Building a growing genomic repository for maternal and fetal health through the PING Consortium

Abstract

Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Of note, prenatal Zika infection can cause a spectrum of neurodevelopmental disorders, including congenital Zika syndrome. Currently, there is no preventative treatment or cure. The Prenatal Infection and Neurodevelopmental Genetics (PING) Consortium aims to identify modulators of brain injury and adverse neurodevelopmental outcomes for Zika and other prenatal viral infections.

Methods: The Consortium pools information from eight multi-site studies conducted at 23 research centers in six countries to build a growing clinical and genomic repository, which is being mined for modifiers of virally induced brain injury. Partners include Children's National Hospital (USA), Instituto Nacional de Salud (Colombia), the Natural History of Zika Virus Infection in Gestation program (Brazil), Zika Instituto Fernandes Figueira (Brazil), the Centers for Disease Control and Prevention, and the National Institutes of Health.

Results: We have enrolled 4102 mothers and 3877 infants with 3063 biological samples and clinical data covering over 80 phenotypic fields and 5000 variables. Thus far, we have performed whole exome sequencing on 1226 participants.

Conclusion: Here, we present the Consortium's formation and overarching study design.

Impact: The PING Consortium brings together investigators and institutions to determine the causes of virally induced brain injury and neurological deficits. The clinical and genomic repository, with data from over 8000 patients, will serve as a foundation for a variety of basic and clinical studies.

Fig. 1. Partnerships and Sites.

Through collaborations at Children’s National Hospital with the U.S. Centers for Disease Control and Prevention, Colombia Instituto Nacional de Salud, the Natural History of Zika Virus Infection in Gestation cohort, Zika Instituto Fernandes Figueira cohort, and the National Institutes of Health, the Consortium represents six countries and 22 research cohort sites (there are two ZIP cohorts in Puerto Rico). For the purposes of the Consortium, Puerto Rico is considered as a US territory.

Fig. 2. Data collection, processing, and storage.

As listed in Stage I, the Consortium gained access to clinical data and biospecimens. Clinical data included pre- and postnatal imaging and subclinical phenotyping, and up to two years of neurodevelopmental follow-up. As described in Stage II, biospecimens, which included blood, tissue, and placenta samples, were collected for DNA extraction. Tissue and DNA biobanks were established to preserve samples for future research purposes. Whole exome sequencing was performed on collected samples, with the goal of creating a databank that will serve as a resource in current and future research on prenatal viral infections, as represented in Stage III. Gray arrows refer to processes, purple arrows indicate biobank storage.

Fig. 3. Harmonizing study data.

Clinical data from each study was reviewed and converted into a categorical format. Then, data from each study site was aligned across the cohorts. Next, a data dictionary was created to provide a key for importing the clinical outcomes into the database. Lastly, participant information was imported into REDCap to evaluate its operational capabilities. Finally, the data was imported in a de-identified manner and validated.

Fig. 4. REDCap creation plan.

Participant’s demographics, clinical evaluations, laboratory testing, and radiological findings were reviewed among the studies and iteratively aligned per the Study Data Harmonization process outlined in Fig. 3. As radiological findings and clinical evaluations contained the most variable information across studies, these phases were prioritized during REDCap drafting.