A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement

Background: Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure.Methods: This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS.Results: The following six priority recommendations were developed by the working group: 1) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; 2) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; 3) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; 4) further development of the tools necessary for the real-time application of precision medicine approaches; 5) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and 6) the securement and maintenance of adequate and sustainable funding for precision medicine efforts.Conclusions: Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.

## Overview
Sepsis and acute respiratory distress syndrome (ARDS) are well-described clinical syndromes (1, 2) that constitute a substantial portion of ICU admissions and hospital deaths [bib_ref] Hospital deaths in patients with sepsis from 2 independent cohorts, Liu [/bib_ref] with few therapies demonstrating consistent benefit in clinical trials [bib_ref] National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials..., Matthay [/bib_ref] [bib_ref] Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome..., Mcauley [/bib_ref] [bib_ref] PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock, Ranieri [/bib_ref] [bib_ref] ACCESS Study Group. Effect of eritoran, an antagonist of MD2-TLR4, on mortality..., Opal [/bib_ref]. A major impediment to identifying new therapies is unrecognized heterogeneity that may influence patients' susceptibility to these syndromes and their response to specific treatments [bib_ref] Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis, Seymour [/bib_ref] [bib_ref] Peeking under the hood of acute respiratory distress syndrome phenotypes: deeper insights..., Sinha [/bib_ref] [bib_ref] The search for efficacious new therapies in sepsis needs to embrace heterogeneity, Scicluna [/bib_ref]. Precision medicine approaches that incorporate variability in genomic, biologic, environmental, and lifestyle factors into the optimal therapeutic strategy may provide a path forward for sepsis and ARDS management [bib_ref] Precision medicine for all? Challenges and opportunities for a precision medicine approach..., Seymour [/bib_ref] [bib_ref] Heterogeneity in sepsis: new biological evidence with clinical applications, Leligdowicz [/bib_ref].
For this research statement, we convened a workshop to discuss the challenges for implementing precision medicine in the ICU and to suggest a research agenda in precision medicine that could spur advances for sepsis and ARDS. Key recommendations include the following:
1. Creating large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS. 2. Implementing novel trial designs that facilitate precision medicine approaches. 3. Continuing to innovate in the data science and engineering methods required to identify heterogeneity of treatment effect. 4. Further developing the tools necessary for the real-time application of precision medicine in the ICU. 5. Ensuring that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups. [bib_ref] National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials..., Matthay [/bib_ref]. Securing and maintaining adequate and sustainable funding for precision medicine efforts.

# Introduction
The terms "precision medicine" and "personalized (or individualized) medicine" are sometimes used interchangeably. In precision medicine, the focus is on identifying which approaches will be effective for a group of patients based on similar unifying characteristics. Although the eventual goal is to tailor care for each individual (personalized medicine), most current efforts are focused on precision medicine because predicting treatment response at an individual patient level is challenging [bib_ref] Classification, ontology, and precision medicine, Haendel [/bib_ref]. Significant breakthroughs have been made in precision medicine in non-critical care settings, including oncology, asthma, and chronic obstructive pulmonary disease, by leveraging extensive clinical data and molecular phenotyping to uncover subgroups that share dysregulation of specific pathways [bib_ref] Biomarker development in the precision medicine era: lung cancer as a case..., Vargas [/bib_ref] [bib_ref] KEYNOTE-001 Investigators. Pembrolizumab for the treatment of nonsmall-cell lung cancer, Garon [/bib_ref] [bib_ref] Mepolizumab for eosinophilic chronic obstructive pulmonary disease, Pavord [/bib_ref] [bib_ref] Asthma genetics and personalised medicine, Meyers [/bib_ref] [bib_ref] RAPID Trial Study Group. Intravenous augmentation treatment and lung density in severe..., Chapman [/bib_ref] [bib_ref] SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe..., Bleecker [/bib_ref]. These advancements have engendered a hope that we could rapidly apply similar techniques for sepsis and ARDS, but there are key differences [bib_ref] Precision medicine for all? Challenges and opportunities for a precision medicine approach..., Seymour [/bib_ref]. The molecular landscapes of sepsis and ARDS are complex and evolve rapidly, and clinicians often make therapeutic decisions within hours in contrast to days or weeks for outpatient decisions. Although "omics" platforms may improve molecular characterization of diseases, rapid turnaround times for complex assays are currently not readily available. Thus, initial steps toward precision medicine for patients with sepsis and ARDS include using clinical markers or easy-to-measure biomarkers. Importantly, clinical benefits of future precision medicine approaches in sepsis and ARDS, if any, will need to be tested and confirmed in rigorous wellconducted prospective clinical trials.

# Methods
This project was proposed by members as an American Thoracic Society (ATS) project and approved for funding by the ATS Board of Directors. Participants included the project proposers and an invited diverse group of individuals with 1) expertise in managing critically ill pediatric or adult patients; 2) experience in patient-oriented research from mechanistic, clinical, translational, or bioinformatic perspectives; and 3) representation from different geographic regions (e.g., North America, South America, Europe, Africa, and Australia) and federal funding agencies (e.g., National Institute of Health), and reflecting different perspectives based on sex, seniority, and race/ethnicity.
A small working group met initially to review the available literature, develop a conceptual framework, agree on definitions for key terms, and determine the goals of the document. Members of the panel met in person at the Critical Care Canada Forum in November 2018 and the ATS International Conference in May 2019 to develop and prioritize recommendations. The chairs and a small working group prepared an initial draft of the document on the basis of the in-person meetings and circulated it to the panel for iterative feedback. Members of the committee were asked to vote on the prioritization of recommendations. The revised document was shared electronically and iteratively refined until all authors approved the work. and may exclude some patients who could be part of a subgroup identified with alternate definitions and approaches. We use the term "subgroups" to generally include several commonly used terms, including phenotypes, subphenotypes, and endotypes [bib_ref] Identifying distinct subgroups of ICU patients: a machine learning approach, Vranas [/bib_ref] [bib_ref] Prognostic and predictive enrichment in sepsis, Stanski [/bib_ref]. Prior work has identified subgroups of patients with sepsis and ARDS who are more or less likely to have poor clinical outcome on the basis of clinical or biologic biomarkers (prognostic markers). The efficacy (relative or absolute benefit or harm) of a treatment may vary across patient subgroups, such that the benefit (or harm) is concentrated in one or more subgroups-a variability referred to as heterogeneity of treatment effect (HTE) [bib_ref] Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal, Kent [/bib_ref]. Understanding HTE and identifying biomarkers based on genomic, biologic, environmental, and lifestyle factors that predict benefit or harm from a treatment (predictive markers) is key to advancing precision medicine strategies [bib_ref] Heterogeneity in sepsis: new biological evidence with clinical applications, Leligdowicz [/bib_ref] [bib_ref] Biomarker definitions and their applications, Califf [/bib_ref].
Prognostic markers have an established discovery pipeline and can be identified in any observational cohort by testing for association with outcome. In contrast, predictive markers are most readily determined through the interrogation of a dataset in which patients are randomly assigned to a treatment, such as a randomized controlled trial (RCT). Without random allocation, causal inference that patients with a set of observed variables are more or less responsive to therapy is limited by potential confounding. Confounding variables may be measured or unmeasured (residual confounding). A common example is confounding due to indication, in which a treatment is more or less likely to be administered on the basis of illness severity, comprising both inadequate adjustment of measured confounders and residual unmeasured confounding [bib_ref] Control of confounding and reporting of results in causal inference studies. Guidance..., Lederer [/bib_ref] [bib_ref] Clinical knowledge from observational studies. Everything you wanted to know but were..., Gershon [/bib_ref].
We propose a conceptual framework to develop precision medicine strategies for sepsis and ARDS through the creation of knowledge networks as recommended by the National Academy of Sciences. A knowledge network can include both observational studies and RCTs to integrate layers of clinical, lifestyle, environmental, and biological data about a disease (similar to a geographic information system map), allowing us to understand the connections within and across layers. Depending on the research questions and treatments being studied, knowledge networks could be small (and potentially include observational studies only) or large (including multiple large observational studies and RCTs). These knowledge networks will enable the identification of subgroups and the elucidation of complex pathways using a combination of observational studies and RCTs, and the discovery of HTE using RCTs. The confidence in subgroups identified as "likely to benefit" may vary, and, on the basis of the certainty of subgroup identification, trial designs could employ traditional (enroll only the subgroup that is most likely to benefit under settings of a very high level of certainty) or novel (e.g., adaptive platform trial design) methods to identify and validate precision medicine strategies [fig_ref] Figure 1: Conceptual model of the path forward for precision medicine in sepsis and... [/fig_ref]. The financial investment required for the advancement of precision medicine in sepsis and ARDS will be substantial, but it ultimately could reduce costs through improved targeting of treatments and patient outcomes.

## Recommendations recommendation 1
Create large richly phenotyped harmonized knowledge networks of clinical, imaging, and multianalyte molecular data from patients with sepsis and ARDS.
Rationale. Discovery of prognostic and predictive biomarkers in complex heterogeneous disorders, including cancer, asthma, and cardiovascular disease, have occurred through the coordinated establishment and harmonization of knowledge networks. Similar collaborative efforts for sepsis and ARDS are necessary to advance precision medicine efforts. Observational studies, both already completed and future studies, recruit a broad group of patients unlike those enrolled in RCTs and can provide platforms for the discovery of phenotypes using clinical, imaging, and multianalyte molecular data (e.g., DNA, RNA, proteomics, microbiome, and metabolomics) from whole blood, plasma/serum, sputum/tracheal aspirate, BAL, or urine samples, as well as facilitate deep phenotyping (precise and comprehensive analysis of phenotypic abnormalities). Previously completed RCTs contribute to knowledge networks as venues for validation of phenotypes and HTE hypotheses. Multiple RCTs, if available for the same treatment, will enable the identification of HTE in subgroups of patients and for validation of observations identified in a single trial. The variables defining HTE may not be known or measured (or the technologies to uncover these variables may not be readily accessible) at the time of enrollment in observational studies and RCTs and may potentially be identified retrospectively as new knowledge becomes available without the need to conduct new studies.
Despite the increased financial cost of collecting and storing a variety of biospecimens in clinical studies, such efforts are necessary for the advancement of precision medicine in sepsis and ARDS. Successful harmonization of data will be essential to reduce and account for variability between studies and to facilitate validation of promising [bib_ref] A core outcome set for critical care ventilation trials, Blackwood [/bib_ref]. For molecular data, developing uniform protocols for sample collection, processing, storage, and assay selection as well as encouraging the use of consistent imaging and biochemical platforms, similar to clinical minimal data elements. 4. Prioritizing funding for sepsis and ARDS studies with discrete and transparent data sharing plans (e.g., requiring submission of data to a common online data repository) and by allocating funds specifically for the creation and maintenance of data harmonization initiatives because the expense and effort required for harmonization can be substantial and are often not budgeted in initial study designs.

## Recommendation 2
Implement novel trial designs to identify precision medicine strategies for sepsis and ARDS.
Rationale. The RCT is a valuable tool to test efficacy, avoid confounding, and establish causal effect of an intervention. Traditional RCTs are conducted in a broad group of patients anticipating that the average treatment effect across trial participants will demonstrate benefit.
Adaptive designs allow prospective modifications of one or more aspects of the study on the basis of interim analyses of participants already enrolled in the study [bib_ref] The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) study. Rationale..., Angus [/bib_ref]. These designs may be more efficient than traditional trial designs for identifying patients who benefit in settings in which HTE exists within the study population. Frequentist or Bayesian statistical approaches may be used in these designs depending on the complexity of potential modifications [bib_ref] Clinical trials in critical care: can a Bayesian approach enhance clinical and..., Yarnell [/bib_ref] [bib_ref] Bayesian methodology for the design and interpretation of clinical trials in critical..., Kalil [/bib_ref]. The additional interim analyses and modifications potentially increase the risk of false positive results. Defining all modifications a priori and building strong partnerships with statisticians are essential to reduce bias. Examples of designs that may identify precision medicine approaches are included in .
Additional considerations include embedding trial procedures in the electronic health records (EHRs) and using response adaptive randomization strategies to increase trial efficiency, participant enrollment, and generalizability of results [bib_ref] Feasibility of embedding a scalable, virtually enabled biorepository in the electronic health..., Demerle [/bib_ref] [bib_ref] Can response-adaptive randomization increase participation in acute stroke trials?, Tehranisa [/bib_ref]. These aspects of trial design allow the integration of research and clinical care (e.g., REMAP-CAP) and the creation of a "learning health system" [bib_ref] Implementation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 (REMAP-COVID) trial..., Upmc Remap-Covid [/bib_ref].

## Recommendation 3
Advance data science and engineering approaches to facilitate precision medicine strategies for sepsis and ARDS.
Rationale. Continued innovations in data science and engineering methods are essential to identify HTE and advance the use of novel trial designs. Both applying approaches developed for other conditions to sepsis and ARDS and developing novel approaches will be necessary. Potential areas for advancement include methods to identify patients who benefit by incorporating combinations of clinical and molecular markers across multiple omics platforms (combining deep phenotyping with HTE identification), as has recently been explored in other non-critical care disorders [bib_ref] Highdimensional profiling clusters asthma severity by lymphoid and nonlymphoid status, Camiolo [/bib_ref] [bib_ref] Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset, Stelzer [/bib_ref] , to modify treatment approaches in response to the rapid changes in the host immune response over time, and to use causal modeling when RCT data are sparse and only results of observational studies are available (42) (

## American thoracic society documents
Develop the tools necessary for the real-time application of precision medicine approaches.
Rationale. Precision medicine for sepsis and ARDS will require rapid assessment of patient phenotype and subgroups that benefit, in contrast to other disorders, such as cancer or asthma, in which precision medicine decisions can be made days or weeks after initial assessment. Potential strategies to facilitate the rapid deployment of precision medicine strategies include leveraging EHRs and novel technologies to ensure rapid turnaround of biomarker results. This situation creates a regulatory and development paradox in that the major investment needed to develop a diagnostic test is not attractive to pharmaceutical companies until the diagnostic's market has been confirmed, yet the therapeutic's utility may be uncertain without the diagnostic test to identify patients who will benefit. In the United States, the Food and Drug Administration has mechanisms to codevelop a diagnostic assay with a therapeutic agent during the approval process. Second, these efforts may require partnerships between academic investigators and pharmaceutical companies. It would be important to ensure that the intellectual property rights of the various stakeholders are maintained.

## Recommendation 5
Ensure that precision medicine advances be applicable to a broad range of patients across different healthcare delivery systems; resource-rich and resource-limited settings; racial, ethnic, socioeconomic, and demographic groups; and social and environmental practices.
Rationale. Precision medicine should improve care for patients with sepsis and ARDS globally and not worsen healthcare inequalities. A threat to this goal is to solely focus on molecular substratification, which may require complex assays and apply only to highly resourced quaternary medical centers. More than 80% of the world's population resides in resource-limited or developing countries, and patients in these countries account for .85% of the global sepsis burden [bib_ref] Genomic medicine without borders: which strategies should developing countries employ to invest..., Mitropoulos [/bib_ref]. However, these patients may not have access to results of complex assays to target treatments precisely and rapidly. Similarly, critical care outcomes vary significantly by race, ethnicity, and sex, and clinical trials have often underrepresented minoritized and socioeconomically disadvantaged groups [bib_ref] Racial disproportionality in Covid clinical trials, Chastain [/bib_ref] [bib_ref] Temporal trends in critical care outcomes in U.S. minority-serving hospitals, Danziger [/bib_ref]. Differences in lifestyle factors such as diet, physical activity, and tobacco and alcohol exposure among groups warrant consideration in precision medicine approaches, as they potentially may be of equal if not greater importance compared with biologic markers in explaining differences in prognosis and 

## . trial design strategies for precision medicine in sepsis and acute respiratory distress syndrome

## Approach brief description
Adaptive trial designs Incorporate prospectively planned modification of one or more aspects of trial design (e.g., sample size, dose, treatments, or study endpoints) based on adaptive analyses
Adaptive enrichment Modification of eligibility criteria to target participants likely to benefit and/or exclude participants unlikely to benefit Biomarker-guided adaptive design Stratification of participants based on biomarker level with planned modifications based on treatment response within groups Biomarker-threshold adaptive design Biomarker may predict response to treatment but optimal threshold to guide treatment is not known and is established within the trial Response adaptive randomization Prior analyses suggest efficacy within several potential subgroups that are examined within the trial with allocation into subgroups changed on the basis of interim analyses
Platform trial Multiple interventions are tested within a single trial framework against a single control arm for a single condition. Therapeutic arms are added or dropped from the trial based on interim analyses Seamless phase 2/3 trials Rapid transition of a promising phase 2 to a larger phase 3 study facilitating cost-efficient scaling for effective therapies Perpetual trial Trial framework is established for a condition and new therapies are continually being added or dropped in perpetuity
Integration with the electronic health record Trial procedures including screening, randomization, and deployment of interventions are integrated with the electronic health record, improving efficiency and potentially generalizability AMERICAN THORACIC SOCIETY DOCUMENTS treatment response [bib_ref] Cardiometabolic traits, sepsis, and severe COVID-19: a Mendelian randomization investigation, Ponsford [/bib_ref] [bib_ref] Understanding patient outcomes after acute respiratory distress syndrome: identifying subtypes of physical,..., Brown [/bib_ref]. Potential strategies to enact an equitable and just global deployment of precision medicine include:
1. Consciously including diverse stakeholders from different geographic, economic, cultural, racial/ethnic, and sex backgrounds on advisory panels and peer review committees. Specifically, patient advocates, funding agencies (both federal and nonfederal), medical foundations, public health entities, and pharmaceutical companies should each have a voice in articulating the precision medicine priorities for these conditions and how they might be achieved. Enhanced efforts to promote the inclusion of ethnically and racially diverse populations in observational studies and clinical trials will allow broader applicability of precision medicine. 2. Using approaches tailored for lowresource settings. These include 1) partnerships with industry to develop cost-effective and rapid diagnostic tests, which can be stored and performed easily and used in any healthcare setting; 2) simplifying predictor and classifier models by reducing data redundancy and using surrogate models that are reliant on readily available clinical data instead of complex biological data; 3) using the "Fast-Second Winner model" [bib_ref] Genomic medicine without borders: which strategies should developing countries employ to invest..., Mitropoulos [/bib_ref] , which leverages large-scale discovery efforts elsewhere to develop more site-specific public health strategies to accelerate investment in promising biomarker and diagnostic candidates based on local health burdens and needs in lowresource settings; and 4) artificial intelligence applications that leverage high dimensional clinical data with relatively low local technological investment [bib_ref] Implementing artificial intelligence and digital health in resource-limited settings? Top 10 lessons..., Thomford [/bib_ref] , preferably using electronic data feeds if available.

## Recommendation 6
Secure and maintain adequate and sustainable funding. Rationale. Funding for precision medicine initiatives will require a shared financial investment by academic institutions, federal and nonfederal funding

## American thoracic society documents
agencies, pharmaceutical and biotechnology companies, philanthropic societies, and healthcare systems. No single agency funding precision medicine in isolation will be able to advance quickly enough to meaningfully impact the field. Sustainable funding is required to build and maintain collaborative networks that allow multiple agents to be tested sequentially or in parallel, ensure data and biospecimen harmonization, develop novel trial design and informatic approaches, and enroll patients in new precision medicine studies. The success of precision medicine efforts in breast cancer has come in no small part because of the multiple stakeholders that have provided funding, including academic institutions, pharmaceutical companies, not-for-profit organizations, and food and drug retailers, in addition to the substantial investment from federal sources that ensured stability. However, efforts across multiple stakeholders will have to be coordinated. Recent examples include the REMAP-CAP, RECOVERY (Randomised Evaluation of COVID-19 Therapy), and iSPY-COVID trials, which quickly engaged multiple stakeholders and sponsors (including various pharmaceutical companies whose products were tested, academic healthcare centers, and federal agencies such as the NIH in the United States and the National Health Service in the United Kingdom) to develop the infrastructure, technology, and resources necessary to rapidly and flexibly test multiple therapeutic interventions in the midst of the COVID-19 pandemic. Specific recommendations include increased funding by federal and nonfederal agencies for proposals that advance precision medicine for sepsis and ARDS and improved efforts to coordinate activities across multiple stakeholders.

## Summary
Developing precision medicine approaches will require reexamination of the conduct of observational studies and RCTs for sepsis and ARDS. In particular, the equitable sharing of data and biospecimens and the creation and maintenance of large knowledge networks to identify HTE and subgroups that benefit from a treatment will be imperative. Although observational studies are important, conducting RCTs remains critical to making inferences about causality and validate findings. These steps will require significant investment up front by multiple stakeholders, and, ultimately, successful precision medicine approaches will have several economic advantages. Pharmaceutical and biotechnology companies, trial investigators, and funding agencies will benefit from infrastructures that allow for different treatments to be tested within established precision medicine trial networks, which may reduce costs and improve chances for a successful trial. Healthcare systems and insurance companies will benefit from creating learning healthcare systems by potentially decreasing low-value care. Most importantly, patients will benefit from the ability to receive therapies that have a higher likelihood of success.
This official research statement was prepared by an ad hoc subcommittee of the ATS Assembly on Critical Care.
Members of the subcommittee are as follows:
research support from NIH; and has a U.S. Patent issued for sepsis stratification biomarkers. F.G.Z. served on a data and safety monitoring board for the CLASSIC Trial; and received research support from Bactiguard and Ionis Pharmaceuticals. R.A., A.K., A.L., C.M., and P.S. reported no commercial or relevant noncommercial interests.
[fig] Figure 1: Conceptual model of the path forward for precision medicine in sepsis and the acute respiratory distress syndrome. EHR = electronic health record. [/fig]
[table] Table 3: Potential Statistical Approaches to Improve Use of Knowledge Networks Mendelian randomization Variation of the instrumental variable technique in which the instrument is one or more genetic variants that predict an intermediate variable (e.g., transcript abundance or protein concentration), and the intermediate may contribute to the outcome Plasma protein concentrations (Ang-2 or soluble RAGE) contribute to sepsis and ARDS risk (75, 76) Definition of abbreviations: ARDS = acute respiratory distress syndrome; COVID-19 = coronavirus disease. [/table]