Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

Rapid Genome Sequencing Diagnosis in Pediatric Patients with Liver Dysfunction.

OBJECTIVE: To describe the usefulness of rapid whole genome sequencing (rWGS) in a cohort of children presenting with acute liver dysfunction. STUDY DESIGN: This was a retrospective, population-based cohort study conducted at Primary Children's Hospital in Salt Lake City, Utah. Children meeting criteria for acute liver dysfunction who received rWGS between August 2019 and December 2021 were included. rWGS was performed on blood samples from the patient and parents (1 or both depending on availability). The clinical characteristics of patients with positive rWGS results were compared with those with negative results. RESULTS: Eighteen patients with pediatric acute liver dysfunction who had rWGS were identified. The median turnaround time from the date rWGS testing was ordered to the date an initial report was received was 8 days with a shorter turnaround time in patients with a diagnostic rWGS (4 days vs 10 days; P = .03). A diagnostic result was identified in 7 of 18 patients (39%). Subsequently, 4 patients in this cohort, who had negative rWGS results, were found to have a toxic exposure accounting for their liver dysfunction. With removal of these patients, the diagnostic rate of rWGS was 7 of 14 (50%). The use of rWGS led to a change in management for 6 of 18 patients (33%). CONCLUSIONS: We found that rWGS provided a diagnosis in up to 50% of pediatric acute liver dysfunction. rWGS allows for higher diagnostic rates in an expedited fashion that affects clinical management. These data support the routine use of rWGS for life-threatening disorders in children, specifically acute liver dysfunction.

Open-Source Artificial Intelligence System Supports Diagnosis of Mendelian Diseases in Acutely Ill Infants.

Mendelian disorders are prevalent in neonatal and pediatric intensive care units and are a leading cause of morbidity and mortality in these settings. Current diagnostic pipelines that integrate phenotypic and genotypic data are expert-dependent and time-intensive. Artificial intelligence (AI) tools may help address these challenges. Dx29 is an open-source AI tool designed for use by clinicians. It analyzes the patient's phenotype and genotype to generate a ranked differential diagnosis. We used Dx29 to retrospectively analyze 25 acutely ill infants who had been diagnosed with a Mendelian disorder, using a targeted panel of ~5000 genes. For each case, a trio (proband and both parents) file containing gene variant information was analyzed, alongside patient phenotype, which was provided to Dx29 by three approaches: (1) AI extraction from medical records, (2) AI extraction with manual review/editing, and (3) manual entry. We then identified the rank of the correct diagnosis in Dx29's differential diagnosis. With these three approaches, Dx29 ranked the correct diagnosis in the top 10 in 92-96% of cases. These results suggest that non-expert use of Dx29's automated phenotyping and subsequent data analysis may compare favorably to standard workflows utilized by bioinformatics experts to analyze genomic data and diagnose Mendelian diseases.

Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning.

BACKGROUND: Rapidly and efficiently identifying critically ill infants for whole genome sequencing (WGS) is a costly and challenging task currently performed by scarce, highly trained experts and is a major bottleneck for application of WGS in the NICU. There is a dire need for automated means to prioritize patients for WGS. METHODS: Institutional databases of electronic health records (EHRs) are logical starting points for identifying patients with undiagnosed Mendelian diseases. We have developed automated means to prioritize patients for rapid and whole genome sequencing (rWGS and WGS) directly from clinical notes. Our approach combines a clinical natural language processing (CNLP) workflow with a machine learning-based prioritization tool named Mendelian Phenotype Search Engine (MPSE). RESULTS: MPSE accurately and robustly identified NICU patients selected for WGS by clinical experts from Rady Children's Hospital in San Diego (AUC 0.86) and the University of Utah (AUC 0.85). In addition to effectively identifying patients for WGS, MPSE scores also strongly prioritize diagnostic cases over non-diagnostic cases, with projected diagnostic yields exceeding 50% throughout the first and second quartiles of score-ranked patients. CONCLUSIONS: Our results indicate that an automated pipeline for selecting acutely ill infants in neonatal intensive care units (NICU) for WGS can meet or exceed diagnostic yields obtained through current selection procedures, which require time-consuming manual review of clinical notes and histories by specialized personnel.

A novel RAD51 variant resulting in Fanconi anemia identified in an infant with multiple congenital anomalies.

Fanconi anemia, FA, is a rare, multi-system disease caused by pathogenic variants in DNA repair genes. We report a novel RAD51 variant in an infant with FA whose tracheobronchomalacia has not been described in FA. His severe presentation expands the phenotype of RAD51-associated FA, reported only in three patients previously.

Evaluating visual imagery for participant understanding of research concepts in genomics research.

Informed consent is crucial for participant understanding, engagement, and partnering for research. However, current written informed consents have significant limitations, particularly for complex topics such as genomics and biobanking. Our goal was to identify how participants visually conceptualize terminology used in genomics and biobanking research studies, which might provide a novel approach for informed consent. An online convenience sample was used from May to July 2020 to collect data. Participants were asked to draw 10 randomly chosen words out of 32 possible words commonly used in consent forms for genomics and biobanking research. An electronic application captured drawings that were downloaded into a qualitative software program for analysis. A total of 739 drawings by 269 participants were captured. Participants were mostly female (61.3%), eight different race/ethnicities were represented (15.6% Black, 13.8% Hispanic), and most had some college education (68.8%). Some words had consistent visual themes such as different types of risky activities for risk or consistent specific images such as a double helix for DNA. Several words were frequently misunderstood (e.g., ascend for assent), while others returned few submissions (e.g., phenotype or whole genome sequencing). We found that although some words used in genomics and biobanking research were visually conceptualized in a common fashion, but misunderstood or less well-known words had no, few, or mistaken drawings. Future research can explore the incorporation of visual images to improve participant comprehension during consent processes, and how to utilize visual imagery to address more challenging concepts.

Tibial quantitative ultrasound compared to dual-energy X-ray absorptiometry in preterm infants.

OBJECTIVE: The gold standard for diagnosing metabolic bone disease in pediatrics is dual-energy x-ray absorptiometry (DXA). Bone quantitative ultrasound (QUS) has increasing applications. This study compared the relationship of DXA to QUS in preterm infants. DESIGN: Prospective observational study of preterm infants ≤32 weeks gestation or ≤1800 grams at birth. DXA scans measuring bone mineral content (BMC) and tibial QUS scans measuring bone speed of sound (SOS) were obtained near term gestation. RESULTS: 41 infants had bone scans at mean corrected gestation 37.7 ± 2.1 weeks. BMC and SOS showed weak inverse correlation (R2 0.163, p < 0.01). BMC and SOS correlated with parameters at corrected gestational age at the time of the bone scans (p < 0.05-0.001). SOS correlated with birth gestational age (p < 0.001), not BMC. CONCLUSIONS: A statistically significant weak inverse correlation between DXA and QUS was observed. QUS may have advantages over DXA.

Hospital-level variation in genetic testing in children's hospitals' neonatal intensive care units from 2016 to 2021.

PURPOSE: This study aimed to examine variation in genetic testing between neonatal intensive care units (NICUs) across hospitals over time. METHODS: We performed a multicenter large-scale retrospective cohort study using NICU discharge data from the Pediatric Hospital Information System database between 2016 and 2021. We analyzed the variation in the percentage of NICU patients who had any genetic testing across hospitals and over time. We used a multivariable multilevel logistic regression model to investigate the potential association between patient characteristics and genetic testing. RESULTS: The final analysis included 207,228 neonates from 38 hospitals. Overall, 13% of patients had at least 1 genetic test sent, although this varied from 4% to 50% across hospitals. Over the study period, the proportion of patients tested increased, with the increase disproportionately borne by hospitals already testing high proportions of patients. On average, patients who received genetic testing had higher illness severity. Controlling for severity, however, only minimally reduced the degree of hospital-level variation in genetic testing. CONCLUSION: The percentage of NICU patients who undergo genetic testing varies among hospitals and increasingly so over time. Variation is largely unexplained by differences in severity between hospitals. The degree of variation suggests that clearer guidelines for NICU genetic testing are warranted.

Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome.

Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., Lancet Neurol 14: 420 [2015]; Finsterer, Orphanet J Rare Dis 14: 57 [2019]; Prior and Ghosh, J Child Neurol 36: 610 [2021]). The SNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novo SNAP25 c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported SNAP25 variant phenotype, and paves a foundation for personalized management for CMS18.

Stemless Hemiarthroplasty and Anterior Capsular Reconstruction in the Setting of a Residual Humeral Limb: A Case Report.

CASE: We present a 58-year-old left hand-dominant woman with right glenohumeral osteoarthritis and anterior instability in the setting of a congenital residual limb at the level of the mid-humerus. She had persistent pain and dysfunction despite trying conservative treatments and elected for a stemless or "canal-sparing" hemiarthroplasty with anterior capsular reconstruction. At the 2-year follow-up, there was significant improvement in her pain, motion, and function without signs of radiographic loosening. CONCLUSION: A stemless humeral implant is a versatile component that can be used in the face of humeral dysplasia, such as this patient with a congenital residual limb.

On the edge-A diagnostic odyssey.

The diagnostic odyssey of a child with epileptic encephalopathy was resolved by rapid whole genome sequencing. This identified a rare form of pyridoxine responsive epilepsy due to a pathogenic variant in PLPBP. Access to such potentially life-changing diagnostic technology needs to expand in a thoughtful and equitable manner.

Comprehensive variant calling from whole-genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia.

BACKGROUND: Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases. METHODS: As part of the Utah NeoSeq project, we used a research-based, rapid whole-genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left-sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect. RESULTS: Using both a novel, alignment-free and traditional alignment-based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the ZFPM2 gene, which is associated with both CDH and various congenital heart defects. CONCLUSIONS: Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short-read sequencing and underscore the utility of WGS as a first-line diagnostic tool.

Determining health information-seeking behavior of shoulder patients.

BACKGROUND: Patients today have access to an increasing number of health resources to guide medical decision making, including specialist health care providers, the Internet, friends, and family members. No prior studies, to our knowledge, have comprehensively explored health information-seeking behavior (HISB) for patients being managed for shoulder pain. OBJECTIVE: Our primary objective is to identify which health resources patients use and find helpful in a cohort of patients being either evaluated or managed for shoulder pain. With increased access to the Internet and its use, we also hope to quantify the extent of use of Internet resources and identify predictors of patient use. METHODS: We interviewed a cohort of new and follow-up patients being surgically or nonoperatively managed for shoulder pain by a single fellowship-trained orthopedic surgeon. All patients were administered a questionnaire to determine HISB, which evaluated the types of resources used and those deemed most helpful in guiding medical decision making. For patients using the Internet, specific websites were documented. Additional variables that were collected included age, gender, ethnicity, and highest education attained. Multivariable logistic regression was used to evaluate predictors of Internet use. RESULTS: This study included 242 patients. A discussion with an orthopedic surgeon was reported to be the most informative for nonoperatively treated patients, first postoperative patients, and operative follow-up patients. Patients at the first postoperative visit reported YouTube as their preferred resource almost 4 times more than new patients (odds ratio [OR] 3.9, P = .015). Search engine use was significantly higher in patients at the first postoperative visit (OR 5.8, P = .004) and patients at subsequent surgical follow-up (OR 8.3, P = .001) compared with new patients. Having an undergraduate (OR 0.1, P = .037) or graduate degree (OR 0.03, P = .01) had a significant inverse association with difficulty of using Internet resources. Patients of Black race reported significantly higher rates of distrust for Internet resources than those of White race (OR 5.8, P < .001). CONCLUSION: This study highlights the patterns of HISB among patients with shoulder conditions. A face-to-face discussion with a physician or a shoulder surgeon was the most crucial resource for information compared to other resources. This study has also defined the preferred Internet resources for patients at different time points of care and the reasons for refraining from seeking health information on the Internet. Such findings can aid shoulder surgeons in understanding the optimal methods for delivering health information for different patient demographics and different phases of their care.

Evaluating use of changing technologies for rapid next-generation sequencing in pediatrics.

BACKGROUND: Rapid next-generation sequencing (NGS) offers the potential to shorten the diagnostic process and improve the care of acutely ill children. The goal of this study was to report our findings, including benefits and limitations, of a targeted NGS panel and rapid genome sequencing (rGS) in neonatal and pediatric acute clinical care settings. METHODS: Retrospective analysis of patient characteristics, diagnostic yields, turnaround time, and changes in management for infants and children receiving either RapSeq, a targeted NGS panel for 4500+ genes, or rGS, at the University of Utah Hospital and Primary Children's Hospital, from 2015 to 2020. RESULTS: Over a 5-year period, 142 probands underwent rapid NGS: 66 received RapSeq and 76 rGS. Overall diagnostic yield was 39%. In the majority of diagnostic cases, there were one or more changes in clinical care management. Of note, 7% of diagnoses identified by rGS would not have been identified by RapSeq. CONCLUSIONS: Our results indicate that rapid NGS impacts acute pediatric care in real-life clinical settings. Although affected by patient selection criteria, diagnostic yields were similar to those from clinical trial settings. Future studies are needed to determine relative advantages, including cost, turnaround time, and benefits for patients, of each approach in specific clinical circumstances. IMPACT: The use of comprehensive Mendelian gene panels and genome sequencing in the clinical setting allows for early diagnosis of patients in neonatal, pediatric, and cardiac intensive care units and impactful change in management. Diagnoses led to significant changes in management for several patients in lower acuity inpatient units supporting further exploration of the utility of rapid sequencing in these settings. This study reviews the limitations of comparing sequencing platforms in the clinical setting and the variables that should be considered in evaluating diagnostic rates across studies.

Clin.iobio: A Collaborative Diagnostic Workflow to Enable Team-Based Precision Genomics.

The primary goal of precision genomics is the identification of causative genetic variants in targeted or whole-genome sequencing data. The ultimate clinical hope is that these findings lead to an efficacious change in treatment for the patient. In current clinical practice, these findings are typically returned by expert analysts as static, text-based reports. Ideally, these reports summarize the quality of the data obtained, integrate known gene-phenotype associations, follow allele segregation and affected status within the sequenced samples, and weigh computational evidence of pathogenicity. These findings are used to prioritize the variant(s) most likely to cause the given patient's phenotypes. In most diagnostic settings, a team of experts contribute to these reports, including bioinformaticians, clinicians, and genetic counselors, among others. However, these experts often do not have the necessary tools to review genomic findings, test genetic hypotheses, or query specific gene and variant information. Additionally, team members often rely on different tools and methods based on their given expertise, resulting in further difficulties in communicating and discussing genomic findings. Here, we present clin.iobio-a web-based solution to collaborative genomic analysis that enables diagnostic team members to focus on their area of expertise within the diagnostic process, while allowing them to easily review and contribute to all steps of the diagnostic process. Clin.iobio integrates tools from the popular iobio genomic visualization suite into a comprehensive diagnostic workflow, encompassing (1) genomic data quality review, (2) dynamic phenotype-driven gene prioritization, (3) variant prioritization using a comprehensive set of knowledge bases and annotations, (4) and an exportable findings summary. In conclusion, clin.iobio is a comprehensive solution to team-based precision genomics, the findings of which stand to inform genomic considerations in clinical practice.

Vitamin D, bone density, and nephrocalcinosis in preterm infants: a prospective study.

BACKGROUND: Vitamin D (VitD) supplementation is recommended by the American Academy of Pediatrics (AAP) for preterm infants to improve bone density. Complications of VitD supplementation include hypercalciuria and nephrocalcinosis (NC). NC has been reported in 7-64% infants < 32 weeks gestational age (GA) or < 1500 g birth weight (BW). The relationships between VitD supplementation, serum 25-hydroxy VitD levels, bone density, hypercalciuria and development of NC in preterm infants are not well established. METHODS: Prospective, observational cohort study of 56 infants with GA ≤ 32 weeks or BW ≤ 1800 g. Demographics, dietary intakes, serum 25-hydroxy VitD levels and weekly urinalyses were collected until 40 weeks corrected GA or discharge. Bone mineral density (BMD) and content (BMC) were assessed using dual-energy X-ray absorptiometry (DEXA) scan. NC was identified by kidney ultrasound. RESULTS: 56 infants received on average 447 IU/day of VitD with average serum 25-hydoxy VitD level 39.6 ng/mL. DEXA scan showed average BMD 0.13 g/cm2 and BMC 35.8 g. 23/56 (41%) infants were diagnosed with NC. Infants with NC had lower GA (p < 0.01) and BW (p < 0.01) and increased presence of calcium oxalate crystals (78% vs. 36%) (p = 0.002). There were no differences in VitD intake, urine calcium/creatinine ratios or BMD and BMC in infants with versus without NC. CONCLUSIONS: VitD supplementation per AAP guidelines resulted in acceptable serum 25-hydroxyVitD levels, but no improvement in BMD or BMC compared to previously reported values. However, infants receiving recommended amounts born at earlier GA and lower BW are at increased risk of NC. VitD supplementation and serum levels should be closely monitored in this high-risk population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Factors Driving Rapid Adoption of Telemedicine in an Academic Orthopedic Surgery Department.

Introduction: With the COVID-19 epidemic ever-expanding, nonemergent access to health care resources has been reduced to decrease the exposure for patients and health care providers. Alternatives to in-office outpatient medical evaluations are necessary. We aimed to analyze how quickly orthopedic surgery providers at a large academic institution adopted telemedicine, and identify any factors that were associated with earlier or "faster" telemedicine adoption. Methods: We analyzed the telemedicine activity of 39 providers within the Department of Orthopedic Surgery between March 16, 2020, and May 30, 2020, and constructed logistic regression models to identify characteristics with significant association to earlier or faster telemedicine adoption. Results: No significant predictors of percentage of visits conducted via telemedicine were found. However, increased experience and practice at multiple locations was associated with slower telemedicine adoption time, while Professor level academic rank was associated with a faster time to achieving 10% of pre-COVID visit volumes via telemedicine. Higher pre-COVID visit volumes were also significantly associated with faster telemedicine adoption. Demographic factors, including, age, gender, practice locations, academic degrees, pediatric specialty, and use of physician assistants/nurse practitioners, were not found to have significant associations with telemedicine use. Conclusions: These results indicate that telemedicine has an important role to play within academic orthopedic surgery practices, with a wide and diverse range of orthopedic surgery providers choosing to utilize it during the COVID-19 pandemic. Given the rapid expansion and urgency driving the adoption of telemedicine, these results illustrate the importance of considering provider-side characteristics in ensuring that providers are well equipped to utilize telemedicine.

Age and Racial Disparities in Telemedicine Utilization in an Academic Orthopedic Surgery Department.

Introduction: The COVID-19 pandemic has highlighted significant racial and age-related health disparities. In response to pandemic-related restrictions, orthopedic surgery departments have expanded telemedicine use. We analyzed data from a tertiary care institute during the pandemic to understand potential racial and age-based disparities in access to care and telemedicine utilization. Materials and Methods: Data on patient race and age, and numbers of telemedicine visits, in-person office visits, and types of telemedicine were extracted for time periods during and preceding the pandemic. We calculated odds ratios for visit occurrence and type across race and age groups. Results: Patients ages 27-54 were 1.3 (95% confidence interval [CI] 1.1-1.4, p < 0.01) and 1.2 (95% CI 1.0-1.3, p < 0.05) times more likely to be seen than patients <27 during the pandemic, versus the 2019 and 2020 controls. Patients 54-82 were 1.3 (95% CI 1.1-1.5, p < 0.001) times more likely to be seen than patients <27 during the pandemic versus the 2019 control. Patients 27-54, 54-82, and 82+, respectively, were 3.3 (95% CI 2.6-4.2, p < 1e-20), 3.5 (95% CI 2.8-4.4, p < 1e-24), and 1.9 (95% CI 1.1-3.4, p < 0.05) times more likely to be seen by telemedicine than patients <27. Among pandemic telemedicine appointments, Black patients were 1.5 (95% CI 1.2-1.9, p < 1e-3) times more likely to be seen by audio-only telemedicine than White patients, as compared with video telemedicine. Conclusions: Telemedicine access barriers must be reduced to ensure that disparities during the pandemic do not persist.

Addressing ethical and laboratory challenges for initiation of a rapid whole genome sequencing program.

Rapid whole genome sequencing (rapid WGS) is a powerful diagnostic tool that is becoming increasingly practical for widespread clinical use. However, protocols for its use are challenging to implement. A significant obstacle to clinical adoption is that laboratory certification requires an initial research development phase, which is constrained by regulations from returning results. Regulations preventing return of results have ethical implications in cases which might impact patient outcomes. Here, we describe our experience with the development of a rapid WGS research protocol, that balanced the requirements for laboratory-validated test development with the ethical needs of clinically relevant return of results.