This overview covers studies published over the course of a month by Institute investigators and their collaborators spans a wide variety of topics, including:

Antibiotic treatment for sepsis; sexual violence reporting among student-athletes; research methods; medical product safety during pregnancy; the effect of trace elements on liver function in early pregnancy; longitudinal developmental origins of health and disease (DOHaD) research; associations of greenness, parks, and blue space with neurodegenerative disease hospitalizations among older us adults; associations of neighborhood opportunity and social vulnerability with trajectories of childhood body mass index and obesity among us children; environmental health

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The controversy over timing and spectrum of antibiotic treatment for sepsis, explained
Sepsis guidelines and mandates encourage increasingly aggressive time-to-antibiotic targets for broad-spectrum antimicrobials for suspected sepsis and septic shock. This has caused controversy: weaknesses exist in the underlying evidence, while fear that overly strict antibiotic deadlines may harm patients by perpetuating or escalating overtreatment persists. A new publication led by Institute fellow Theodore Pak, with Michael Klompas and Chanu Rhee, examines this controversy more closely, looking at challenges in interpreting evidence on antibiotic delays and outcomes, conflicting guidelines set forth over the years, the optimal breadth of broad-spectrum antibiotics, and what 2021 and beyond may bring for sepsis treatment and recommended guidelines. Read it now in Infectious Disease Clinics of North America.

Institute Investigator(s): Michael Klompas, Chanu Rhee
 

Student-athlete preferences for sexual violence reporting: a discrete choice experiment
Sexual violence is prevalent among US college athletes, but formal reports of it to university officials are rare. What’s more, little is known about adaptations to institution-level reporting policies and procedures that could facilitate reporting. A team including senior author Davene Wright conducted a discrete choice experiment survey with 1004 student-athletes at ten Division I NCAA member institutions to examine how attributes of the reporting system influence the decision to formally report sexual violence to their institution. Results, published in Patient, suggest that changes to reporting policies and procedures (for example, transparency about SV reporting outcomes, implementing substance use amnesty policies) may be promising institution-level interventions to increase formal reporting of sexual violence among student-athletes. The research team suggests that more research is needed to understand preference heterogeneity between students and generalize these findings to broader student populations.

Institute Investigator(s): Davene Wright

High-dimensional propensity scores for empirical covariate selection in secondary database studies: Planning, implementation, and reporting
The high-dimensional propensity score (hdPS) is an automated, data-driven analytic approach for covariate selection that empirically identifies pre-exposure variables and proxies to include in a propensity score model. However, best practice guidelines explaining when and how to implement hdPS are lacking, as is guidance to support decision-makers in fully understanding this method where it has been applied. A team including Darren Toh provides a comprehensive overview of the hdPS approach, including a guide on the planning, implementation, and reporting of hdPS approaches for causal treatment effect estimations using longitudinal healthcare databases. The study, published in Pharmacoepidemiology & Drug Safety, also includes a checklist with key considerations as a supportive decision tool to aid investigators in the implementation and transparent reporting of hdPS techniques, and to aid decision-makers unfamiliar with hdPS in the understanding and interpretation of studies employing this approach. 

Institute Investigator(s): Darren Toh

Assessing medical product safety during pregnancy using parameterizable tools in the Sentinel distributed database
The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. One component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. A Sentinel research team led by Institute investigators assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in offspring. Results, published in Pharmacoepidemiology and Drug Safety, suggest an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results, demonstrating the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

Institute Investigator(s): Jennifer Lyons, Judith Maro, Mayura Shinde, Darren Toh

Filling in the blanks: a simulation study to better understand multiple imputation in concert with other methods in distributed research network settings
In distributed research network (DRN) settings, multiple imputation (a general approach to the problem of missing data that is available in several commonly used statistical packages) cannot be directly applied because pooling individual-level data are often not possible. However, the performance of multiple imputation in combination with meta-analysis is not well understood within DRNs. A team led by Dongdong Li, with Jenna Wong, Xiaojuan Li, Darren Toh, and Rui Wang, sought to evaluate the performance of imputation for missing baseline covariate data in combination with meta-analysis for time-to-event analysis within DRNs. The team’s findings, published in Pharmacoepidemiology & Drug Safety, suggest the validity and feasibility of imputation within DRNs in the presence of missing covariate data in time-to-event analysis under various settings. The performance of the four imputation algorithms varies with the effect sizes and level of missingness.

Institute Investigator(s): Dongdong Li, Xiaojuan Li, Darren Toh, Rui Wang, Jenna Wong
 

Non-essential and essential trace element mixtures and kidney function in early pregnancy - A cross-sectional analysis in Project Viva

Though some trace elements are classified as toxic to the kidneys, their associations with kidney function during pregnancy are largely understudied. Debby Lin led a study, along with fellow Institute investigators Izzuddin Aris, Marie-France Hivert and collaborators, that tapped into Project Viva data to learn more. The team aimed to estimate the individual and joint associations of trace element mixtures in pregnant women during the 1st trimester with kidney function, hypothesizing that exposure to non-essential trace elements (both as individual elements and as a mixture) would be associated with reduced kidney function—whereas higher levels of essential trace elements would be protective of kidney function. They also sought to examine how these associations differ by race/ethnicity and socioeconomic status. Study results, published in Environmental Research, suggest that exposure to trace elements, even at low circulating levels, may be associated kidney function in early pregnancy.

Institute Investigator(s): Izzuddin Aris, Marie-France Hivert, Pi-I Debby Lin

Workforce Considerations When Building a Precision Medicine Program
While many, including primary care service providers, view the integration of genetics and genetic testing into health care as inevitable, few healthcare systems have attempted to work proactive genetic screening into primary care. Sanford Health, one of the first to do so, is used as a case study in a new publication out in Journal of Personalized Medicine, senior authored by Kurt Christensen. The research team summarizes personnel changes that facilitated the integration of genetics into patient care across the Sanford Health system, discusses their observations, and provides data to demonstrate one model of how healthcare systems that pursue a greater integration of genetics into patient care should be prepared to adapt staffing over time. While the integration of genetics into the Sanford Health system is not a one-size-fits all approach, the team’s case study highlights important lessons from which other health care systems can learn.

Institute Investigator(s): Kurt Christensen
 

Awareness and utilization of genetic testing among Hispanic and Latino adults living in the US: The Hispanic Community Health Study/Study of Latinos
Though genomic testing’s role in all aspects of medicine is rapidly expanding, disparities in uptake between racial and ethnic groups remain, including Hispanic and Latino populations—the largest racial and ethnic group in the US. Awareness and perceived usefulness of genomic testing may be of particular importance when considering these disparities. Limited research has examined factors that may influence the perceived usefulness of genomic testing specifically among this population, a gap that Kurt Christensen and team sought to close in their latest study, published in HGG Advances. They surveyed participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), with the goal of providing population-based insights about factors that may influence awareness, perceived usefulness, and genomic testing uptake. They found that only just over half of respondents reported awareness of at least one of the four types of genetic tests. Awareness of testing applications, including tailored treatment, was much lower than awareness about personal disease risks or risks to children in the population. Few reported being offered genetic testing, and only 3% reported ever using these tests. Overall, results highlight concerns about the potential for important segments of Hispanic and Latino populations to miss opportunities to benefit from improvements in genetic testing. The team suggests that education and outreach are likely to yield improvements in genetic test awareness and better ensure that all are able to reap the benefits of genomic medicine.

Institute Investigator(s): Kurt Christensen

When a birth cohort grows up: challenges and opportunities in longitudinal developmental origins of health and disease (DOHaD) research

Experiences can encode lifelong risks for a range of chronic health conditions. This concept evolved from a controversial theory to a generally accepted model known as the developmental origins of health and disease, or DOHaD. While the study of animals has demonstrated this concept, human evidence is essential—though obtaining it is challenging. Leaders of successful birth cohorts, including lead author Emily Oken, co-PI of Project Viva, teamed up to pen a publication reflecting on the challenges of studying a long-running cohort study, strategies for success, and the future of this type of research. Published in the Journal of Developmental Origins of Health and Disease, the paper aims to be a resource for other scientists and study staff.  

Institute Investigator(s): Marie-France Hivert, Emily Oken

Tree-based data mining for safety assessment of first COVID-19 booster doses in the Vaccine Safety Datalink
The Centers for Disease Control and Prevention’s Vaccine Safety Datalink (VSD), of which the Institute is a member, has been performing safety surveillance for COVID-19 vaccines since their earliest authorization in the United States. Complementing its real-time surveillance for pre-specified health outcomes using pre-specified risk intervals, the VSD conducts tree-based data-mining to look for clustering of a broad range of health outcomes after COVID-19 vaccination. Led by Katherine Yih, a new study, published in Vaccine used this untargeted, hypothesis-generating approach to assess the safety of first booster doses of Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Janssen (Ad26.COV2.S) COVID-19 vaccines. detected clusters of unspecified adverse effects; common vaccine reactions such as fever, myalgia, and headache; and, for the mRNA vaccines, chest pain and palpitations, as well as myocarditis/pericarditis after Pfizer-BioNTech Dose 2.  Regarding first boosters, clusters of urticaria/allergy/rash were found during Days 10–15 after the Moderna booster, as had been reported after Moderna vaccination previously.  Other outcomes that clustered after mRNA boosters included unspecified adverse effects and common vaccine reactions.  No previously unknown serious adverse reactions were found. 

Institute Investigator(s): Judith Maro, Katherine Yih
 

Key drivers of family-level utility of pediatric genomic sequencing: a qualitative analysis to support preference research
Pediatric genomic sequencing can have far-reaching effects on the health and well-being of both the child and family. But what do families have to say about its usefulness from their perspective? A team led by Hadley Stevens Smith explored what is important to caregivers of pediatric patients regarding clinical in a new publication out now in European Journal of Human Genetics. The team found that caregivers raised important family-level considerations, in addition to those specifically for their child, which included wanting the best chance at good quality of life for the family, the ability to learn about family health, the impact on the caregiver’s well-being, privacy concerns among family members, and the cost of testing to the family. Furthermore, they developed a framework of key drivers of utility consisting of four domains that influenced caregivers’ decision making.

Institute Investigator(s): Hadley Stevens Smith
 

Associations of Neighborhood Opportunity and Social Vulnerability With Trajectories of Childhood Body Mass Index and Obesity Among US Children
Residence in neighborhoods with higher opportunity or lower vulnerability in early life, especially at birth, may be associated with lower mean BMI trajectory and lower risk of obesity through adolescence, according to a new study led by Izzuddin Aris. The physical and social attributes of neighborhoods where children reside is increasingly recognized as an important determinant of health across the lifecourse. Compared with adults, children may be particularly vulnerable to adverse neighborhood conditions with consequences for lifelong health. The extent to which these attributes relate to childhood BMI and obesity risk remains understudied. Results, published in JAMA Network Open, suggest that residing in neighborhoods with higher-opportunity or lower-vulnerability early in life, especially at birth, is associated with lower mean BMI trajectory and lower risk of obesity from childhood to adolescence. Results also support the need for a focus on investments that address the structures that consistently compromise the health of marginalized communities. 

Institute Investigator(s): Izzuddin Aris, Peter James, Emily Oken