Overall and By Domain
| Domain | Criteria for Meeting Trigger | Criteria for Defining Adverse Event (Case) | Met Trigger Criteria | Met Case Criteriaa
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| Among those meeting Triggers | Overall | ||||||||
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| Number Evaluated | N (%) | 95% CI | Number Evaluated | N (%) | Cases/Evaluable (%) | 95% CI | |||
| Language Impairment | Language test score >2 SDs below population norms on age-specific testsb | Verification of language scores below threshold | 1499 | 200 (13.3%) | 11.7–15.2% | 200 | 198 (99.0%) | 198/1499 (13.2%) | 11.5–15.0% |
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| Metabolic Abnormality | BMI or weight-for-length > 95th percentile, among participants ≥ 2 years of age | Abnormal fasting lipids (cholesterol, HDL, LDL, or TG) or insulin resistance defined by HOMA score | 1790 | 515 (28.8%) | 26.7–30.9% | 398 | 190 (47.7%) | 190/1673 (11.4%) | 9.9–13.0% |
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| Impaired Growth | Weight or height <3rd percentile, a drop in weight or height Z-score of >1.3 SDs, or either triceps skinfold or mid-upper arm circumference < 5th percentile | Growth trigger met at 2 or more study visits (consecutive or not) | 2667 | 494 (18.5%) | 17.1–20.1% | 454 | 160 (35.2%) | 160/2097 (7.6%) | 6.5–8.9% |
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| Neurologic Diagnosis | Febrile or afebrile seizure, microcephaly, or other neurologic diagnosis | Confirmed neurologic diagnosis based on pediatric neurology consultation and expert review | 2674 | 269 (10.1%) | 8.9–11.3% | 256 | 163 (63.7%) | 163/2661 (6.1%) | 5.2–7.1% |
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| Neurodevelopmental Impairment | Score > 2 SDs below population norm on age specific testsc | Verification of scores below age-specific threshold | 1295 | 60 (4.6%) | 3.6–5.9% | 60 | 58 (96.7%) | 58/1295 (4.5%) | 3.4–5.8% |
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| Elevated Lactate | Repeatedly elevated point-of-care blood lactate >3 mmol/L (on two assessments at same visit) | Venous lactate > 3 mmol/L and ratio of lactate to pyruvate >20, if obtained | 2576 | 161 (6.3%) | 5.3–7.3% | 128 | 53 (41.4%) | 53/2543 (2.1%) | 1.6–2.7% |
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| Chemistry or Hematology Toxicity | Grade ≥ 3 value for target hematologic or clinical chemistry measurement, confirmed by repeat assessmentd | Confirmation of laboratory abnormality on repeat testing without alternative etiology | 2670 | 21 (0.8%) | 0.5–1.2% | 21 | 11 (52.4%) | 11/2670 (0.4%) | 0.2–0.7% |
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| Hearing Impairment | Abnormal newborn hearing screen or mixed or sensorineural hearing loss for non-newborns | Confirmation of sensorineural or mixed hearing loss based on audiologic examination and by otolaryngologist, with no alternative explanation for hearing loss. | 1906 | 75 (3.9%) | 3.1–4.9% | 54 | 5 (9.3%) | 5/1885 (0.3%) | 0.1–0.6% |
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| Case in any Domain | 2680 | 1281 (47.8%) | 45.9–49.7% | 670/2680 (25.0%) | 23.4–26.7% | ||||
| Case in ≥ 2 Domains | 2680 | 374 (14.0%) | 12.7–15.3% | 137/2680 (5.1%) | 4.3–6.0% | ||||
BMI= body mass index, CI=confidence interval, LDL= low density lipoprotein, HDL=high density lipoprotein, HOMA=homeostatic model assessment, SD=standard deviation Full trigger and case definitions appear in Williams et al.21
Some subjects were evaluated for triggers but pending or indeterminate for case status, including 570 for growth domain (due to lack of at least 2 visits with growth measurements, including 40 who met growth trigger), 117 for metabolic (lacking fasting lipids and insulin measures), 33 for lactate (lacking venous lactate), 21 for hearing (lacking full audiologic exam), and 13 for neurologic domain (lacking follow-up consult or necessary assessments).
Age specific tests include MacArthur-Bates Communicative Development Index at age 1, Ages and Stages at age 2, and Test of Language Development at age 5.
Age specific tests include Bayley III at age 1 and 3, WPPSI at age 5, WISC at age 9 and older.
Specific laboratory tests included white blood count (WBC), polymorphonuclear neutrophil (PMN), lymphocytes, platelets, and hemoglobin for hematology and alanine aminotransferase (ALT), lactate dehydrogenase (LDH), lipase, creatine phosphokinase (CPK), blood urea nitrogen (BUN), creatinine, and glucose for clinical chemistry. Grade 3 or higher toxicity based on NIH Division of AIDS Toxicity tables37