Evaluation of Concordance Between Original Death Certifications and an Expert Panel Process in the Determination of Sudden Unexplained Death in Childhood

Crandall, Laura A.; Lee, Joyce H.; Friedman, Daniel; Lear, Kelly; Maloney, Katherine F.; Pinckard, J. Keith; Lin, Peter T.; Andrew, Tom W.; Roman, Kristin; Landi, Kristen; Jarrell, Heather S.; Williamson, Alex; Downs, J. C. Upshaw; Pinneri, Kathy; William, Christopher; Maleszewski, Joseph J.; Reichard, R. Ross; Devinsky, Orrin

doi:10.1001/jamanetworkopen.2020.23262

Cited by 12 publications

(14 citation statements)

References 20 publications

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“…Sudden unexplained death in childhood (SUDC) is now a leading cause of death in toddlers (children 1–4 years of age). Although hundreds of SUDC cases are certified by medical examiners each year—392 cases were recorded by the CDC in 2018—in a recent study by Crandall et al [ 64 ], experts disagreed with the original certified cause-of-death in 40 % of cases, including many that were originally considered accidental or natural but adjudicated as "unexplained." There is a low rate of consistency and precision in death certification of SUDC, so true SUDC incidence is likely to be higher than official rates reported by the CDC.…”

Section: Discussionmentioning

confidence: 99%

Vaccines and sudden infant death: An analysis of the VAERS database 1990–2019 and review of the medical literature

Miller¹

2021

Toxicology Reports

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Highlights Additive or synergistic toxicity may occur following multivalent vaccination. Infant deaths post-vaccination are often misclassified as SIDS or suffocation in bed. Of all reported SIDS cases post-vaccination, 75 % occurred within 7 days (p < 0.00001). Inflammatory cytokines in the infant medulla act as neuromodulators causing prolonged apneas. Adjuvants that cross the BBB may induce fatal disorganization of respiratory control.

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Section: Discussionmentioning

confidence: 99%

Vaccines and sudden infant death: An analysis of the VAERS database 1990–2019 and review of the medical literature

Miller¹

2021

Toxicology Reports

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“…Cases are referred from multiple sites, including NYU, Columbia University, the Mayo Clinic (Minnesota), and over 30 clinical and forensic collaborators at medical examiner and coroner offices. Ancillary analyses done at autopsy [ 8 ] included microbiology, with various testing performed ( n = 17, all cases were not necessarily tested for all of the same viruses/bacteria). Of the cases with microbiology testing, 4/17 had positive post-mortem virology from respiratory and brain samples that were not considered as contributing to COD.…”

Section: Methodsmentioning

confidence: 99%

“…There have been few molecular studies in SUDC and several related studies in sudden unexpected infant death (SUID) cases (< 1 year of age). Genetic variants may influence SUDC risk, particularly neurological and/or cardiomyopathies [ 8 , 22 , 24 , 29 , 52 ]. De novo mutations that occur post-zygotically can result in somatic mosaicism and occur in SUDC and SUDEP cases, which can influence brain development in the form of abnormal neuronal migration, brain overgrowth disorders, as well as epileptic encephalopathies, intellectual disability, autism, and neuropsychiatric diseases [ 10 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

et al. 2022

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Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10–15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10–21, z = − 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10–6, z = 2.65) and CA1-3 (p = 4.7 × 10–6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10–5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10–3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10–5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10–3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.

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“…Children and young adults are less likely to suffer SCA compared to middle-aged and older persons 4, 5 . Autopsy results fail to reveal an explanation for SCA in approximately 40% of cases 6 and the attributed cause of death may be inaccurate 7 . Studies using genetic testing have revealed a significant portion (∼12-30%) of children/young adults with sudden cardiac death (SCD) that have pathogenic rare variants in genes associated with arrhythmic syndromes and cardiomyopathy 6, 8 .…”

Section: Introductionmentioning

confidence: 99%

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Holmström

Chaudhary

Nakamura

et al. 2022

Preprint

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Background: Sudden cardiac arrest (SCA) is a rare and tragic event among the young and often caused by inherited cardiac disease. Previous studies have investigated referral cohorts, but the prevalence of disease-associated variants is unclear at the community level. We investigated the prevalence of genetic variants among community-based cases of SCA aged <21 years. Methods: The study sample is obtained from two prospective, community-based studies of out-of-hospital SCA ongoing in the Portland, OR metro area (population ~1 million) and Ventura County CA (population ~850,000). We performed next-generation whole genome sequencing and then rare variant analysis of candidate genes associated with arrhythmic syndromes and cardiomyopathy in ClinGen. Results: The mean age of the study subjects was 11.3 years (SD 8.0 years, 30% non-white, 45% female). We found that 36 of 52 young SCA victims (69%) harbored uncertain, likely pathogenic (LP), or pathogenic (P) variants. Eight subjects (15%) carried 9 LP/P variants. Patients with clinical histories suggesting primary arrhythmic syndromes or hypertrophic cardiomyopathy were more likely to harbor clinically actionable variants or variants of unknown significance (VUS), than subjects with myocarditis, sudden infant death syndrome, or sudden arrhythmic death. Variants were more likely to be classified as LP/P among Whites (8/9, 88.9%) as compared to non-Whites (1/9, 11.1%, p = 0.036). Conclusions: A notable proportion of young SCA victims in the community harbor rare, potentially disease-associated gene variants, and further studies are needed to understand variants of unknown significance. We identified differences by phenotype groups and race that have potential implications for genetic testing.

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Evaluation of Concordance Between Original Death Certifications and an Expert Panel Process in the Determination of Sudden Unexplained Death in Childhood

Cited by 12 publications

References 20 publications

Vaccines and sudden infant death: An analysis of the VAERS database 1990–2019 and review of the medical literature

Vaccines and sudden infant death: An analysis of the VAERS database 1990–2019 and review of the medical literature

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

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