Boston Children's Hospital
  • Boston, MA, United States
Recent publications
Repeat expansion disorders are complex, primarily neurological, conditions deriving from repetition of nucleotide stretches. These disorders exhibit a wide range of clinical manifestations, many characterized by the presence of ataxia or lack of coordination. The most common of these entail an expansion of trinucleotide repeats in coding regions of certain genes resulting in a pathologic polyglutamine-expanded protein. Other mechanisms include peptides generated from noncanonical translation, repeat expansions in noncoding regions, which perturb gene expression, or the generation of toxic RNA intermediates. A multitude of factors, including repeat length, genomic location, and disruption of endogenous gene function are thought to drive pathology from the subcellular level to the clinical patient phenotypes. In this chapter, we attempt to unravel this complexity, beginning with the pathophysiological ramifications of repeat expansion disorders at the nucleotide level and working our way to anatomic consequences and patient-level presentations. We comment on therapeutic efforts of the past and provide some perspective on novel genetic treatments and clinical trial redesign that pave the way for the future.
Migraine is a neurological pain condition that affects millions of people. It is the most common neurological disease that has significant effects on the brain and consequently on behaviors associated with repeated migraine attacks. The stress of migraine is associated with premigraine, intermigraine, and postmigraine processes. Recent understanding of migraine includes how normally nonpainful stimuli such as light may exacerbate the pain of migraine and how the migraine headache may produce changes in skin sensitivity (allodynia) that can involve the whole body as a marker of central sensitization. Alterations in the brain's function and structure, as revealed by advanced imaging techniques, have provided new insights into the mechanisms and treatments of the disease. Finally, migraine can be studied in the context of multiple stressors (different physiological, psychological, and environmental factors) contributing to abnormal homeostasis or allostatic load.
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genitourinary tract. CAKUT accounts for up to 50% of end-stage kidney disease (ESKD) in childhood and between 7% and 10% of adult-onset ESKD. CAKUT can occur in isolation or in association with extrarenal features of disease, which is sometimes referred to as syndromic CAKUT. The pathogenesis of CAKUT is due to disturbances in the various stages of the embryonic development of either the kidney or genitourinary tract, which can results in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin with studies demonstrating single gene defects in approximately 10–20% of patients with CAKUT. Multiple molecular pathways have been implicated in CAKUT including the RET tyrosine kinase signaling system, the Fraser complex and the extracellular matrix complex, and more recently, the vitamin A and retinoic acid signaling pathway.
The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn's disease, and epidemiological associations between Crohn's disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association.
Background/introduction: One way the goal of establishing a partnership with families is accomplished, specific to the pediatric intensive care units, is 24-hour visitation and presence/participation during medical rounds and procedures. Despite the breadth of literature on the positive effect of parent presence, as well as the nearly nationwide adoption of 24-hour pediatric intensive care unit visitation, there is little to no research about how these changes have affected parents' perception of their role in the pediatric cardiac intensive care unit (PCICU). Objectives/aims: The purpose of this study was to explore and better understand the experience of parents in the PCICU within a patient/family-centered care model. Methods: Using a qualitative descriptive approach, interviews were conducted with parents of children currently admitted as inpatients in the PCICU. Participants were asked broad, open-ended questions and probes to attain qualitative descriptions of their experiences and perceptions of their parental role in the PCICU. The research design for this study was based on naturalistic inquiry and was used to describe rather than interpret parental experiences in their own words. Results: Eleven parents from 7 families were interviewed; parents described their role in terms of 2 main categories, as one who is an advocate and decision maker and one who provides emotional and physical support. Parents valued the expertise of the PCICU team but also shared the significance of the team recognizing their role as parents. Incorporating parents as an integral member of the health care team is a fundamental component to PCICU care. Discussion/conclusion: The role of parents is irreplaceable, particularly in the PCICU. The medical complexity of the intensive care can be a barrier to act as parents resulting in a disruption of family-centered care. Nursing staff avert this disruption through modeling parenting to their child's present circumstances and involvement in normal parenting tasks.
Recent advances in technology and expanding therapeutic opportunities in neuromuscular disorders has resulted in greater interest in and development of remote assessments. Over the past year, the rapid and abrupt COVID-19 shutdowns and stay-at-home orders imposed challenges to routine clinical management and clinical trials. As in-person services were severely limited, clinicians turned to remote assessments through telehealth to allow for continued care. Typically, disease-specific clinical outcome assessments (COAs) for neuromuscular disorders (NMD) are developed over many years through rigorous and iterative processes to fully understand their psychometric properties. While efforts were underway towards developing remote assessments for NMD before the pandemic, few if any were fully developed or validated. These included assessments of strength, respiratory function and patient-reported outcomes, as well as wearable technology and other devices to quantify physical activity and function. Without many choices, clinicians modified COAs for a virtual environment recognizing it was not yet known how they compared to standard in-person administration. Despite being able to quickly adapt to the demands of the COVID-19 pandemic, these experiences with remote assessments uncovered limitations and opportunities. It became clear that existing COAs required modifications for use in a virtual environment limiting the interpretation of the information gathered. Still, the opportunity for real-world evaluation and reduced patient burden were clear benefits to remote assessment and may provide a more robust understanding and characterization of disease impact in NMD. Hence, we propose a roadmap navigating an informed post-pandemic path toward development and implementation of safe and successful use of remote assessments for patients with NMD.
In times of crisis, communication by leaders is essential for mobilizing an effective public response. During the COVID-19 pandemic, compliance with public health guidelines has been critical for the prevention of infections and deaths. We assembled a corpus of over 1500 pandemic-related speeches, containing over 4 million words, delivered by all 50 US state governors during the initial months of the COVID-19 pandemic. We analyzed the semantic, grammatical and linguistic-complexity properties of these speeches, and examined their relationships to COVID-19 case rates over space and time. We found that as COVID-19 cases rose, governors used stricter language to issue guidance, employed greater negation to defend their actions and highlight prevailing uncertainty, and used more extreme descriptive adjectives. As cases surged to their highest levels, governors used shorter words with fewer syllables. Investigating and understanding such characteristic responses to stress is important for improving effective public communication during major health crises.
Background: Differences in face processing in individuals with ASD is hypothesized to impact the development of social communication skills. This study aimed to characterize the neural correlates of face processing in 12-month-old infants at familial risk of developing ASD by (1) comparing face-sensitive event-related potentials (ERP) (Nc, N290, P400) between high-familial-risk infants who develop ASD (HR-ASD), high-familial-risk infants without ASD (HR-NoASD), and low-familial-risk infants (LR), and (2) evaluating how face-sensitive ERP components are associated with development of social communication skills. Methods: 12-month-old infants participated in a study in which they were presented with alternating images of their mother's face and the face of a stranger (LR = 45, HR-NoASD = 41, HR-ASD = 24) as EEG data were collected. Parent-reported and laboratory-observed social communication measures were obtained at 12 and 18 months. Group differences in ERP responses were evaluated using ANOVA, and multiple linear regressions were conducted with maternal education and outcome groups as covariates to assess relationships between ERP and behavioral measures. Results: For each of the ERP components (Nc [negative-central], N290, and P400), the amplitude difference between mother and stranger (Mother-Stranger) trials was not statistically different between the three outcome groups (Nc p = 0.72, N290 p = 0.88, P400 p = 0.91). Marginal effects analyses found that within the LR group, a greater Nc Mother-Stranger response was associated with better expressive language skills on the Mullen Scales of Early Learning, controlling for maternal education and outcome group effects (marginal effects dy/dx = 1.15; p < 0.01). No significant associations were observed between the Nc and language or social measures in HR-NoASD or HR-ASD groups. In contrast, specific to the HR-ASD group, amplitude difference between the Mother versus Stranger P400 response was positively associated with expressive (dy/dx = 2.1, p < 0.001) and receptive language skills at 12 months (dy/dx = 1.68, p < 0.005), and negatively associated with social affect scores on the Autism Diagnostic Observation Schedule (dy/dx = - 1.22, p < 0.001) at 18 months. Conclusions: In 12-month-old infant siblings with subsequent ASD, increased P400 response to Mother over Stranger faces is positively associated with concurrent language and future social skills.
During the critical early stages of an emerging pandemic, limited availability of pathogen-specific testing can severely inhibit individualized risk screening and pandemic tracking. Standard clinical laboratory tests offer a widely available complementary data source for first-line risk screening and pandemic surveillance. Here, we propose an integrated framework for developing clinical-laboratory indicators for novel pandemics that combines population-level and individual-level analyses. We apply this framework to 7,520,834 clinical laboratory tests recorded over five years and find clinical-lab-test combinations that are strongly associated with SARS-CoV-2 PCR test results and Multisystem Inflammatory Syndrome in Children (MIS-C) diagnoses: Interleukin-related tests (e.g. IL4, IL10) were most strongly associated with SARS-CoV-2 infection and MIS-C, while other more widely available tests (ferritin, D-dimer, fibrinogen, alanine transaminase, and C-reactive protein) also had strong associations. When novel pandemics emerge, this framework can be used to identify specific combinations of clinical laboratory tests for public health tracking and first-line individualized risk screening.
Clinical risk prediction models powered by electronic health records (EHRs) are becoming increasingly widespread in clinical practice. With suicide-related mortality rates rising in recent years, it is becoming increasingly urgent to understand, predict, and prevent suicidal behavior. Here, we compare the predictive value of structured and unstructured EHR data for predicting suicide risk. We find that Naive Bayes Classifier (NBC) and Random Forest (RF) models trained on structured EHR data perform better than those based on unstructured EHR data. An NBC model trained on both structured and unstructured data yields similar performance (AUC = 0.743) to an NBC model trained on structured data alone (0.742, p = 0.668), while an RF model trained on both data types yields significantly better results (AUC = 0.903) than an RF model trained on structured data alone (0.887, p < 0.001), likely due to the RF model’s ability to capture interactions between the two data types. To investigate these interactions, we propose and implement a general framework for identifying specific structured-unstructured feature pairs whose interactions differ between case and non-case cohorts, and thus have the potential to improve predictive performance and increase understanding of clinical risk. We find that such feature pairs tend to capture heterogeneous pairs of general concepts, rather than homogeneous pairs of specific concepts. These findings and this framework can be used to improve current and future EHR-based clinical modeling efforts.
Introduction: The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States. Methods: An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics. Results: Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all). Conclusions: We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.
Background Computational phenotypes are most often combinations of patient billing codes that are highly predictive of disease using electronic health records (EHR). In the case of rare diseases that can only be diagnosed by genetic testing, computational phenotypes identify patient cohorts for genetic testing and possible diagnosis. This article details the validation of a computational phenotype for PTEN hamartoma tumor syndrome (PHTS) against the EHR of patients at three collaborating clinical research centers: Boston Children's Hospital, Children's National Hospital, and the University of Washington. Methods A combination of billing codes from the International Classification of Diseases versions 9 and 10 (ICD-9 and ICD-10) for diagnostic criteria postulated by a research team at Cleveland Clinic was used to identify patient cohorts for genetic testing from the clinical data warehouses at the three research centers. Subsequently, the EHR—including billing codes, clinical notes, and genetic reports—of these patients were reviewed by clinical experts to identify patients with PHTS. Results The PTEN genetic testing yield of the computational phenotype, the number of patients who needed to be genetically tested for incidence of pathogenic PTEN gene variants, ranged from 82 to 94% at the three centers. Conclusions Computational phenotypes have the potential to enable the timely and accurate diagnosis of rare genetic diseases such as PHTS by identifying patient cohorts for genetic sequencing and testing.
The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019.
Background: Screening for substance use within pediatric primary care provides a unique opportunity to identify adolescents in need of intervention. Methods: This study analyzed screening data collected across 13 Federally Qualified Health Centers over the course of an 18-month project designed to implement Screening Brief Intervention Referral to Treatment (SBIRT) for adolescents aged 12–21. A mixed-effects modeling strategy was used to describe associations between demographic, procedural, and clinical factors and adolescent reports of substance use. Results: In total, 10,813 adolescents were screened between December 2017 and May 2019, with 17% reporting past year use, including 11% at lower risk and 6% at high risk of a substance use disorder. Females, Hispanic, Black/African American, heterosexual, non-primary English speakers, and patients who did not have a co-occurring mental health disorder were all less likely to report past year substance use. While rates of disclosing any past year substance use were equivalent between patients screened by a staff member and those who completed self-administered screens, patients who were screened by a staff member were associated with reporting overall greater frequencies of use. Patients who were screened by a staff member with a parent present were less likely to disclose any past year substance use. Conclusion: While overall rates of disclosure of any past year substance use (17.2%) were lower than reported in research settings, a substantial proportion (6.3%) had screen results indicating a high risk for substance use disorder.
Background Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. Methods Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. Results Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). Conclusion Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. Trial registration NCT00299312 and NCT02738281
Easy access to large quantities of accurate health data is required to understand medical and scientific information in real-time; evaluate public health measures before, during, and after times of crisis; and prevent medical errors. Introducing a system in the USA that allows for efficient access to such health data and ensures auditability of data facts, while avoiding data silos, will require fundamental changes in current practices. Here, we recommend the implementation of standardized data collection and transmission systems, universal identifiers for individual patients and end users, a reference standard infrastructure to support calibration and integration of laboratory results from equivalent tests, and modernized working practices. Requiring comprehensive and binding standards, rather than incentivizing voluntary and often piecemeal efforts for data exchange, will allow us to achieve the analytical information environment that patients need.
Cardiovascular magnetic resonance (CMR) is widely used for diagnostic imaging in the pediatric population. In addition to structural congenital heart disease (CHD), for which published guidelines are available, CMR is also performed for non-structural pediatric heart disease, for which guidelines are not available. This article provides guidelines for the performance and reporting of CMR in the pediatric population for non-structural (“non-congenital”) heart disease, including cardiomyopathies, myocarditis, Kawasaki disease and systemic vasculitides, cardiac tumors, pericardial disease, pulmonary hypertension, heart transplant, and aortopathies. Given important differences in disease pathophysiology and clinical manifestations as well as unique technical challenges related to body size, heart rate, and sedation needs, these guidelines focus on optimization of the CMR examination in infants and children compared to adults. Disease states are discussed, including the goals of CMR examination, disease-specific protocols, and limitations and pitfalls, as well as newer techniques that remain under development.
Background ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA. Methods Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support. Results Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9–10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9–16.4) months and at death was ~ 41.2 (7.3–not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking. Interpretation Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease’s devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation.
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2,252 members
Brian H Walsh
  • Division of Newborn Medicine
Joana Caetano-Lopes
  • Department of Orthopaedic Surgery
Mark Kellogg
  • Department of Laboratory Medicine
Ruei-Zeng Lin
  • Department of Cardiac Surgery
Linda Dagi
  • Department of Ophthalmology
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