Reply to Goligher et al.: Physiology Is Vital to Precision Medicine in Acute Respiratory Distress Syndrome and Sepsis

From the Authors:

We thank Goligher and colleagues for their insightful comments on our recent research statement highlighting the need to incorporate physiology in ongoing and future precision medicine studies for sepsis and the acute respiratory distress syndrome (ARDS) (1). We completely agree that the inclusion of physiologic variables and physiologic responses is necessary and in our research statement had intended them to be considered under the broader category of “clinical” biomarkers. Currently, the variables or combination of variables that contribute to heterogeneity of treatment effect in sepsis and ARDS are unknown, and we agree that excluding any domain of variables is potentially harmful. We appreciate the opportunity to clarify and expand the discussion.

Physiologic variables and physiologic responses do indeed have a proven track record of informing heterogeneity of treatment effect in pulmonary and critical care as exemplified by distribution of emphysema and ventilatory parameters for lung volume reduction surgery and endobronchial coils in chronic obstructive pulmonary disease, lung elastance for ARDS ventilation, or markers of fluid responsiveness in sepsis (2–5). Physiologic variables may both explain and predict response to treatment with several advantages for precision medicine strategies. First, as suggested by Goligher and colleagues, physiologic responses can potentially inform whether a patient is benefitting from or being harmed by a therapy in a manner that is more rapid than a biochemical assay. Second, physiologic variables may be measured more readily across a variety of geographic and socioeconomic settings than with other variables; thus, precision medicine strategies incorporating physiology may be more easily deployed when molecular assays or complex computational approaches are not feasible.

We respectfully add that the caveats addressed in our research statement must apply to physiologic variables. Similar rigor is required for the inclusion of physiologic variables in precision medicine for sepsis and ARDS as is necessary for other domains such as biochemical assays. Consensus definitions and standardized protocols for the measurement of physiologic variables should be used to ensure reproducibility and to facilitate validation of findings, and conscious efforts should be made to harmonize physiologic data in sepsis and ARDS knowledge networks. Evidence that change in a physiologic measure impacts patient-centered outcomes is vital. Importantly, as addressed by Goligher and colleagues, findings suggesting heterogeneity of treatment effect based on physiologic variables, no matter how intuitive, must still be confirmed in prospective clinical trials. In this regard, ongoing trials testing driving pressure for ARDS are exemplars of translating computational approaches suggesting heterogeneity of treatment effect to advance precision medicine (6–8).

We similarly agree that combinations of data from multiple domains are likely to inform precision medicine moving forward. The variables determining heterogeneity of treatment effect may not be limited to molecular, clinical, or physiologic variables alone, reinforcing the need to remain inclusive. Indeed, we believe that the knowledge networks necessary to detect and explain why patients are or are not responding to treatment will require all types of data, and assessment for interactions between them, to advance precision medicine for sepsis and ARDS.