Total Parenteral Nutrition (TPN), which uses intravenous administration of nutrients, minerals and vitamins, is essential for sustaining premature infants until they transition to enteral feeds, but there is limited information on metabolomic differences between infants on TPN and enteral feeds. We performed untargeted global metabolomics on urine samples collected between 23–30 days of life from 314 infants born <29 weeks gestational age from the TOLSURF and PROP cohorts. Principal component analysis across all metabolites showed a separation of infants solely on TPN compared to infants who had transitioned to enteral feeds, indicating global metabolomic differences between infants based on feeding status. Among 913 metabolites that passed quality control filters, 609 varied in abundance between infants on TPN vs. enteral feeds at p < 0.05. Of these, 88% were in the direction of higher abundance in the urine of infants on enteral feeds. In a subset of infants in a longitudinal analysis, both concurrent and delayed changes in metabolite levels were observed with the initiation of enteral feeds. These infants had higher concentrations of essential amino acids, lipids, and vitamins, which are necessary for growth and development, suggesting the nutritional benefit of an enteral feeding regimen.

Total Parenteral Nutrition (TPN), which uses intravenous administration of nutrients, minerals and vitamins, is essential in sustaining premature infants until they transition to enteral feeds. There is limited information on metabolomic differences between infants on TPN and enteral feeds. We performed untargeted global metabolomics on urine samples collected between 23-30 days of life from 314 infants born <29 weeks gestational age from the TOLSURF and PROP cohorts. Principal component analysis across all metabolites showed a separation of infants solely on TPN as compared to infants who had transitioned to enteral feeds, indicating global metabolomic differences between infants based on feeding status. Among 913 metabolites that passed quality control filters, 609 varied in abundance between infants on TPN vs enteral feeds at p<0.05. Of these, 88% were in the direction of higher abundance in the urine of infants on enteral feeds. In a subset of infants with longitudinal analysis, both concurrent and delayed changes in metabolite levels were observed with initiation of enteral feeds. Infants on enteral feeds had higher concentrations of essential amino acids, lipids, and vitamins, which are necessary for growth and development, suggesting a nutritional benefit of an enteral feeding regimen.

Background Large-scale family pedigrees are commonly used across medical, evolutionary, and forensic genetics. These pedigrees are tools for identifying genetic disorders, tracking evolutionary patterns, and establishing familial relationships via forensic genetic identification. However, there is a lack of software to accurately simulate different pedigree structures along with genomes corresponding to those individuals in a family pedigree. This limits simulation-based evaluations of methods that use pedigrees. Results We have developed a python command-line-based tool called py_ped_sim that facilitates the simulation of pedigree structures and the genomes of individuals in a pedigree. py_ped_sim represents pedigrees as directed acyclic graphs, enabling conversion between standard pedigree formats and integration with the forward population genetic simulator, SLiM. Notably, py_ped_sim allows the simulation of varying numbers of offspring for a set of parents, with the capacity to shift the distribution of sibship sizes over generations. We additionally add simulations for events of misattributed paternity, which offers a way to simulate half-sibling relationships. We validated the accuracy of our software by simulating genomes onto diverse family pedigree structures, showing that the estimated kinship coefficients closely approximated expected values. Conclusions py_ped_sim is a user-friendly and open-source solution for simulating pedigree structures and conducting pedigree genome simulations. It empowers medical, forensic, and evolutionary genetics researchers to gain deeper insights into the dynamics of genetic inheritance and relatedness within families.

BACKGROUND: Extremely premature infants are treated with acetaminophen (APAP) for discomfort and patent ductus arteriosus. A recent study found an association between APAP metabolite levels in mothers’ breast milk and the diagnoses of both bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in their infants. METHODS: Urine samples from 314 infants <29 weeks gestation in the TOLSURF and PROP studies were analyzed by untargeted UHPLC:MS/MS. We performed multivariate logistic regression and meta-analysis to examine associations between APAP metabolite levels and clinical outcomes. RESULTS: 4-APAP sulfate was the highest detected and most abundant metabolite of 8 detected and was present in 98% of urines. In longitudinal studies (day 6-56), periods of elevated urinary 4-APAP-sulfate occurred in 24 of 28 infants and were of longer duration (10.1 vs 4.2 days, p=0.004) and higher levels (13.3 vs 5.6, p=0.013) in infants on enteral vs total parenteral nutrition. At both day 10 and 28 there were no significant associations between levels of APAP metabolites and BPD or ROP in all infants or only those on TPN or enteral feeds. CONCLUSION: In two cohorts of premature infants, APAP metabolites were detected uniformly and levels were not associated with increased risk for two adverse clinical outcomes. Impact Statement: Premature infants are treated with acetaminophen (APAP) for analgesia and closure of patent ductus arteriosus, however an association has been reported between APAP levels in maternal milk and infant bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). In an untargeted metabolomic study of 2 cohorts of premature infants, the major urinary APAP metabolite was detected in most urine samples of all infants, and there were intervals of elevated levels. Using both longitudinal and cross-sectional analyses, we found no association between APAP levels and either BPD or ROP. Although APAP is known to have toxic effects at high doses, our findings suggest that APAP exposure, at doses experienced by infants in these cohorts, does not increase the risk for two adverse outcomes in the neonatal period.

SUMMARY: Forensic investigation of DNA samples from multiple contributors has become commonplace. These complex analyses use statistical frameworks accounting for multiple levels of uncertainty in allelic contributions from different individuals, particularly for samples containing few molecules of DNA. These methods have been thoroughly tested along some axes of variation, but less attention has been paid to accuracy across human genetic variation. Here, we quantify the accuracy of DNA mixture analysis over 244 human groups. We find higher false inclusion rates for mixtures with more contributors, and for groups with lower genetic diversity. Even for two-contributor mixtures where one contributor is known and the reference group is correctly specified, false inclusion rates are 1e-5 or higher for 56 out of 244 groups. This means that, depending on multiple testing, some false inclusions may be expected. These false positives could be lessened with more selective and conservative use of DNA mixture analysis. HIGHLIGHTS: Groups with lower genetic diversity have higher mixture analysis false positive rates. Analyses with mis-specified references have somewhat higher false positive rates. Mixture analysis accuracy decreases with more mixture contributors. GRAPHICAL

Background: Large-scale family pedigrees are commonly used across medical, evolutionary, and forensic genetics. These pedigrees are tools for identifying genetic disorders, tracking evolutionary patterns, and establishing familial relationships via forensic genetic identification. However, there is a lack of software to accurately simulate different pedigree structures along with genomes corresponding to those individuals in a family pedigree. This limits simulation-based evaluations of methods that use pedigrees. Results: We have developed a python command-line-based tool called py_ped_sim that facilitates the simulation of pedigree structures and the genomes of individuals in a pedigree. py_ped_sim represents pedigrees as directed acyclic graphs, enabling conversion between standard pedigree formats and integration with the forward population genetic simulator, SLiM. Notably, py_ped_sim allows the simulation of varying numbers of offspring for a set of parents, with the capacity to shift the distribution of sibship sizes over generations. We additionally add simulations for events of misattributed paternity, which offers a way to simulate half-sibling relationships, and simulations to extend the breadth of a family pedigree. We validated the accuracy of both our genome simulator and pedigree simulator. We show that we can simulate genomes onto family pedigrees with levels of expected kinship. Conclusions: py_ped_sim is a user-friendly and open-source solution for simulating pedigree structures and conducting pedigree genome simulations. It empowers medical, forensic, and evolutionary genetics researchers to gain deeper insights into the dynamics of genetic inheritance and relatedness within families.