Publications

This paper addresses the problem of detecting possible serious bacterial infection (pSBI) of infancy, i.e. a clinical presentation consistent with bacterial sepsis in newborn infants using cranial ultrasound (cUS) images. The captured image set for each patient enables multiview imagery: coronal and sagittal, with geometric overlap. To exploit this geometric relation, we develop a new learning framework, called the intersection-guided Crossview Local-and Image-level Fusion Network (CLIF-Net). Our technique employs two distinct convolutional neural network branches to extract features from coronal and sagittal images with newly developed multi-level fusion blocks. Specifically, we leverage the spatial position of these images to locate the intersecting region. We then identify and enhance the semantic features from this region across multiple levels using cross-attention modules, facilitating the acquisition of mutually beneficial and more representative features from both views. The final enhanced features from the two views are then integrated and projected through the image-level fusion layer, outputting pSBI and non-pSBI class probabilities. We contend that our method of exploiting multi-view cUS images enables a first of its kind, robust 3D representation tailored for pSBI detection. When evaluated on a dataset of 302 cUS scans from Mbale Regional Referral Hospital in Uganda, CLIF-Net demonstrates substantially enhanced performance, surpassing the prevailing state-of-the-art infection detection techniques.

BACKGROUND: Congenital heart disease (CHD) is an important cause of childhood mortality as well as morbidity in children and adults. While genetic risk contributes to the majority of CHD, most individuals with CHD do not have an identified genetic diagnosis. Short tandem repeat (TR) elements are composed of repeated base pair motifs for 2-6 basepairs that are highly polymorphic in length between individuals. These regions had been difficult to study with short read sequencing, and they have not been studied at a large scale in the context of CHD. New software and sequencing platforms have allowed for more accurate TR element genotyping. Therefore, we aimed to identify TR element variants that could impact the expression of known CHD genes.

RESULTS: We identified de novo and inherited TR element variants near known CHD genes in participants with CHD (n = 1,899) in the Pediatric Cardiac Genomics Consortium cohort as well as unaffected participants (n = 1,932) from the Simons Foundation Autism Research Initiative using short-read sequencing followed by variant calling with the gangSTR pipeline. Comparison with long-read sequencing confirmed proband genotypes for 75% (91/120) of the TR element variants identified using short read sequencing. 114 TR element regions had 3 or more de novo TR element variants, compared to an expectation of 74 TR element regions (1.54-fold enrichment, p < 1.5E-5). CHD genes CACNA1C and EVC2 had the strongest enrichment of TR element variants in the CHD cohort, determined by a higher frequency of nearby de novo TR length variants in the CHD cohort compared to the non-CHD cohort. Within CHD trios, there was over-transmission of a TR element variant near Tab 2.

CONCLUSIONS: In a targeted analysis of de novo and transmitted TR element variants in a large cohort of CHD probands, each individual had   1 de novo TR element variant near a CHD gene, and participants with CHD demonstrate clustering of variants within TR element regions. Long-read sequencing confirmed the majority of TR element variants identified using the gangSTR pipeline. De novo variants in known CHD genes were enriched in participants with CHD, with specific enrichment in TR elements near CACNA1C, EVC2, and Tab 2 in the CHD cohort. Many individual TR element variants were in known regulatory regions, but further work is needed to determine their functional impact.

While exome and whole genome sequencing have transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we use artificial intelligence (AI) technologies to explore the predictive value of whole exome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a prospective observational cohort study of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes are associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes is further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes is also informative, reducing the risk for some adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

OBJECTIVE: We previously identified Paenibacillus species in the cerebrospinal fluid of 44% of infants presenting for neurosurgical evaluation with findings consistent with postinfectious hydrocephalus (PIH) in Eastern Uganda. Here we sought to compare outcomes among hydrocephalic infants with and without Paenibacillus detection at the time of hydrocephalus surgery.

METHODS: In a prospective observational study, 78 infants with PIH who underwent a cerebrospinal fluid (CSF) diversion prior to 90 days of age had a positive CSF polymerase chain reaction result for Paenibacillus species (PP), and 111 had a negative result (PN). The primary outcome was diversion failure-free survival defined as being alive without diversion failure at last patient contact. Secondary outcomes included overall survival and diversion success.

RESULTS: After a median follow-up period of 35.7 months, the primary outcome was observed in 42 PP patients (54%) and in 76 PN patients (68%) (adjusted hazard ratio (aHR), 2.45; 95% confidence interval [CI], 1.42 to 4.22; P=0.001). PP patients who underwent endoscopic diversion had the worst primary event rate (aHR, 6.47; 95% CI, 2.40 to 17.42; P<0.001). Death from any cause occurred in 16 PP patients (20%) and 9 PN patients (8%) (aHR, 3.47; 95% CI, 1.44 to 8.37; P=0.006). Diversion failure occurred in 28 PP patients (36%) and in 29 PN patients (26%) (aHR, 2.24; 95% CI, 1.31 to 3.85; P=0.003).

CONCLUSIONS: In this study, Paenibacillus detection in the CSF at the time of hydrocephalus surgery was associated with a significantly increased rate of the composite of diversion failure or death, death, and diversion failure, and was particularly increased for patients who had an endoscopic diversion.

This paper addresses the problem of detecting possible serious bacterial infection (pSBI) of infancy, i.e. a clinical presentation consistent with bacterial sepsis in newborn infants using cranial ultrasound (cUS) images. The captured image set for each patient enables multiview imagery: coronal and sagittal, with geometric overlap. To exploit this geometric relation, we develop a new learning framework, called the intersection-guided Crossview Local- and Image-level Fusion Network (CLIF-Net). Our technique employs two distinct convolutional neural network branches to extract features from coronal and sagittal images with newly developed multi-level fusion blocks. Specifically, we leverage the spatial position of these images to locate the intersecting region. We then identify and enhance the semantic features from this region across multiple levels using cross-attention modules, facilitating the acquisition of mutually beneficial and more representative features from both views. The final enhanced features from the two views are then integrated and projected through the image-level fusion layer, outputting pSBI and non-pSBI class probabilities. We contend that our method of exploiting multi-view cUS images enables a first of its kind, robust 3D representation tailored for pSBI detection. When evaluated on a dataset of 302 cUS scans from Mbale Regional Referral Hospital in Uganda, CLIF-Net demonstrates substantially enhanced performance, surpassing the prevailing state-of-the-art infection detection techniques.

OBJECTIVE: To increase length board use for eligible neonatal intensive care unit (NICU) infants.

STUDY DESIGN: We implemented a quality improvement study involving 704 infants in our level IV NICU. A multidisciplinary workgroup developed guidelines for length measurement technique and completed Plan-Do-Study-Act cycles. Outcome measure was the weekly proportion of eligible infants who received a length board measurement. Process measures were the weekly proportion of infants with any length measurement or had method documented. Balancing measure was the incidence of unplanned dislodgements of drains, tubes, or catheters.

RESULTS: After the guideline launch, both process measure proportions increased. Weekly mean percentage of length board increased from 11 to 63%. There were no dislodgement events. Length board measurements were less likely to demonstrate a negative change week-to-week (10% vs 18%, 16/161 vs 59/326, Fisher p = 0.02).

CONCLUSION: In a level IV NICU, a quality improvement initiative increased the safe use of length boards.

The use of genomic sequencing (GS) for prenatal diagnosis of fetuses with sonographic abnormalities has grown tremendously over the past decade. Fetal GS also offers an opportunity to identify incidental genomic variants that are unrelated to the fetal phenotype but may be relevant to fetal and newborn health. There are currently no guidelines for reporting incidental findings from fetal GS. In the United States, GS for adults and children is recommended to include a list of "secondary findings" genes (ACMG SF v.3.2) that are associated with disorders for which surveillance or treatment can reduce morbidity and mortality. The genes on ACMG SF v.3.2 predominantly cause adult-onset disorders. Importantly, many genetic disorders with fetal and infantile onset are treatable as well. A proposed solution is to create a "treatable fetal findings list," which can be offered to pregnant individuals undergoing fetal GS or, eventually, as a standalone cell-free fetal DNA screening test. In this integrative review, we propose criteria for a treatable fetal findings list, then identify genetic disorders with clinically available or emerging fetal interventions and those for which clinical detection and intervention in the first week of life might lead to improved outcomes. Finally, we synthesize the potential benefits, limitations, and risks of a treatable fetal findings list.

Functional impact of noncoding variants can be predicted using computational approaches. Although predictive scores can be insightful, implementing the scores for a custom variant set and associating scores with complex traits require multiple phases of analysis. Here, we present a protocol for prioritizing variants by generating deep-learning-predicted functional scores and relating them with brain traits. We describe steps for score prediction, statistical comparison, phenotype correlation, and functional enrichment analysis. This protocol can be generalized to different models and phenotypes. For complete details on the use and execution of this protocol, please refer to Mondragon-Estrada et al.1.

Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent-offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in MYH6 were enriched in multiple CHD phenotypes and account for  1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.