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BACKGROUND: Risk identification and communication tools have the potential to improve health care by supporting clinician-patient or family discussion of treatment risks and benefits and helping patients make more informed decisions; however, they have yet to be tailored to pediatric surgery. User-centered design principles can help to ensure the successful development and uptake of health care tools. OBJECTIVE: We aimed to develop and evaluate the usability of an easy-to-use tool to communicate a child's risk of postoperative pain to improve informed and collaborative preoperative decision-making between clinicians and families. METHODS: With research ethics board approval, we conducted web-based co-design sessions with clinicians and family participants (people with lived surgical experience and parents of children who had recently undergone a surgical or medical procedure) at a tertiary pediatric hospital. Qualitative data from these sessions were analyzed thematically using NVivo (Lumivero) to identify design requirements to inform the iterative redesign of an existing prototype. We then evaluated the usability of our final prototype in one-to-one sessions with a new group of participants, in which we measured mental workload with the National Aeronautics and Space Administration (NASA) Task Load Index (TLX) and user satisfaction with the Post-Study System Usability Questionnaire (PSSUQ). RESULTS: A total of 12 participants (8 clinicians and 4 family participants) attended 5 co-design sessions. The 5 requirements were identified: (A) present risk severity descriptively and visually; (B) ensure appearance and navigation are user-friendly; (C) frame risk identification and mitigation strategies in positive terms; (D) categorize and describe risks clearly; and (E) emphasize collaboration and effective communication. A total of 12 new participants (7 clinicians and 5 family participants) completed a usability evaluation. Tasks were completed quickly (range 5-17 s) and accurately (range 11/12, 92% to 12/12, 100%), needing only 2 requests for assistance. The median (IQR) NASA TLX performance score of 78 (66-89) indicated that participants felt able to perform the required tasks, and an overall PSSUQ score of 2.1 (IQR 1.5-2.7) suggested acceptable user satisfaction with the tool. CONCLUSIONS: The key design requirements were identified, and that guided the prototype redesign, which was positively evaluated during usability testing. Implementing a personalized risk communication tool into pediatric surgery can enhance the care process and improve informed and collaborative presurgical preparation and decision-making between clinicians and families of pediatric patients.
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Background : Genome-wide DNA methylation (DNAme) profiling of the placenta with Illumina Infinium Methylation bead arrays is often used to explore the connections between in utero exposures, placental pathology, and fetal development. However, many technical and biological factors can lead to signals of DNAme variation between samples and between cohorts, and understanding and accounting for these factors is essential to ensure meaningful and replicable data analysis. Recently, "epiphenotyping" approaches have been developed whereby DNAme data can be used to impute information about phenotypic variables such as gestational age, sex, cell composition, and ancestry. These epiphenotypes offer avenues to compare phenotypic data across cohorts, and to understand how phenotypic variables relate to DNAme variability. However, the relationships between placental epiphenotyping variables and other technical and biological variables, and their application to downstream epigenome analyses, have not been well studied. Results : Using DNAme data from 204 placentas across three cohorts, we applied the PlaNET R package to estimate epiphenotypes gestational age, ancestry, and cell composition in these samples. PlaNET ancestry estimates were highly correlated with independent polymorphic ancestry informative markers, and epigenetic gestational age, on average, was estimated within 4 days of reported gestational age, underscoring the accuracy of these tools. Cell composition estimates varied both within and between cohorts, but reassuringly were robust to placental processing time. Interestingly, the ratio of cytotrophoblast to syncytiotrophoblast proportion decreased with increasing gestational age, and differed slightly by both maternal ethnicity (lower in white vs. non-white) and genetic ancestry (lower in higher probability European ancestry). The cohort of origin and cytotrophoblast proportion were the largest drivers of DNAme variation in this dataset, based on their associations with the first principal component. Conclusions : This work confirms that cohort, array (technical) batch, cell type proportion, self-reported ethnicity, genetic ancestry, and biological sex are important variables to consider in any analyses of Illumina DNAme data. Further, we demonstrate that estimating epiphenotype variables from the DNAme data itself, when possible, provides both an independent check of clinically-obtained data and can provide a robust approach to compare variables across different datasets.
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Practitioners aim to improve healthcare systems and clinical care through a variety of activities as part of a learning healthcare system. Yet the distinction between projects requiring Research Ethics Board (REB) approval or not is becoming increasingly blurred, making it difficult for researchers and others to classify projects and then navigate the required compliance pathway appropriately. To address this challenge, the Provincial Health Services Authority (PHSA) of British Columbia (BC) created a decision tool called the "PHSA Project Sorter Tool" to serve its diverse community while also meeting the unique needs of the BC regulatory and policy environment. The goal of the tool was to standardize and clarify organizational project review and ensure project leads were referred to the appropriate review body or service provider within the PHSA in the most efficient manner possible. In this paper, we describe the ethics needs assessment that was conducted to inform the tool and the results of our ongoing evaluation of the tool since it was launched in January, 2020. Our project shows that this simple tool can reduce burdens on staff and provide clarity to users by standardizing processes and terms and directing users to appropriate internal resources.
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Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has impacted healthcare services and outcomes. We aimed to investigate healthcare resource utilization and early health outcomes of infants born to mothers with perinatal SARS-CoV-2 infection. Methods: The study included all infants born alive between February 1, 2020, and April 30, 2021, in British Columbia. We used linked provincial population-based databases including data on COVID-19 testing, birth, and health information for up to one year from birth. Perinatal COVID-19 exposure for infants was defined being born to mothers with a positive test for SARS-CoV-2 infection during pregnancy or at delivery. Cases of COVID-19-exposed infants were matched with up to four non-exposed infants by birth month, sex, birthplace, and gestational age in weeks. Outcomes included hospitalizations, emergency department visits, and in-/outpatient diagnoses. Outcomes were compared between groups using conditional logistic regression and linear mixed effects models including effect modification by maternal residence. Results: Among 52,711 live births, 484 infants had perinatal exposure to SARS-CoV-2, an incidence rate of 9.18 per 1000 live births. Exposed infants (54.6% male) had a mean gestational age of 38.5 weeks, and 99% were born in hospital. Proportions of infants requiring at least one hospitalization (8.1% vs. 5.1%) and at least one emergency department visit (16.9% vs. 12.9%) were higher among the exposed vs. unexposed infants, respectively. Among infants from the urban area, those with exposure were more likely to have respiratory infectious diseases (odds ratio: 1.74; 95% confidence intervals: 1.07, 2.84), compared with those without exposure. Interpretation. In our cohort, infants born to mothers with SARS-CoV-2 infection have increased healthcare demands in their early infancy, which warrants further investigation.
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Selective serotonin reuptake inhibitors (SSRIs) for treatment of prenatal maternal depression have been associated with neonatal neurobehavioral disturbances, though the molecular mechanisms remain poorly understood. In utero exposure to SSRIs may affect DNA methylation (DNAme) in the human placenta, an epigenetic mark that is established during development and is associated with gene expression. Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip; clinical assessments of maternal mood and SSRI treatment records were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression was defined using a mean maternal Hamilton Depression score > 8 to indicate symptomatic depressed mood ("maternally-depressed"), and we further classified cases into SSRI-exposed, maternally-depressed (n = 14); SSRI-exposed, not maternally-depressed (n = 6); SSRI non-exposed, maternally-depressed (n = 20); and SSRI non-exposed, not maternally-depressed (n = 24). For replication, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n = 17 SSRI-exposed, n = 17 SSRI non-exposed). No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, in a model adjusted for mean maternal Hamilton Depression score, or in a model restricted to maternally-depressed cases with and without SSRI exposure. However, at a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δß| > 0.03) by SSRI exposure status. Four were covered by the replication cohort measured by the 450K array, but none replicated. No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n = 31; males n = 33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment, as compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.
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Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Masculino , Recém-Nascido , Gravidez , Humanos , Feminino , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Placenta/metabolismo , Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Afeto , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismoRESUMO
BACKGROUND: The perioperative period is a data-rich environment with potential for innovation through digital health tools and predictive analytics to optimize patients' health with targeted prehabilitation. Although some risk factors for postoperative pain following pediatric surgery are already known, the systematic use of preoperative information to guide personalized interventions is not yet widespread in clinical practice. OBJECTIVE: Our long-term goal is to reduce the incidence of persistent postsurgical pain (PPSP) and long-term opioid use in children by developing personalized pain risk prediction models that can guide clinicians and families to identify targeted prehabilitation strategies. To develop such a system, our first objective was to identify risk factors, outcomes, and relevant experience measures, as well as data collection tools, for a future data collection and risk modeling study. METHODS: This study used a patient-oriented research methodology, leveraging parental/caregiver and clinician expertise. We conducted virtual focus groups with participants recruited at a tertiary pediatric hospital; each session lasted approximately 1 hour and was composed of clinicians or family members (people with lived surgical experience and parents of children who had recently undergone a procedure requiring general anesthesia) or both. Data were analyzed thematically to identify potential risk factors for pain, as well as relevant patient-reported experience and outcome measures (PREMs and PROMs, respectively) that can be used to evaluate the progress of postoperative recovery at home. This guidance was combined with a targeted literature review to select tools to collect risk factor and outcome information for implementation in a future study. RESULTS: In total, 22 participants (n=12, 55%, clinicians and n=10, 45%, family members) attended 10 focus group sessions; participants included 12 (55%) of 22 persons identifying as female, and 12 (55%) were under 50 years of age. Thematic analysis identified 5 key domains: (1) demographic risk factors, including both child and family characteristics; (2) psychosocial risk factors, including anxiety, depression, and medical phobias; (3) clinical risk factors, including length of hospital stay, procedure type, medications, and pre-existing conditions; (4) PREMs, including patient and family satisfaction with care; and (5) PROMs, including nausea and vomiting, functional recovery, and return to normal activities of daily living. Participants further suggested desirable functional requirements, including use of standardized and validated tools, and longitudinal data collection, as well as delivery modes, including electronic, parent proxy, and self-reporting, that can be used to capture these metrics, both in the hospital and following discharge. Established PREM/PROM questionnaires, pain-catastrophizing scales (PCSs), and substance use questionnaires for adolescents were subsequently selected for our proposed data collection platform. CONCLUSIONS: This study established 5 key data domains for identifying pain risk factors and evaluating postoperative recovery at home, as well as the functional requirements and delivery modes of selected tools with which to capture these metrics both in the hospital and after discharge. These tools have been implemented to generate data for the development of personalized pain risk prediction models.
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BACKGROUND: Pediatric surgery is associated with a risk of postoperative pain that can impact the family's quality of life. Although some risk factors for postoperative pain are known, these are often not consistently communicated to families. In addition, although tools for risk communication exist in other domains, none are tailored to pediatric surgery. OBJECTIVE: As part of a larger project to develop pain risk prediction tools, we aimed to design an easy-to-use tool to effectively communicate a child's risk of postoperative pain to both clinicians and family members. METHODS: With research ethics board approval, we conducted virtual focus groups (~1 hour each) comprising clinicians and family members (people with lived surgical experience and parents of children who had recently undergone surgery/medical procedures) at a tertiary pediatric hospital to understand and evaluate potential design approaches and strategies for effectively communicating and visualizing postoperative pain risk. Data were analyzed thematically to generate design requirements and to inform iterative prototype development. RESULTS: In total, 19 participants (clinicians: n=10, 53%; family members: n=9, 47%) attended 6 focus group sessions. Participants indicated that risk was typically communicated verbally by clinicians to patients and their families, with severity indicated using a descriptive or a numerical representation or both, which would only occasionally be contextualized. Participants indicated that risk communication tools were seldom used but that families would benefit from risk information, time to reflect on the information, and follow-up with questions. In addition, 9 key design requirements and feature considerations for effective risk communication were identified: (1) present risk information clearly and with contextualization, (2) quantify the risk and contextualize it, (3) include checklists for preoperative family preparation, (4) provide risk information digitally to facilitate recall and sharing, (5) query the family's understanding to ensure comprehension of risk, (6) present the risk score using multimodal formats, (7) use color coding that is nonthreatening and avoids limitations with color blindness, (8) present the most significant factors contributing to the risk prediction, and (9) provide risk mitigation strategies to potentially decrease the patient's level of risk. CONCLUSIONS: Key design requirements for a pediatric postoperative pain risk visualization tool were established and guided the development of an initial prototype. Implementing a risk communication tool into clinical practice has the potential to bridge existing gaps in the accessibility, utilization, and comprehension of personalized risk information between health care professionals and family members. Future iterative codesign and clinical evaluation of this risk communication tool are needed to confirm its utility in practice.
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OBJECTIVES: Pediatric diabetes health-care providers and decision-makers in British Columbia (BC) have prioritized the creation of a provincial pediatric diabetes clinical registry to improve care quality. Our objective is to build the first BC Pediatrics Diabetes Registry (BC-PDR) for quality improvement and coordination of pediatric diabetes care across the province. METHODS: Patients <19 years of age and diagnosed with diabetes were invited to participate in our study. Recruitment began in 2017 at the BC Children's Hospital (BCCH) and expanded to 6 community-based pediatric diabetes clinics in the Interior Health Authority (HA) in 2019. In response to COVID-19, recruitment shifted from in-person to virtual using an electronic consent system. Patient-level (e.g. age at diabetes onset, ethnicity) and visit-level (e.g. glycated hemoglobin [A1C], blood pressure, diabetes regimen, technology use, medications) data were collected in addition to screening for and presence of diabetes complications. RESULTS: As of January 2021, 635 patients from the BCCH and Interior HA were included in the BC-PDR. From the BCCH, 94% of 590 patients were diagnosed with type 1 diabetes and the median A1C was 7.8% and increased with age. Just under half of the BCCH patients were using insulin pump technology and/or a continuous glucose monitoring system. CONCLUSIONS: Over the last 3 years, we have worked to adapt and operationalize the BC-PDR. The next steps for the BC-PDR include engaging diabetes stakeholders in the development of an electronic benchmarking dashboard along with linkage of the data to patient-reported outcome and experience measures and provincial administrative databases.
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Diabetes Mellitus Tipo 1 , Sistema de Registros , Adolescente , Glicemia , Automonitorização da Glicemia , Colúmbia Britânica/epidemiologia , COVID-19 , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Hemoglobinas Glicadas/análise , HumanosRESUMO
Understanding and identifying the risk factors associated with suicide in youth experiencing mental health concerns is paramount to early intervention. 45% of patients are admitted annually for suicidality at BC Children's Hospital. Natural Language Processing (NLP) approaches have been applied with moderate success to psychiatric clinical notes to predict suicidality. Our objective was to explore whether machine-learning-based sentiment analysis could be informative in such a prediction task. We developed a psychiatry-relevant lexicon and identified specific categories of words, such as thought content and thought process that had significantly different polarity between suicidal and non-suicidal cases. In addition, we demonstrated that the individual words with their associated polarity can be used as features in classification models and carry informative content to differentiate between suicidal and non-suicidal cases. In conclusion, our study reveals that there is much value in applying NLP to psychiatric clinical notes and suicidal prediction.
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Suicídio , Adolescente , Criança , Humanos , Aprendizado de Máquina , Saúde Mental , Processamento de Linguagem Natural , Ideação SuicidaRESUMO
OBJECTIVE: The objective of this study was to estimate the impact of the coronavirus disease 2019 pandemic on pediatric emergency department (PED) visits after declaration of stay-at-home orders within British Columbia, Canada, and the change in cases by acuity and age for 6 months during the pandemic. METHODS: Retrospective data on PED visits at British Columbia Children's Hospital were collected between December 1, 2019, and August 31, 2020, and for 2 previous years. An interrupted time-series analysis was performed to estimate the difference in daily visits after stay-at-home orders on March 17, 2020, as well as before and after. Further analysis was performed to estimate the drop and recovery of admission and visits by age and acuity. RESULTS: After adjustment for year and seasonality, we documented a drop in the expected number of daily visits of 83 (95% confidence interval [CI], 78-89) after stay-at-home orders. Thereafter, daily visits increased by 12.9 (95% CI, 11.3-14.4) every month. Probability of admission adjusted for seasonality and acuity increased 6.9% (95% CI, 4.9%-9.0%) after stay-at-home orders and decreased in the odds of -0.7% (95% CI, -1% to -0.4%) monthly thereafter. CONCLUSIONS: The coronavirus disease 2019 pandemic has had a dramatic and lasting impact on the number of PED visits, with contracted rates 6 months into the pandemic. Further increase in acuity-adjusted rate of admissions after stay at home orders suggests that individuals may be delaying arrival to the emergency department. Further assessment is needed to determine if patients are seeking care through other venues or not seeking care altogether.
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Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Hospitais Pediátricos/estatística & dados numéricos , Colúmbia Britânica/epidemiologia , COVID-19/epidemiologia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Análise de Séries Temporais Interrompida , Pandemias , Estudos Retrospectivos , SARS-CoV-2RESUMO
BACKGROUND: Public health mitigation strategies in British Columbia during the pandemic included stay-at-home orders and closure of non-essential services. While most primary physicians' offices were closed, hospitals prepared for a pandemic surge and emergency departments (EDs) stayed open to provide care for urgent needs. We sought to determine whether ED paediatric presentations prior and during the COVID-19 pandemic changed and review acuity compared with seasonal adjusted prior year. METHODS: We analysed records from 18 EDs in British Columbia, Canada, serving 60% of the population. We included children 0-16 years old and excluded those with no recorded acuity or discharge disposition and those left without being seen by a physician. We compared prepandemic (before the first COVID-19 case), early pandemic (after first COVID-19 case) and peak pandemic (during public health emergency) periods as well as a similar time from the previous year. RESULTS: A reduction of 57% and 70% in overall visits was recorded in the children's hospital ED and the general hospitals EDs, respectively. Average daily visits declined significantly during the peak-pandemic period (167.44±40.72) compared with prepandemic period (543.53±58.8). Admission rates increased mainly due to the decrease in the rate of visits with lower acuity. Children with complaints of 'fever' and 'gastrointestinal' symptoms had both the largest overall volume and per cent reduction in visits between peak-pandemic and prior year (79% and 74%, respectively). CONCLUSION: Paediatric emergency medicine attendances were reduced to one-third of normal numbers during the 2020 COVID-19 lockdown in British Columbia, Canada, with the reduction mainly seen in minor illnesses that do not usually require admission.
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Infecções por Coronavirus/epidemiologia , Medicina de Emergência/organização & administração , Serviço Hospitalar de Emergência/organização & administração , Hospitais Pediátricos/organização & administração , Pneumonia Viral/epidemiologia , Adolescente , Betacoronavirus/patogenicidade , Colúmbia Britânica/epidemiologia , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Emergências/epidemiologia , Medicina de Emergência/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Acessibilidade aos Serviços de Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Pandemias/prevenção & controle , Admissão do Paciente/estatística & dados numéricos , Alta do Paciente/estatística & dados numéricos , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , SARS-CoV-2 , Triagem/organização & administração , Triagem/estatística & dados numéricosRESUMO
BACKGROUND: Integrated data repositories (IDRs), also referred to as clinical data warehouses, are platforms used for the integration of several data sources through specialized analytical tools that facilitate data processing and analysis. IDRs offer several opportunities for clinical data reuse, and the number of institutions implementing an IDR has grown steadily in the past decade. OBJECTIVE: The architectural choices of major IDRs are highly diverse and determining their differences can be overwhelming. This review aims to explore the underlying models and common features of IDRs, provide a high-level overview for those entering the field, and propose a set of guiding principles for small- to medium-sized health institutions embarking on IDR implementation. METHODS: We reviewed manuscripts published in peer-reviewed scientific literature between 2008 and 2020, and selected those that specifically describe IDR architectures. Of 255 shortlisted articles, we found 34 articles describing 29 different architectures. The different IDRs were analyzed for common features and classified according to their data processing and integration solution choices. RESULTS: Despite common trends in the selection of standard terminologies and data models, the IDRs examined showed heterogeneity in the underlying architecture design. We identified 4 common architecture models that use different approaches for data processing and integration. These different approaches were driven by a variety of features such as data sources, whether the IDR was for a single institution or a collaborative project, the intended primary data user, and purpose (research-only or including clinical or operational decision making). CONCLUSIONS: IDR implementations are diverse and complex undertakings, which benefit from being preceded by an evaluation of requirements and definition of scope in the early planning stage. Factors such as data source diversity and intended users of the IDR influence data flow and synchronization, both of which are crucial factors in IDR architecture planning.
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Eosinophilic esophagitis (EoE) is a chronic condition that requires repeated endoscopies/biopsies to track the disease and treatment response. This invasive procedure involves risk to the patient and has significant costs. We studied whether the detection of specific proteins (cytokines and eosinophil degranulation products) from oral swabs could serve as a minimally invasive test for EoE. Swabs of the oral cavity (buccal and oropharyngeal) were obtained prior to endoscopy/biopsies in patients with EoE, possible EoE, and non-EoE patients in addition to obtaining additional esophageal biopsy tissue. ELISAs measuring the levels of cytokines IL-5, IL-8, IL-13, and eosinophil degranulation products including major basic protein (MBP), eosinophil derived neurotoxin (EDN), and eosinophil peroxidase (EPO) were performed on the samples. Comparisons were made to peak esophageal eosinophil counts. Tolerability of the swabs was evaluated. 43 patients, 4-17 years old, participated in the study. Swabs were well tolerated and all showed measurable protein. 26 patients had EoE [14 active (> 15 eosinophils/high power field), 12 non-active], 17 patients did not have EoE. Results obtained from oral swabs showed poor correlation with those from esophageal tissue. Only measurement of eosinophil degranulation products EDN and EPO from esophageal tissues showed strong correlations with eosinophil counts. In this study, the levels of cytokines and eosinophil degranulation products detected from oral swabs did not correlate with esophageal eosinophilia, and their detection would be insufficient to displace endoscopy/biopsies.
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Esofagite Eosinofílica , Eosinófilos , Adolescente , Biomarcadores , Criança , Pré-Escolar , Neurotoxina Derivada de Eosinófilo , Esofagite Eosinofílica/diagnóstico , HumanosRESUMO
BACKGROUND: Health and health-related data collected as part of clinical care is a foundational component of quality improvement and research. While the importance of these data is widely recognized, there are many challenges faced by researchers attempting to use such data. It is crucial to acknowledge and identify barriers to improve data sharing and access practices and ultimately optimize research capacity. OBJECTIVE: To better understand the current state, explore opportunities, and identify barriers, an environmental scan of investigators at BC Children's Hospital Research Institute (BCCHR) was conducted to elucidate current local practices around data access and usage. METHODS: The Clinical and Community Data, Analytics and Informatics group at BCCHR comprises over 40 investigators with diverse expertise and interest in data who share a common goal of facilitating data collection, usage, and access across the community. Semistructured interviews with 35 of these researchers were conducted, and data were summarized qualitatively. A total impact score, considering both frequency with which a problem occurs and the impact of the problem, was calculated for each item to prioritize and rank barriers. RESULTS: Three main themes for barriers emerged: the lengthy turnaround time before data access (18/35, 51%), inconsistent and opaque data access processes (16/35, 46%), and the inability to link data (15/35, 43%) effectively. Less frequent themes included quality and usability of data, ethics and privacy review barriers, lack of awareness of data sources, and efforts required duplicating data extraction and linkage. The two main opportunities for improvement were data access facilitation (14/32, 44%) and migration toward a single data platform (10/32, 31%). CONCLUSIONS: By identifying the current state and needs of the data community onsite, this study enables us to focus our resources on combating the challenges having the greatest impact on researchers. The current state parallels that of the national landscape. By ensuring protection of privacy while achieving efficient data access, research institutions will be able to maximize their research capacity, a crucial step towards achieving the ultimate and shared goal between all stakeholders-to better health outcomes.
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OBJECTIVE: Eosinophilic esophagitis (EoE) is considered a TH2-mediated food allergy disease that leads to submucosal esophageal fibrosis and strictures. Recent studies focused on adults with EoE identified a strong association with elevated esophageal IgG4 immunostaining. Our study aimed to determine the association of IgG4 with EoE in pediatric patients. METHODS: Using our local EoE research registry, we identified 41 adequate biopsies from EoE patients. We used 10 age- and sex-matched patients with no diagnostic abnormalities at endoscopy or on biopsy. Using a monoclonal antibody to Immunoglobulin G4 (IgG4), we determined the maximum density of IgG4-positive plasma cells (IgG4-PC) per high-power field (hpf). Using a semi-quantitative assessment, we also graded the noncellular staining of the lamina propria and epithelium. RESULTS: Our EoE cohort consisted predominantly of boys with an average age of 5.9 years and 63% had a documented IgE-based food allergy. Median peak eosinophilia was 40âeosinophils/hpf and the median IgG4-PC density was 39/hpf in the active esophagitis patients, compared with a median of 0 IgG4-PC/hpf in the non-EoE patients (Pâ=â0.0001). EoE patients with a food allergy showed a significantly higher IgG4-PC density (44.5/hpf) than those without a food allergy (8/hpf; Pâ=â0.0385). There was no significant association between IgG4-PC density and peak eosinophilia (râ=â0.0011). CONCLUSIONS: We demonstrate that active esophagitis in pediatric EoE patients is associated with elevated levels of IgG4-positive plasma cells, which was more significant in EoE patients with a documented food allergy. Our study also adds to the growing literature that EoE may involve more than just an exaggerated TH2 immune response.
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Esofagite Eosinofílica/patologia , Imunoglobulina G/metabolismo , Mucosa/citologia , Plasmócitos/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. METHODS: Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. RESULTS: After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. CONCLUSIONS: These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.
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BACKGROUND: Small promoters that recapitulate endogenous gene expression patterns are important for basic, preclinical, and now clinical research. Recently, there has been a promising revival of gene therapy for diseases with unmet therapeutic needs. To date, most gene therapies have used viral-based ubiquitous promoters-however, promoters that restrict expression to target cells will minimize off-target side effects, broaden the palette of deliverable therapeutics, and thereby improve safety and efficacy. Here, we take steps towards filling the need for such promoters by developing a high-throughput pipeline that goes from genome-based bioinformatic design to rapid testing in vivo. METHODS: For much of this work, therapeutically interesting Pleiades MiniPromoters (MiniPs; ~4 kb human DNA regulatory elements), previously tested in knock-in mice, were "cut down" to ~2.5 kb and tested in recombinant adeno-associated virus (rAAV), the virus of choice for gene therapy of the central nervous system. To evaluate our methods, we generated 29 experimental rAAV2/9 viruses carrying 19 different MiniPs, which were injected intravenously into neonatal mice to allow broad unbiased distribution, and characterized in neural tissues by X-gal immunohistochemistry for icre, or immunofluorescent detection of GFP. RESULTS: The data showed that 16 of the 19 (84 %) MiniPs recapitulated the expression pattern of their design source. This included expression of: Ple67 in brain raphe nuclei; Ple155 in Purkinje cells of the cerebellum, and retinal bipolar ON cells; Ple261 in endothelial cells of brain blood vessels; and Ple264 in retinal Müller glia. CONCLUSIONS: Overall, the methodology and MiniPs presented here represent important advances for basic and preclinical research, and may enable a paradigm shift in gene therapy.
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Encéfalo/metabolismo , Dependovirus/metabolismo , Olho/metabolismo , Expressão Gênica , Regiões Promotoras Genéticas/genética , Animais , Barreira Hematoencefálica/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Vetores Genéticos/metabolismo , Integrases/metabolismo , Camundongos Endogâmicos C57BL , Recombinação Genética/genética , Células Bipolares da Retina/metabolismo , Transdução GenéticaRESUMO
Identifying variants causal for complex genetic disorders is challenging. With the advent of whole-exome and whole-genome sequencing, computational tools are needed to explore and analyze the list of variants for further validation. Correlating genetic variants with subject phenotype is crucial for the interpretation of the disease-causing mutations. Often such work is done by teams of researchers who need to share information and coordinate activities. To this end, we have developed a powerful, easy to use Web application, ASPIREdb, which allows researchers to search, organize, analyze, and visualize variants and phenotypes associated with a set of human subjects. Investigators can annotate variants using publicly available reference databases and build powerful queries to identify subjects or variants of interest. Functional information and phenotypic associations of these genes are made accessible as well. Burden analysis and additional reporting tools allow investigation of variant properties and phenotype characteristics. Projects can be shared, allowing researchers to work collaboratively to build queries and annotate the data. We demonstrate ASPIREdb's functionality using publicly available data sets, showing how the software can be used to accomplish goals that might otherwise require specialized bioinformatics expertise. ASPIREdb is available at http://aspiredb.chibi.ubc.ca.
Assuntos
Biologia Computacional/métodos , Variação Genética , Bases de Dados Genéticas , Exoma , Predisposição Genética para Doença , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , NavegadorRESUMO
BACKGROUND: The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array. RESULTS: No difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites). CONCLUSIONS: We suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.
RESUMO
INTRODUCTION: Research on complex health conditions such as neurodevelopmental disorders increasingly relies on large-scale research and clinical studies that would benefit from data sharing initiatives. Organizations that share data stand to maximize the efficiency of invested research dollars, expedite research findings, minimize the burden on the patient community, and increase citation rates of publications associated with the data. OBJECTIVE: This study examined ethics and governance information on websites of databases involving neurodevelopmental disorders to determine the availability of information on key factors crucial for comprehension of, and trust and participation in such initiatives. METHODS: We identified relevant databases identified using online keyword searches. Two researchers reviewed each of the websites and identified thematic content using principles from grounded theory. The content for each organization was interrogated using the gap analysis method. RESULTS: Sixteen websites from data sharing organizations met our inclusion criteria. Information about types of data and tissues stored, data access requirements and procedures, and protections for confidentiality were significantly addressed by data sharing organizations. However, special considerations for minors (absent from 63%), controls to check if data and tissues are being submitted (absent from 81%), disaster recovery plans (absent from 81%), and discussions of incidental findings (absent from 88%) emerged as major gaps in thematic website content. When present, content pertaining to special considerations for youth, along with other ethics guidelines and requirements, were scattered throughout the websites or available only from associated documents accessed through live links. CONCLUSION: The complexities of sharing data acquired from children and adolescents will only increase with advances in genomic and neuro science. Our findings suggest that there is a need to improve the consistency, depth and accessibility of governance and policies on which these collaborations can lean specifically for vulnerable young populations.