Survey on the Impact of COVID-19 on People Who Live With Rare Diseases and Their Families

Cincinnati Children’s began operating the Data Management and Coordinating Center of the Rare Diseases Clinical Research Network (RDCRN) in August 2019. The RDCRN coordinating center facilitates network operations, research, participant engagement, and data sharing across the national research network, with funding from the National Institutes of Health through its National Center for Advancing Translational Sciences. The 23 RDCRN teams research how particular rare diseases progress and work to develop improved approaches for diagnosis and treatment.

As the COVID-19 pandemic reached the United States, it became apparent that understanding the impact of COVID-19 on rare disease patients was important because of the high vulnerability of this population. Targeted research was necessary. In April 2020, the coordinating center led a group of RDCRN investigators to design a survey of rare disease patients launched in May. The investigation aims to estimate the proportion of patients who live with rare diseases who receive a diagnosis of COVID-19 infection; to learn about the COVID-19 presentation and the course of the infection (including treatment) among patients with rare diseases; to determine whether certain subgroups of patients become infected more frequently or experienced increased severity of the infection; to learn about potential interaction between specific rare disease treatment regimens and COVID-19 infection; to assess the extent to which the COVID-19 pandemic impacts the lives of rare disease patients and their families including their access to medical care and routine medication; and to determine how the RDCRN can respond by providing information and advice through its network of experts, its consortia and in collaboration with patient advocacy groups.

As of publication date, more than 3,500 rare disease patients or their caregivers throughout the nation have completed the survey. Respondents represent nearly 130 rare disease types. Survey enrollment extended through the end of August with a planned first analysis of the data in September. The survey is available in English and Spanish through the RDCRN website. The site also includes a dashboard with routine updates on select statistics from the survey.

Rare Diseases Clinical Research Network (RDCRN) Transition to Cincinnati Children's

In the past year, the Data Management and Analysis Center (DMAC) worked on the transition of the Rare Diseases Clinical Research Network (RDCRN) to Cincinnati Children’s. This transition included working with more than 20 individual consortia, or rare disease research teams, to rebuild over 30 legacy protocols in REDCap. These builds make up nearly 45,000 variables, over 900 data collection forms, and over 850 existing datasets imported into REDCap in order to allow the consortia to continue the recruitment and data collection for their important research protocols.

The DMAC completed approximately 90% of this transition and also works with the consortia on the development of new protocols and REDCap databases for eight research studies, in parallel with the legacy transition.

The Impact of Short-term Air Pollution on Psychiatric Exacerbations in Children and Adolescents

Research conducted by Cole Brokamp, PhD, and Patrick Ryan, PhD, MS, both from the Division of Biostatistics and Epidemiology; Andrew Beck, MD, MPH, from the Divisions of General & Community Pediatrics and Hospital Medicine; and Jeffrey Strawn, MD, from the University of Cincinnati’s Department of Psychiatry and Behavioral Neuroscience, found that short-term exposure to ambient air pollution associates with exacerbations of psychiatric disorders in children one to two days later, as indicated by increased utilization of the Cincinnati Children’s emergency department for psychiatric issues. The study, published in Environmental Health Perspectives, also found that children living in disadvantaged neighborhoods may be more susceptible to the effects of air pollution compared to other children, especially for disorders related to anxiety and suicidality.

This work represents the first study to show an association between daily outdoor air pollution levels and increased symptoms of psychiatric disorders in children. These findings could eventually lead to new prevention strategies for children experiencing symptoms related to a psychiatric disorder. The fact that children living in high-poverty neighborhoods experienced greater health effects of air pollution could mean that pollutant and neighborhood stressors can have synergistic effects on psychiatric symptom severity and frequency.

Linking Prenatal and Postnatal Psychosocial Determinants, DNA Methylation, and Early Developmental Health Disparities

Through an R01 grant from the National Institute of Minority Health and Health Disparity, Katherine Bowers, PhD, MPH, and Ted Folger, PhD, MS, are studying the relationship between the early psychosocial environment, infant epigenetic changes (i.e., DNA methylation), and child developmental outcomes including adaptive functioning, communication, cognitive ability, motor skills, and social-emotional skills. The study is recruiting 375 mother-infant dyads who participate in Every Child Succeeds, a home visiting program based at Cincinnati Children’s serving the Greater Cincinnati region.

In this prospective cohort study, data collection occurs during five study visits that span pregnancy through 18 months postnatal. The research team hopes to determine the association between the life-course maternal psychosocial experience and the change in infant DNAm during the first year of life, a sensitive developmental window; characterize the association between postnatal maternal psychosocial experiences in the infant’s first year of life and infant DNAm at one year; and determine the impact of DNAm at two time points of infant development across the first 18 months (one month and 12 months).

This work contributes to scientific knowledge regarding how early psychosocial experiences can influence a child’s development and behavior through the dynamic early epigenome. The findings will support the potential development of models that can predict significantly elevated developmental risk within the context of a prevention program.

Technology-Assisted Language Intervention (TALI)

Although hearing loss is identifiable earlier than ever before, children who are deaf/hard of hearing are still at higher risk for delayed language outcomes. Early intervention for language and vocabulary development can help bridge the difference for infants and toddlers. However, many children continue to fall behind age-appropriate levels—a delay with potential long-term impacts on academic achievement.

That’s why researchers from the Divisions of Biostatistics and Epidemiology and Developmental and Behavioral Pediatrics at Cincinnati Children’s, led by Jareen Meinzen-Derr, PhD, MPH, FACE, began the Technology-Assisted Language Intervention (TALI) project in 2016 with a randomized trial funded by the National Institute on Disability, Independent Living, and Rehabilitation Research. Now, a five-year, $3 million grant from the National Institute on Deafness and Other Communication Disorders will enable the team to help more children who are deaf/hard of hearing improve their language skills.

Each child in the TALI study receives an iPad to access an assistive technology known as augmentative and alternative communication. When users touch images on the screen, the app announces corresponding words, phrases, and messages.

Results from the original trial indicate significant improvements in spoken language outcomes over traditional therapy. The new study will expand to nearly 120 children across two different study sites. Researchers hope to not only replicate the original findings, but also evaluate how the intervention may benefit other populations who struggle with language development.

“Ultimately, our goal is to provide a ‘boost’ in language skills for children who are deaf or hard of hearing,” says Meinzen-Derr. “We believe that this work will give families and providers more therapeutic intervention choices, and we hope to continue to empower them.”

Microbial Metagenomics Analysis Center (MMAC)

Advances in next-generation sequencing revolutionizes our understanding of the human microbiome with host-associated bacteria, viruses, or fungi now implicated in numerous disease states. However, incorporating microbiome research into existing translational research programs presents unique challenges—not only with collecting and sequencing microbial community samples, but also with properly analyzing the large amounts of sparse, compositional, high-dimensional data generated by next-generation sequencing.

To support advancing microbiome research across the University of Cincinnati (UC) Academic Health Center (AHC), Nicholas Ollberding, PhD, will develop a Microbial Metagenomics Analysis Center (MMAC) focusing on the bioinformatic processing and statistical analysis of next-generation sequencing data derived from microbial community samples.

With funding through an Innovative Core Grant Award from UC’s Center for Clinical & Translational Science & Training, Ollberding and a collaborative team of researchers in the Divisions of Biostatistics and Epidemiology (Mekibib Altaye, PhD), Biomedical Informatics (Michael Wagner, PhD), and Infectious Diseases (David Haslam, MD) will provide state-of-the-art solutions to investigators across the AHC in the areas of study design, bioinformatic processing of amplicon and shotgun metagenomic sequencing data, integration of metagenomic and clinical data structures, and the statistical analyses of microbial community samples. In the coming year, the MMAC will work to build core staff capacity, increase the network of investigators utilizing the center’s services, and oversee an RFA for pilot projects. Additionally, the MMAC will work with the Microbial Genomics and Metagenomics Laboratory and collaborators in the Division of Biomedical Informatics to streamline workflows for metagenomic sequencing, bioinformatic processing, and statistical analysis of microbiome projects conducted at Cincinnati Children’s.

Serology of COVID-19 Patients and Contact in Cincinnati, Ohio

As of mid-August 2020, more than 4,200 Cincinnati residents received a diagnosis of coronavirus disease 2019 (COVID-19) with a majority receiving a positive laboratory PCR test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The remaining cases received a label probable COVID-19 based on symptoms and circumstance.

As the Cincinnati region and nationwide receive more COVID-19 cases, historically underrepresented racial and ethnic groups continue to be disproportionately affected by the pandemic. In Cincinnati, Hispanic individuals make up only 4% of the region’s population yet account for nearly 18% of its COVID-19 cases. Also, individuals who identify as black so far experienced an expected frequency of infections based on population distribution, but account for a higher proportion of COVID-19 related deaths, suggesting more severe disease.

In order to respond to these disparities in Cincinnati, Bowers is leading a study in collaboration with Folger and a cross-institutional team of Cincinnati Children’s and Cincinnati Health Department researchers to better understand the prevalence of both current and past SARS-CoV-2 infections, how transmission occurs, and identify risk factors for infection, severe disease, and death. With funding from the Cincinnati Health Department and the COVID-19 Critical Community Challenge Grant Program from the University of Cincinnati’s Center for Clinical & Translational Science & Training, the research team will study the symptomatology of close contacts, document potential transmission pathways through family environments, and establish methods for community-based serologic testing among high-risk, vulnerable populations. By testing sera of asymptomatic individuals and those with established infections previously identified by reverse transcription polymerase chain reaction (RT-PCR), the research team will help characterize the course of disease by assessing changes in immune response over time. Lastly, these researchers will explore potential heterogeneity of transmission by sociodemographic indicators.