Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease.

Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter-AAV9-gfaABC(1)D-EIF2B5-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

Lithium: effects in animal models of vanishing white matter are not promising.

Vanishing white matter (VWM) is a devastating autosomal recessive leukodystrophy, resulting in neurological deterioration and premature death, and without curative treatment. Pathogenic hypomorphic variants in subunits of the eukaryotic initiation factor 2B (eIF2B) cause VWM. eIF2B is required for regulating the integrated stress response (ISR), a physiological response to cellular stress. In patients' central nervous system, reduced eIF2B activity causes deregulation of the ISR. In VWM mouse models, the extent of ISR deregulation correlates with disease severity. One approach to restoring eIF2B activity is by inhibition of GSK3ß, a kinase that phosphorylates eIF2B and reduces its activity. Lithium, an inhibitor of GSK3ß, is thus expected to stimulate eIF2B activity and ameliorate VWM symptoms. The effects of lithium were tested in zebrafish and mouse VWM models. Lithium improved motor behavior in homozygous eif2b5 mutant zebrafish. In lithium-treated 2b4he2b5ho mutant mice, a paradoxical increase in some ISR transcripts was found. Furthermore, at the dosage tested, lithium induced significant polydipsia in both healthy controls and 2b4he2b5ho mutant mice and did not increase the expression of other markers of lithium efficacy. In conclusion, lithium is not a drug of choice for further development in VWM based on the limited or lack of efficacy and significant side-effect profile.

Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model.

Background: Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults. Methods: We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts. Results: The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes. Conclusions: We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.

Progress in leukodystrophies with zebrafish.

Inherited leukodystrophies are genetic disorders characterized by abnormal white matter in the central nervous system. Although individually rare, there are more than 400 distinct types of leukodystrophies with a cumulative incidence of 1 in 4500 live births. The pathophysiology of most leukodystrophies is poorly understood, there are treatments for only a few, and there is significant morbidity and mortality, suggesting a critical need for improvements in this field. A variety of animal, cell, and induced pluripotent stem cell-derived models have been developed for leukodystrophies, but with significant limitations in all models. Many leukodystrophies lack animal models, and extant models often show no or mixed recapitulation of key phenotypes. Zebrafish (Danio rerio) have become increasingly used as disease models for studying leukodystrophies due to their early onset of disease phenotypes and conservation of molecular and neurobiological mechanisms. Here, we focus on reviewing new zebrafish disease models for leukodystrophy or models with recent progress. This includes discussion of leukodystrophy with vanishing white matter disease, X-linked adrenoleukodystrophy, Zellweger spectrum disorders and peroxisomal disorders, PSAP deficiency, metachromatic leukodystrophy, Krabbe disease, hypomyelinating leukodystrophy-8/4H leukodystrophy, Aicardi-Goutières syndrome, RNASET2-deficient cystic leukoencephalopathy, hereditary diffuse leukoencephalopathy with spheroids-1 (CSF1R-related leukoencephalopathy), and ultra-rare leukodystrophies. Zebrafish models offer important potentials for the leukodystrophy field, including testing of new variants in known genes; establishing causation of newly discovered genes; and early lead compound identification for therapies. There are also unrealized opportunities to use humanized zebrafish models which have been sparsely explored.

Early genetic testing in pediatric epilepsy: Diagnostic and cost implications.

The identification of numerous genetically based epilepsies has resulted in the widespread use of genetic testing to inform epilepsy etiology. Our study aims to investigate whether a difference exists in the diagnostic evaluation and healthcare-related cost expenditures of pediatric patients with epilepsy of unknown etiology who receive a genetic diagnosis through multigene epilepsy panel (MEP) testing and comparing those who underwent early (EGT) versus late genetic testing (LGT). Testing was defined as early (less than 1 year), or late (more than 1 year), following clinical epilepsy diagnosis. A retrospective chart review of pediatric individuals (1-17 years) with epilepsy of unknown etiology who underwent multigene epilepsy panel (MEP) testing identified 28 of 226 (12%) individuals with a pathogenic epilepsy variant [EGT n = 8 (29%); LGT n = 20 (71%)]. The average time from clinical epilepsy diagnosis to genetic diagnosis was 0.25 years (EGT), compared with 7.1 years (LGT). The EGT cohort underwent fewer metabolic tests [EGT n = 0 (0%); LGT n = 16 (80%) (P < 0.01)] and invasive procedures [EGT n = 0 (0%); LGT n = 5 (25%) (P = 0.06)]. Clinical management changes implemented due to genetic diagnosis occurred in 10 (36%) patients [EGT n = 2 (25%); LGT n = 8 (40%) (P = 0.76)]. Early genetic testing with a MEP in pediatric patients with epilepsy of unknown etiology who receive a genetic diagnosis is associated with fewer non-diagnostic tests and invasive procedures and reduced estimated overall healthcare-related costs. PLAIN LANGUAGE SUMMARY: This study aims to investigate whether a difference exists in the diagnostic evaluation and cost expenditures of pediatric patients (1-17 years) with epilepsy of unknown cause who are ultimately diagnosed with a genetic cause of epilepsy through multigene epilepsy panel testing and comparing those who underwent early testing (less than 1 year) versus late testing (more than 1 year) after clinical epilepsy diagnosis. Of the 28 of 226 individuals with a confirmed genetic cause of epilepsy on multigene epilepsy panel testing, performing early testing was associated with fewer non-diagnostic tests, fewer invasive procedures and reduced estimated overall healthcare-related costs.

Rapid Access Scheduler: A Web-Based System for Direct Provider Scheduling to Pediatric Neurology.

Purpose of Review: Access to pediatric neurology care is limited, and outpatient waits can exceed 6 months. The referral process is often complex and burdensome. Our objective was to trial a program for scheduling access to pediatric neurology, to be controlled and accessed directly by outside providers. Recent Findings: We developed a web-based automated system, "Rapid Access Scheduler" (RASr), for direct scheduling by outside providers. RASr is built around a calendar view that allows the provider to see and reserve an available slot at the time of care. Once a slot is reserved, the scheduling team contacts the family to finalize scheduling. Summary: The RASr system is a novel approach for facilitating pediatric neurology patient access through direct scheduling by outside providers using a web-based portal. Advantages of this include control and responsibility by outside providers, easy visibility of availability, and opportunity to inform patients and families at their point-of-care.

Transgenic expression in zebrafish embryos with an intact chorion by electroporation and microinjection.

Electroporation is regularly used to deliver agents into cells, including transgenic materials, but it is not used for mutating zebrafish embryos due to the lack of suitable systems, information on appropriate operating parameters, and the challenges posed by the protective chorion. Here, a novel method for gene delivery in zebrafish embryos was developed by combining microinjection into the space between the chorion and the embryo followed by electroporation. This method eliminates the need for chorion removal and injecting into the space between the chorion and embryo eliminates the need for finding and identifying key cell locations before performing an injection, making the process much simpler and more automatable. We also developed a microfluidic electroporation system and optimized electric pulse parameters for transgenesis of embryos. The study provided a novel method for gene delivery in zebrafish embryos that can be potentially implemented in a high throughput transgenesis or mutagenesis system.

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.

Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.

BACKGROUND: The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization. METHODS: To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM Consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥ 18 years, ≥ 6 to < 18 years and < 6 years. We chose double-blind, randomized, placebo-controlled design for patients aged ≥ 6 years; and open-label non-randomized natural-history-controlled design for patients < 6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations. DISCUSSION: The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM. TRIAL REGISTRATION: NA. From a scientific and ethical perspective, it is strongly recommended that all interventional trials using this core protocol are registered in a clinical trial register.

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.

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.

SARS-CoV-2 Infection and Increased Risk for Pediatric Stroke.

BACKGROUND: There is an increased risk of stroke in adults with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) infection, but whether there is a similar association with stroke in children is unclear. Our objective was to determine whether there is a correlation between COVID-19 infection, multisystem inflammatory syndrome in children (MIS-C), and pediatric ischemic stroke. METHODS: This was a retrospective, population-based cohort analysis between March 1, 2020, and June 30, 2021, conducted at a children's hospital. Pediatric patients with a diagnosis of ischemic stroke were identified using ICD-10 diagnoses of ischemic stroke, cerebrovascular accident, or cerebral infarction. RESULTS: We identified 16 patients, seven male and nine female, with ischemic stroke. Ages were 8 months to 17 years (median 11.5 years). More Asian (6%) and black (13%) patients had strokes compared with population prevalence (2% each, respectively). No patients had active COVID-19 infection. COVID-19 antibodies were identified in five of 11 patients tested (45%), of whom three were diagnosed with MIS-C. 82% of the strokes occurred between February and May 2021. The peak incidence was in February 2021, which was two months after peak incidence of pediatric cases of COVID-19 and one month after the peak of MIS-C cases. CONCLUSIONS: Our study suggests that prior COVID-19 infection, but not acute infection, is correlated with a risk for stroke in the pediatric population. The risk for stroke appears to be distinct from the risk for MIS-C.

HerediGene Population Study IT infrastructure: A model to support genomic research recruitment and precision public health.

The HerediGene Population Study is a large research study focused on identifying new genetic biomarkers for disease prevention, diagnosis, prognosis, and development of new therapeutics. A substantial IT infrastructure evolved to reach enrollment targets and return results to participants. More than 170,000 participants have been enrolled in the study to date, with 5.87% of those whole genome sequenced and 0.46% of those genotyped harboring pathogenic variants. Among other purposes, this infrastructure supports: (1) identifying candidates from clinical criteria, (2) monitoring for qualifying clinical events (e.g., blood draw), (3) contacting candidates, (4) obtaining consent electronically, (5) initiating lab orders, (6) integrating consent and lab orders into clinical workflow, (7) de-identifying samples and clinical data, (8) shipping/transmitting samples and clinical data, (9) genotyping/sequencing samples, (10) and re-identifying and returning results for participants where applicable. This study may serve as a model for similar genomic research and precision public health initiatives.

Novel SLC13A3 Variants and Cases of Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation and Literature Review.

Objectives: Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the SLC13A3 gene. ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported in the literature to date. Our objective is to report newly identified patients and their genetic variants and phenotypes and review published literature on ARLIAK. Methods: This report contributes 4 additional patients to the literature; describes novel variants in SLC13A3; and reviews genetic, biochemical, clinical, and radiologic features of all published patients with ARLIAK. Results: We provide additional genetic, imaging, and laboratory insights into ARLIAK, an atypical leukodystrophy with clinical and radiologic findings that can normalize. Discussion: Our case series highlights the importance of reanalysis of next-generation sequencing in the diagnostic workup.

Using Electroporation to Improve and Accelerate Zebrafish Embryo Toxicity Testing.

Zebrafish have emerged as a useful model for biomedical research and have been used in environmental toxicology studies. However, the presence of the chorion during the embryo stage limits cellular exposure to toxic elements and creates the possibility of a false-negative or reduced sensitivity in fish embryo toxicity testing (FET). This paper presents the use of electroporation as a technique to improve the delivery of toxic elements inside the chorion, increasing the exposure level of the toxins at an early embryo stage (<3 h post-fertilization). A custom-made electroporation device with the required electrical circuitry has been developed to position embryos between electrodes that provide electrical pulses to expedite the entry of molecules inside the chorion. The optimized parameters facilitate material entering into the chorion without affecting the survival rate of the embryos. The effectiveness of the electroporation system is demonstrated using Trypan blue dye and gold nanoparticles (AuNPs, 20-40 nm). Our results demonstrate the feasibility of controlling the concentration of dye and nanoparticles delivered inside the chorion by optimizing the electrical parameters, including pulse width, pulse number, and amplitude. Next, we tested silver nanoparticles (AgNPs, 10 nm), a commonly used toxin that can lower mortality, affect heart rate, and cause phenotypic defects. We found that electroporation of AgNPs reduces the exposure time required for toxicity testing from 4 days to hours. Electroporation for FET can provide rapid entry of potential toxins into zebrafish embryos, reducing the time required for toxicity testing and drug delivery experiments.

The Development of an Infrastructure to Facilitate the Use of Whole Genome Sequencing for Population Health.

The clinical use of genomic analysis has expanded rapidly resulting in an increased availability and utility of genomic information in clinical care. We have developed an infrastructure utilizing informatics tools and clinical processes to facilitate the use of whole genome sequencing data for population health management across the healthcare system. Our resulting framework scaled well to multiple clinical domains in both pediatric and adult care, although there were domain specific challenges that arose. Our infrastructure was complementary to existing clinical processes and well-received by care providers and patients. Informatics solutions were critical to the successful deployment and scaling of this program. Implementation of genomics at the scale of population health utilizes complicated technologies and processes that for many health systems are not supported by current information systems or in existing clinical workflows. To scale such a system requires a substantial clinical framework backed by informatics tools to facilitate the flow and management of data. Our work represents an early model that has been successful in scaling to 29 different genes with associated genetic conditions in four clinical domains. Work is ongoing to optimize informatics tools; and to identify best practices for translation to smaller healthcare systems.