Child Health CheckPoint: cohort summary and methodology of a physical health and biospecimen module for the Longitudinal Study of Australian Children

Objectives‘Growing Up in Australia: The Longitudinal Study of Australian Children’ (LSAC) is Australia's only nationally representative children’s longitudinal study, focusing on social, economic, physical and cultural impacts on health, learning, social and cognitive development. LSAC's first decade collected wide-ranging repeated psychosocial and administrative data; here, we describe the Child Health CheckPoint, LSAC’s dedicated biophysical module.Design, setting and participantsLSAC recruited a cross-sequential sample of 5107 infants aged 0–1 year and a sample of 4983 children aged 4–5 years in 2004, since completing seven biennial visits. CheckPoint was a cross-sectional wave that travelled Australia in 2015–2016 to reach LSAC’s younger cohort at ages 11–12 years between LSAC waves 6 and 7. Parent–child pairs participated in comprehensive assessments at 15 Assessment Centres nationwide or, if unable to attend, a shorter home visit.MeasuresCheckPoint’s intergenerational, multidimensional measures were prioritised to show meaningful variation within normal ranges and capture non-communicable disease (NCD) phenotype precursors. These included anthropometry, physical activity, fitness, time use, vision, hearing, and cardiovascular, respiratory and bone health. Biospecimens included blood, saliva, buccal swabs (also from second parent), urine, hair and toenails. The epidemiology and parent–child concordance of many measures are described in separate papers.Results1874 (54% of eligible) parent–child pairs and 1051 second parents participated. Participants' geographical distribution mirrored the broader Australian population; however, mean socioeconomic position and parental education were higher and fewer reported non-English-speaking or Indigenous backgrounds. Application of survey weights partially mitigates that the achieved sample is less population representative than previous waves of LSAC due to non-random attrition. Completeness was uniformly high for phenotypic data (>92% of eligible), biospecimens (74%–97%) and consent (genetic analyses 98%, accessing neonatal blood spots 97%, sharing 96%).ConclusionsCheckPoint enriches LSAC to study how NCDs develop at the molecular and phenotypic levels before overt disease emerges, and clarify the underlying dimensionality of health in childhood and mid-adulthood.

NOTCH1 mutation can be an early, prenatal genetic event in T-ALL

NOTCH1 mutations are common in T-lineage acute lymphoblastic leukemia (T-ALL). Twin studies and retrospective screening of neonatal blood spots provide evidence that fusion genes and other chromosomal abnormalities associated with pediatric leukemias can originate prenatally. Whether this is also the case for NOTCH1 mutations is unknown. Eleven cases of T-ALL were screened for NOTCH1 mutations and 4 (36%) had mutations in either the heterodimerization (HD) or proline glutamic acid/serine/threonine (PEST) domains. Of these 4, 3 could be amplified by mutation-specific polymerase chain reaction primers. In one of these 3, with the highest sensitivity, NOTCH1 mutation was detected in neonatal blood spots. In this patient, the blood spot was negative for SIL-TAL1 fusion, present concomitant with NOTCH1 mutation, in the diagnostic sample. We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion.

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first- and second-hit genetic alterations (TCRD-LMO2 breakpoint regions, n = 2; TAL1 deletions, n = 3; Notch1 mutations, n = 1) and nononcogenic T-cell receptor rearrangements (n = 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100 000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth.