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.

Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.

Development and Usability Testing of the Society for Pediatric Anesthesia Pedi Crisis Mobile Application.

When life-threatening, critical events occur in the operating room, the fast-paced, high-distraction atmosphere often leaves little time to think or deliberate about management options. Success depends on applying a team approach to quickly implement well-rehearsed, systematic, evidence-based assessment and treatment protocols. Mobile devices offer resources for readily accessible, easily updatable information that can be invaluable during perioperative critical events. We developed a mobile device version of the Society for Pediatric Anesthesia 26 Pediatric Crisis paper checklists-the Pedi Crisis 2.0 application-as a resource to support clinician responses to pediatric perioperative life-threatening critical events. Human factors expertise and principles were applied to maximize usability, such as by clustering information into themes that clinicians utilize when accessing cognitive aids during critical events. The electronic environment allowed us to feature optional diagnostic support, optimized navigation, weight-based dosing, critical institution-specific phone numbers pertinent to emergency response, and accessibility for those who want larger font sizes. The design and functionality of the application were optimized for clinician use in real time during actual critical events, and it can also be used for self-study or review. Beta usability testing of the application was conducted with a convenience sample of clinicians at 9 institutions in 2 countries and showed that participants were able to find information quickly and as expected. In addition, clinicians rated the application as slightly above "excellent" overall on an established measure, the Systems Usability Scale, which is a 10-item, widely used and validated Likert scale created to assess usability for a variety of situations. The application can be downloaded, at no cost, for iOS devices from the Apple App Store and for Android devices from the Google Play Store. The processes and principles used in its development are readily applicable to the development of future mobile and electronic applications for the field of anesthesiology.

Whole Blood in Pediatric Craniofacial Reconstruction Surgery.

BACKGROUND: Pediatric complex cranial vault reconstruction (CCVR) surgery is often associated with significant blood loss and transfusion. The authors recently changed our transfusion practice during CCVR to using whole blood (WB) instead of reconstituted blood (RB). The aim of this study was to assess the impact of this practice change. Our hypothesis was that replacement with WB would be as effective as RB for the outcomes of total perioperative blood donor exposures (BDEs) and the incidence of laboratory evidence of postoperative coagulopathy. METHODS: The authors queried the Pediatric Craniofacial Surgery Perioperative Registry for children ages ≤48 months from our institution who underwent CCVR and received either RB or WB. The primary outcomes of total perioperative BDEs and the incidence of laboratory evidence of postoperative coagulopathy were compared between the 2 cohorts. RESULTS: The query returned 59 subjects in the RB cohort and 52 subjects in the WB cohort. There were no significant differences in demographic variables between the 2 groups. Patients in the WB cohort were more likely to have ≤1 BDEs when compared to the RB cohort (62% versus 39%, respectively, P = 0.02). There was no significant difference in the incidence of postoperative coagulation laboratory test abnormalities between the WB and RB cohorts (0% versus 3.4%, respectively, P = 0.50). CONCLUSION: There was no postoperative coagulopathy in the WB cohort. Whole blood was also associated with significantly fewer perioperative BDEs. Whole blood appears to be as effective as RB for replacement of blood loss in craniofacial surgery.

Pediatric perioperative adverse events requiring rapid response: a retrospective case-control study.

BACKGROUND: Perioperative pediatric adverse events have been challenging to study within and across institutions due to varying definitions, low event rates, and incomplete capture. AIM: The aim of this study was to determine perioperative adverse event prevalence and to evaluate associated case characteristics and potential contributing factors at an academic pediatric quaternary-care center. METHODS: At the Children's Hospital of Philadelphia (CHOP), perioperative adverse events requiring rapid response assistance are termed Anesthesia Now (AN!) events. They have been accurately captured and entered into a quality improvement database since 2010. Adverse events involving open heart and cardiac catheterization cases are managed separately and not included in this database. We conducted a retrospective case-control study utilizing Compurecord (Phillips Healthcare, Andover, MA, USA), EPIC (EPIC, Verona, WI, USA), and Chartmaxx (MedPlus, Mason, OH, USA) systems matching AN! event cases to noncardiac controls (1 : 2) based on surgical date. RESULTS: From April 16, 2010 to September 25, 2012, we documented 213 AN! events in the noncardiac perioperative complex and remote sites at our main hospital. AN! prevalence was 0.0043 (1 : 234) with a 95% confidence interval (CI) (0.0037, 0.0049). Respiratory events, primarily laryngospasm, were most common followed by events of cardiovascular etiology. Median age was lower in the AN! group than in controls, 2.86 years (interquartile range 0.94, 10.1) vs 6.20 (2.85, 13.1), P < 0.0001. Odds ratios (with 95% CI) for age, 0.969 (0.941, 0.997); American Society of Anesthesiologists physical status, 1.67 (1.32, 2.12); multiple (≥2) services, 2.27 (1.13, 4.55); nonoperating room vs operating room location, 0.240 (0.133, 0.431); and attending anesthesiologist's experience, 0.976 (0.959, 0.992) were all significant. CONCLUSIONS: Decreased age, increased comorbidities, multiple (vs single) surgical services, operating room (vs nonoperating room) location, and decreased staff experience were associated with increased risk of AN! events, which were predominantly respiratory in origin.

Characterization of Fine Motor and Visual Motor Skills in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.In a cohort of 74 subjects, the Peabody Developmental Motor Scales-2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales-2 scores within a genotype was assessed by interquartile ranges (IQRs).Peabody Developmental Motor Scales-2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales-2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.

Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Exploration of Gross Motor Function in Aicardi-Goutières Syndrome.

Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. While the Aicardi-Goutières syndrome severity score favors severely impacted individuals, there is an unmet need to define tools measuring function across the Aicardi-Goutières syndrome spectrum as potential outcome assessments for future clinical trials. Methods: Gross Motor Function Measure-88 (GMFM-88) and AGS Severity Scale were administered in individuals affected by Aicardi-Goutières syndrome (n = 71). We characterized the performance variability by genotype. Derived versions of the GMFM-88, including the GMFM-66, GMFM-66 item set (GMFM-66IS), and GMFM-66 Basal&Ceiling (GMFM-66BC) were calculated. The Aicardi-Goutières syndrome cohort was divided into severe (AGS Severity Scale score <4) or attenuated (≥4). Performance on the AGS Severity Scale highly correlated with total GMFM-88 scores (Spearman Correlation: R = 0.91). To assess variability of the GMFM-88 within genotypic subcohorts, interquartile ranges (IQRs) were compared. Results: GMFM-88 performance in the TREX1 cohort had least variability while the SAMHD1 cohort had the largest IQR (4.23 vs 81.8). Floor effect was prominent, with most evaluations scoring below 20% (n = 46, 64.79%), particularly in TREX1- and RNASEH2-cohorts. Performance by the GMFM-66, GMFM-66IS, and GMFM-66BC highly correlated with the full GMFM-88. The Aicardi-Goutières syndrome population represents a broad range of gross motor skills. Conclusions: This work identified the GMFM-88 as a potential clinical outcome assessment in subsets of the Aicardi-Goutières syndrome population but underscores the need for additional validation of outcome measures reflective of the diverse gross motor function observed in this population, including low motor function. When time is limited by resources or patient endurance, shorter versions of the GMFM-88 may be a reasonable alternative.

The Church Challenge: A community-based multilevel cluster randomized controlled trial to improve blood pressure and wellness in African American churches in Flint, Michigan.

Chronic disease carries high morbidity and mortality in the United States, with large racial and ethnic disparities observed in chronic disease. Physical activity and healthy food are vital for chronic disease prevention yet challenging to access in economically distressed areas. Public health prevention efforts have become particularly prominent within faith-based organizations over the last three decades. This manuscript describes the protocol of the Church Challenge, a multilevel cluster-randomized controlled nutrition and physical activity trial across 24 churches to reduce blood pressure by 6 mmHg among 576 residents in Flint, MI. The Church Challenge was developed using community-based participatory approaches and is rooted in a church-based program developed by and for primarily African-American Flint church congregations. This three-level intervention addresses health at the community (level 3), church (level 2), and individual (level 1) to reduce blood pressure, reduce chronic disease risk, and promote health equity and wellbeing in Flint. Churches are randomized in a 1:1 ratio to a 16-week physical activity and nutrition program or a 4-session health and wellness workshop. Flint is not a unique community but has a history of traumatic community wide events; even now, the public health infrastructure continues to be a challenge and distract residents from focusing on their health. This trial is highly significant and innovative because it uses a combination of evidence-based practices simultaneously supporting health behavior change for individuals and their faith organizations, and evaluates multilevel efforts to sustain long-term health promotion activities in vulnerable communities like Flint.