Research Recap: April 25 – May 6
A biweekly overview of recent studies published by Institute investigators and their collaborators spans a wide variety of topics, including:
Associations of heterogenous sepsis presentation and antibiotic timing; Unmeasured confounding in the MR Steiger approach; and Inhaled corticosteroid treatment response in older adults with asthma.
For all faculty publications, see our Publications page. For up-to-date media coverage and research findings, visit In the Media, and follow us on Twitter. To search for a subject matter expert, visit our Investigator Directory.
How variations in clinical presentations of sepsis challenge the one-size-fits-all approach in time-to-antibiotic measures
Sepsis is a leading cause of morbidity, mortality, and healthcare costs. The enormous burden of sepsis—coupled with the assumption that at least some fraction of sepsis-related morbidity and mortality is preventable with better hospital-based care—has catalyzed widespread efforts to improve early recognition and treatment. In a new letter to the editor in Critical Care Medicine, Chanu Rhee and Edward Septimus discuss a retrospective analysis study by Usher et al, emphasizing several important insights regarding time-to-antibiotics in sepsis, notably the variations in clinical presentation of sepsis and the resulting pattern of delayed versus early antibiotic administration based on clinical characteristics and severity-of-illness. Authors emphasize that these findings call for more nuanced process metrics that account for these variables and increased efforts to develop better diagnostic tests to detect infection and inform antibiotic selection at the point of care, while balancing the increasing desire for earlier treatment against the potential harms associated with antibiotic overuse.
Continued discussion of unmeasured confounding with the Mendelian Randomization (MR) Steiger approach
The Mendelian Randomization (MR) Steiger approach is used to determine the direction of a possible causal effect between two phenotypes. A recent Genetic Epidemiology publication by a team of researchers including Ann Wu and led by Sharon Lutz examined the ability of the MR Steiger approach to infer the effect direction under pleiotropy, measurement error, and unmeasured confounding. In response to observations and criticisms of their paper from Hemani et al, the authors published a subsequent letter to the editor in Genetic Epidemiology to clarify the aim of their analysis and elucidate their selected data sources and decision to conduct a single SNP analysis rather than extending the MR Steiger approach to multiple SNPs. Lutz et al also mention that their original paper erroneously omitted that the MR Steiger method can be biased in the presence of unmeasured confounding, showing that unmeasured confounding does not bias the correlation when it is zero, but is silent as to how a nonzero correlation may be affected.
Researchers identify new genetic variants associated with inhaled corticosteroid treatment response in older adults with asthma
While older adults have the greatest burden of asthma and poorest outcomes, the pharmacogenetics of inhaled corticosteroid (ICS) treatment response in older adults is not well studied. A team of researchers including Sharon Lutz and senior author Ann Wu performed a genome-wide association study of ICS response in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) followed by validation in the Mass General Brigham Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. Results, published in Thorax, identified multiple novel single-nucleotide polymorphisms (SNPs) associated with ICS response in older adult asthmatics.