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What's birth weight got to do with it?
THE EDITORS’ PERSPECTIVES Data from electronic health records to search for rare clinical events — Sarah S. Long, MD
What's birth weight got to do with it? — Sharon E. Oberfield, MD
Extending precision to phenoytpes — Paul G. Fisher, MD
November 2016
I
n this volume of The Journal, Hornik et al in a Pediatric Trials Network report the marriage of electronic health record data of >130 000 neonates with a published pharmacokinetic model of ampicillin exposure depending on dosage and gestational and postnatal ages in order to evaluate the possible relationship of ampicillin dosing/ exposure with seizures. In multivariable analysis, ampicillin dose was not associated with seizures but simulated maximum ampicillin concentration at steady was associated with slightly increased (OR 1.10; 95% CI 1.03, 1.17) of seizures. The methodology (ie, leveraging warehoused data now available from electronic health records to evaluate circumstances of rare events) is the primary punch of this study. The solid scientific bases of the pharmacokinetic model used in this study is the other necessary ingredient. Together, the mega database and scientific basis can permit testing of various hypotheses; such studies have been impossible due to smaller sample sizes and smaller patients from whom individual blood samplings are difficult. Article page 125 ▶
I
n this volume of The Journal, Zung et al take an in-depth look at the clinical characteristics and short-term outcome of delayed thyroid stimulating hormone (TSH) elevation in a large cohort of infants in the neonatal intensive care unit (13 201 subjects over 6 years with 333 presenting with delayed TSH elevation >15 IU/L, and 66% having a birth weight >1500 g). In contrast to the previously accepted dogma, this study concluded that delayed TSH levels have a higher incidence than previously reported, particularly in those with birth weights >1500 g. Indeed, the incidence of delayed TSH was proportionally higher in sick full-term infants vs preterm newborns. Furthermore, in this cohort, 58% of those with delayed TSH elevations were started on levothyroxine treatment. The authors suggest that repeat TSH measurements be performed as early as the second week of life, irrespective of the birth weight. Furthermore, the authors argue that delayed TSH elevation rise is due not only, as has been cited for this finding in premature newborns, to delayed maturation of the hypothalamic-pituitary thyroid axis, but also may reflect the effect of intercurrent medical conditions on the hypothalamic-pituitary thyroid axis. The findings confirm a previous report suggesting that delayed TSH elevation may be more common than previously thought and recommended routine screenings of infants in intensive care settings (J Pediatr Endocrinol Metab 2007;20:501-10). Long-term outcome data obtained in this population will be of interest. Article page 135 ▶
T
he National Institutes of Health Precision Medicine Initiative is “a groundbreaking approach to disease prevention and treatment based on people’s individual differences in environment, genes, and lifestyle” (https://www.nih.gov/precision -medicine-initiative-cohort-program). Regardless, the term “precision medicine” often has been equated with rigorous genotyping of a patient’s DNA at the level of the germline genome or somatic tissues, sometimes malignant, in order to identify the drug “best targeting” that genotype. The greatest hope is that such a therapeutic approach will maximize efficacy on a molecular level while also avoiding toxicity, an optimization of pharmacogenomics. However, intense phenotyping also is a key component of precision medicine. In this volume of The Journal, Ma et al present their Developmental Encephalopathy Inventory (DEI) as a phenotyping tool to differentiate disorders with complex multisystem neurodevelopmental symptoms. They apply the DEI to distinguish the phenotypic features of 20 subjects with FOXG1 disorder and 11 with MECP2 disorder, described in the past as “Rett variant” and “Rett syndrome,” respectively. The DEI identified differentially affected domains that were then rigorously confirmed by cluster analysis and principal component analysis. Such an intense phenotyping approach results in a wealth of data, which readers should examine in this article’s online-only content (available at www.jpeds.com). Overall, children with FOXG1 disorder were more severely impaired and had lesser ability to walk, worse fine motor skills, more disability 3
What's birth weight got to do with it? — Sharon E. Oberfield, MD
Extending precision to phenoytpes — Paul G. Fisher, MD
November 2016
I
n this volume of The Journal, Hornik et al in a Pediatric Trials Network report the marriage of electronic health record data of >130 000 neonates with a published pharmacokinetic model of ampicillin exposure depending on dosage and gestational and postnatal ages in order to evaluate the possible relationship of ampicillin dosing/ exposure with seizures. In multivariable analysis, ampicillin dose was not associated with seizures but simulated maximum ampicillin concentration at steady was associated with slightly increased (OR 1.10; 95% CI 1.03, 1.17) of seizures. The methodology (ie, leveraging warehoused data now available from electronic health records to evaluate circumstances of rare events) is the primary punch of this study. The solid scientific bases of the pharmacokinetic model used in this study is the other necessary ingredient. Together, the mega database and scientific basis can permit testing of various hypotheses; such studies have been impossible due to smaller sample sizes and smaller patients from whom individual blood samplings are difficult. Article page 125 ▶
I
n this volume of The Journal, Zung et al take an in-depth look at the clinical characteristics and short-term outcome of delayed thyroid stimulating hormone (TSH) elevation in a large cohort of infants in the neonatal intensive care unit (13 201 subjects over 6 years with 333 presenting with delayed TSH elevation >15 IU/L, and 66% having a birth weight >1500 g). In contrast to the previously accepted dogma, this study concluded that delayed TSH levels have a higher incidence than previously reported, particularly in those with birth weights >1500 g. Indeed, the incidence of delayed TSH was proportionally higher in sick full-term infants vs preterm newborns. Furthermore, in this cohort, 58% of those with delayed TSH elevations were started on levothyroxine treatment. The authors suggest that repeat TSH measurements be performed as early as the second week of life, irrespective of the birth weight. Furthermore, the authors argue that delayed TSH elevation rise is due not only, as has been cited for this finding in premature newborns, to delayed maturation of the hypothalamic-pituitary thyroid axis, but also may reflect the effect of intercurrent medical conditions on the hypothalamic-pituitary thyroid axis. The findings confirm a previous report suggesting that delayed TSH elevation may be more common than previously thought and recommended routine screenings of infants in intensive care settings (J Pediatr Endocrinol Metab 2007;20:501-10). Long-term outcome data obtained in this population will be of interest. Article page 135 ▶
T
he National Institutes of Health Precision Medicine Initiative is “a groundbreaking approach to disease prevention and treatment based on people’s individual differences in environment, genes, and lifestyle” (https://www.nih.gov/precision -medicine-initiative-cohort-program). Regardless, the term “precision medicine” often has been equated with rigorous genotyping of a patient’s DNA at the level of the germline genome or somatic tissues, sometimes malignant, in order to identify the drug “best targeting” that genotype. The greatest hope is that such a therapeutic approach will maximize efficacy on a molecular level while also avoiding toxicity, an optimization of pharmacogenomics. However, intense phenotyping also is a key component of precision medicine. In this volume of The Journal, Ma et al present their Developmental Encephalopathy Inventory (DEI) as a phenotyping tool to differentiate disorders with complex multisystem neurodevelopmental symptoms. They apply the DEI to distinguish the phenotypic features of 20 subjects with FOXG1 disorder and 11 with MECP2 disorder, described in the past as “Rett variant” and “Rett syndrome,” respectively. The DEI identified differentially affected domains that were then rigorously confirmed by cluster analysis and principal component analysis. Such an intense phenotyping approach results in a wealth of data, which readers should examine in this article’s online-only content (available at www.jpeds.com). Overall, children with FOXG1 disorder were more severely impaired and had lesser ability to walk, worse fine motor skills, more disability 3