Hello, welcome to the Thought Leader session, Genetics and Genomics in Critical Care. My name is Sheila Alexander, I'm an Associate Professor at the University of Pittsburgh School of Nursing, and I'm the moderator for this session. I'm very excited to introduce our Thought Leader today, and a good friend of mine, Dr. Karen Ruter-Rice. Dr. Ruter-Rice is an Associate Professor of Nursing and Critical Care Medicine, and at the Duke Institute of Brain Sciences at Duke University in Durham, North Carolina, in the United States of America. She's additionally an acute care nurse practitioner with a pediatric focus in the Division of Pediatric Critical Care. She earned a bachelor's, master's, and PhD from the University of San Diego in California. She's spent her career focused on caring for pediatric patients recovering from traumatic brain injury, first as a bedside nurse, then as an acute care pediatric nurse practitioner, and continuing doing research to improve outcomes for this population. Dr. Ruter-Rice has taught and mentored numerous students at all levels, and trainees in nursing and beyond. She truly has a multidisciplinary teaching background. She teaches basic nursing content, advanced practice skills and content, and provides input and guidance on research projects related to pediatric critical care. Dr. Ruter-Rice has done considerable research in the area of recovery from traumatic brain injury in children, much of that with a focus on genetic biomarkers. She's developed a specimen repository to help support future research in the area. Her work has been supported by the National Institutes of Health, National Institute of Nursing Research, the Robert Wood Johnson Foundation, the World Federation of Pediatric Intensive and Critical Care Services, and the Health Resources and Services Administration. Her research has generated results that have advanced our ability to monitor pediatric TBI patients, understand the physiologic and pathophysiologic vascular response to traumatic brain injury, as well as neurocognitive recovery after TBI in children. She's presented her research findings to international audiences, including several presentations at previous SCCM Congresses. She's published her research findings and many thought leader pieces on pediatric critical care, personalized medicine, and other concepts related to genetic and genomic research. Her combined efforts in practice and research in this population have facilitated many contributions to guidelines for pediatric TBI care, the ACCM clinical practice parameters for hemodynamic supportive pediatric and neonatal septic shock, and contributed to the acute care pediatric nurse practitioner practice analysis. She's also edited and or contributed to several books on pediatric critical care and translational research in traumatic brain injury. Her esteemed career has been acknowledged in fellowships to both the American Academy of Nursing and in critical care medicine. Please join me in welcoming Dr. Karen Rudder-Rice to the podium. Welcome to the 51st Critical Care Congress. I'm really pleased to be here and I want to thank the program committee members for selecting me to provide a thought leader session on genetics and genomics in critical care. There are no conflicts that I have to report. Let's just look at the objectives for this thought leader session. The role of genetics and genomics in critical care is what we're going to look at first. Then we're going to delve in a bit deeper into the health challenges and approaches to leveraging omic technologies, both in the critical care environment, and then future precision health and opportunities for critical care research and practice. Let's delve into the role of genetics and genomics in critical care. I want to start by just highlighting really important definitions that I think so that we can be speaking the same language going forward. You've heard of precision medicine and really that uses information about a person's own genes and proteins to prevent, diagnose, or treat disease. Some have also referred to that as personalized medicine. Precision health is a little more inclusive because it includes precision medicine, but it also then envelops disease prevention and health promotion activities. Let's start with just getting on the same page as far as definitions go. There's a definition around precision medicine and that really includes information about the person's own genes or proteins to prevent, diagnose, and treat disease, whereas some have also referred to that as personalized medicine. Precision health is a little more inclusive in that it includes both precision medicine and disease prevention and health promotion activities, which is, I think, the goal overall of us in critical care is really looking for outcomes that promote a high quality of life. Importantly, the Centers for Disease Control and Prevention define precision health as approaches to protect health and interventions that can be tailored to an individual rather than using the same approach to everyone. I think for those of us in critical care, we totally understand that very framework. This is a very, very brief overview of just some basic terminology. When we talk about genetics and genomics, we're thinking about chromosomal, monogenic, and polygenic disorders. What are really the key differences? The differences between monogenic disorders and chromosomal disorders is that monogenic disorders are associated with a single gene, whereas chromosomal disorders are diseases associated with abnormalities in chromosomes or parts of chromosomes. Examples would be monochromic would be sickle cell disease, whereas chromosomal might be a trisomy 21, whereas polygenic disorders are really polygenes. There's a multiple of genes that create the disorder. A really key example of that might be hypertension or coronary artery disease. You can imagine, based on the populations we see and just the population at large, that polygenic disorders occur much more frequently than monogenic or chromosomal disorders. How we approach identifying or evaluating these disorders are really either based on a candidate gene approach or on a whole genome sequencing approach. Let's talk a little bit about genetics, genomics, and susceptibility and why I think that there's a real role for us expanding how we care for patients using genetics and genomics. We know that there's gene-based susceptibility for life-threatening infections and immune-mediated diseases that are either inheritable or known to be associated with a specific genetic variant. Importantly, there also are genetic loci that we're aware of that prompt either increased inflammatory responses, impaired wound healing, decreased tissue oxygen uptake. We also know that there are genes in particularly adult sepsis survivors that increase the risk for cognitive and functional disabilities. I also want to pick up one other piece to this, and that is that one-size-fits-all, which comes out of that CDC definition. Importantly, we want to think about this example, and it's very applicable to the ICU. We have a patient who requires anticoagulant therapy, and then we sit there and pontificate, is warfarin or Coumadin the best choice? What is the patient's genetic susceptibility to cytochrome P450 isoenzyme 2C9? Do they have that polymorphism, which would make them more sensitive to warfarin? Is that really the drug we want to prescribe? There really is room for us to start embedding in our care practices the role of genetics and genomics. What is that role? It might help us with reducing the ambiguity or the complexity of the heterogeneity within our patient population. It might reduce the disease and therapeutic morbidity or mortality that we often see. It ultimately could promote health outcomes, which is, I think, always the overall goal. In children, we've had more experience, I think, with genetics and genomics. I don't know that we've published on it more, but we tend to use it much more heavily. I think what we found within our world of pediatric genetics and genomics is this increasing evidence that children who require pediatric ICU care have underlying genetic disease, yet that in 90% of cases, phenotypic descriptions are poor predictors based on genetic signatures. Hot off the press is this really very cool pilot study that really was a prospective observational study in two tertiary pediatric ICUs where they looked at 26 children who had lower respiratory tract infections and met the criteria for sepsis, severe sepsis, or septic shock. What they did is they wanted to compare genome-wide expression profiles in the immunoparalyzed and non-immunoparalyzed children. What they ultimately found was that there was an increased expression of genes that dampened the immune system and decreased expression of genes involved in regulation and activation of the immune system. Importantly, their analysis also implicated other proteins that potentially, but yet unidentified as of what role they play in the development of immunoparalyzation. I think that we can see that there are people who are starting to adopt genomics and the approaches of technologies to better care for patients or to at least better understand them. As we think about precision health, we can't avoid the challenges, but then I'd also like to think about what might be some of the approaches we can leverage. Omic technologies, as you can see on this slide, is really the use of some type of specimen and then we evaluate it for DNA, RNA, proteins, and metabolites. What's not seen here is the gut microbiome or the lung microbiome and other technologies that are rapidly developing. Why are we a little reluctant to bring them into the critical care environment? Some of that is because most omic-based testing are really slow and that's not really helpful in the ICU. Data that's generated doesn't readily inform clinical decision-making. We often look then to other sources of data to help us make those clinical decisions. There are many other challenges and we'll go through these step-by-step. Interpretation of results, cost and access, the GINA, consent, and evidence. Let's just look a little bit at interpretation of results. This is a really, really nice paper that really came up with three key findings when they examined how providers in the pediatric critical care setting felt about using genome sequencing. What they found was that clinicians really felt they didn't have sufficient training to accurately assess genetic results despite the pressure to incorporate the results into clinical decisions, that they desired knowledge support from genetic specialists, so really counselors and others with that expertise, and the third, that they appropriately incorporate genome sequencing into clinical decisions, but what they needed was more education knowing how to do that. Then this paper back in, I think it's from 2003 by Dr. Pinsky, spoke to cost and access. I think what was really brilliant about this paper is he highlighted, or at least I highlighted, a couple of things that I wanted to share, and that was that how are we using our resources, and then to what extent should these data be available outside of the patient-doctor relationship. Not only are we going to use it for care, but then how does it affect care downstream, which leads us back to cost and access. One of the challenges with cost and access is the fact that highly supported and infrastructured centers often will have the ability to afford and also access OMIC technologies, where smaller community-based centers or rural health community or hospitals may not have that same access to cost and may not have the same access and may not be able to share the burden of the cost of OMIC technologies. Although they are getting cheaper, they're still quite expensive. If you think about our appreciation of social determinants of health and the risk of inequity of care across our populations, depending on not just where you live, but how you access care, really genetics and genomics could be for those of the very well-off or for those that are well-resourced versus those that might need it in the community center but don't have that same access or can't afford it. We really need to think about how, if we bring this into our environment, we're able to cross all domains of critical care. And then importantly, GINA, which is a law that really prevents genetic discrimination. Importantly, this law prevents health insurances and employers from benefiting or denying coverage or health services or health insurance by understanding what your genetic information is and how that might impact your wellness. These are important questions that we need to bring into our critical care units. And then one of the big elephants in the room, of course, is consenting critically ill adults and minor patients. We know they're vulnerable. We know they're fragile. We know they oftentimes have lost their ability to make decisions, have lost their ability for autonomy. They may have family members making decisions for them, or maybe they don't even have legally authorized individuals to give consent. And how do we handle that in the ICU? And I think partnering really with, for example, the American Society of Human Genetics, they might be a way for us to start opening conversations and doors of how do we do that in the ICU well. So, the challenges then in developing evidence. Well, you know, we have a real heterogeneity in critical illness. We have complex physiologic signatures and we have data-rich environments with informatics, but they aren't all well harmonized. So, if we think about heterogeneity, like the end of one and personal omics, you know, this is really difficult to generate evidence. It's great for the one patient, but it really is incompatible with current experimental approaches and it really could impact clinical trials because of recruitment times, complexity, and of course, increased cost. So, what do we mean by personal omics? It's really this kind of mass omic overview of a person's state and it really comprises this holistic molecular, physiologic, and environmental profiling of an individual over time, which would really be beneficial if you wanted to think about what is regular and high-frequency sampling during illness, particularly their movement into the ICU, into the hospital, or out back out into the community. So, this is just one example of what that might look like if you wanted to personalize omics. And then if we think about complex physiologic signatures, well, you know, we have to think about the fact that there's many comorbidities. Our patients, even if they don't come in with them, they may be at risk for them once they're in the ICU, therapeutic interactions, and acutely changing physiology. And then we also know that when we think about precision health, we really want to discover disease etiology and stratified therapies using omic technologies. But then how do we do that within our clinical trials so that we really have a large bandwidth of patients that really allow for true prediction? So that leads me to this discerning complex physiologic signatures and the whole notion of how we develop and validate novel biomarkers that we then can use to enhance treatment precision. And it's a very lengthy process, it's onerous, and it needs a lot of clearance by both the scientific community, the regulatory community, and then if we're commercializing the product, the actual product, how we do that. And so, you know, the big challenge in many of our omic studies, and some of them that I've already shown you, are that we have them in the developing phase or the discovery phase, but then it's very difficult to then validate that novel signature. And so an example of really a nice paper of development and validation is this overview of a multi-omic signature for COVID-19. And so here the investigators really used a multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19, and they integrated the analysis of these omic data to reveal several potential therapeutic targets. Importantly, they found 25 molecular signatures as potential biomarkers for prediction of disease severity, and then what they did is the prediction power was then validated using corresponding urine samples and plasma samples from new COVID-19 patient cohorts. And it's that type of work that we need in order to really, you know, feel comfortable that if we're going to use omic technologies to guide care that they're actually very valid. And then we get to the biggest, even the bigger elephant in the room, and that is that we live in data-rich environments in the informatics in the ICU. We have just so much data, and much of it we don't even actually have, you know, we barely use. We have so many platforms that don't harmonize amongst each other. There are certainly legal and regulatory barriers that we need to address. Data validity and reliability, security, and integrity are key. And then how do we share and data bank all of this data that we collect if we were to use it in our ICUs? So, you know, ultimately, we want the goal to be diagnostic and prognostic signaling, and we have, you know, multiple ways of doing that. And what we've realized is that one of the ways that we're using genomics in the ICU already is for many of the pharmacogenomic type of activities. And then additionally, you know, I think that we can learn from colleagues in oncology who have really adopted the use of genetics and genomics in helping guide care. And then ultimately, this direct-to-consumer testing, which, you know, we've seen with the evolution of COVID, you know, having, you know, a PCR test in the hospital or at your local CVS versus going out and buying a ready-made direct-to-consumer test, although perhaps not, you know, the 99 percent reliable, but close enough that people could at least, you know, govern some of how they wanted to care for themselves. And then what does that look like for us in the ICU? And so this is a really nice schematic looking at big data. And the reason I wanted to put this up here is because I think sometimes we're completely unaware of what sits below all of the larger categories of data. So, when we think about, you know, patient information, we think about contextual data, which is the encounter. We think about diagnostic data, which has many levels of it from billing all the way through to data-driven phenotypes. And then interventions and, you know, thinking then about cellular and molecular. And here you can see that, you know, we have routine labs. We have omic data, which I was so pleased to see on here. And then, of course, you know, patient data and microbial data. We have imaging. We have natural language data. And then we have physiologic data. So with all of those streams of data, you know, we really need infrastructure and informatics. These level of expertise, data scientists, to really help us if we were going to use precision health within critical care, you know, infrastructure is key. It helps us generate and test new hypotheses. We have within that a large band of data, and how do we use that data in a way that we operationalize, you know, the clean data that we can have versus all the missing data that often occurs. And then also, what do we do with the large datasets? You know, large datasets aren't just in the ICU, but precision health, just omics alone, has large swaths of data. And then what do we do with the data? Where do we store it? How much do we pay to keep it stored? And how do we data share it? So I've been pontificating about the future of precision health and opportunities for critical care research and practice, and here's what I've come up with. I've had a little help by a really nice paper that I've got cited here on the bottom right corner, but really thinking about adapting conventional trials to include registry randomized control trials and platform trials might be a novel way that we can approach this. Also thinking about omic technologies that fuel precision-minded research and practice, and where do they belong and when do we insert them? And then third, interdisciplinary collaboration that includes both methodologists, data scientists, informaticians, and others. I really do think this has got to be a team approach. So if we're thinking about, you know, precision health, omic research designs, we need to think about having access to a large number of data, a large number of patients. We need to think about what those implementation processes look like, how adaptable are the designs, how scalable are these designs, and can they be sustained? So a nice example of this actually came out of the INCITE randomized control trial, which is really genome sequencing neonates. And what they're using is a rapid genome-wide studies, and they're looking at diagnosing genetic conditions in time to affect ICU management. And they are really here demonstrating that there's a clinical utility that yet has adequately demonstrated how we use this technology in ICU care. But you know, this is a really nice example of what might that look like, and are we, you know, do we need a consortium to start coming together to think about what should these trials look like in pediatric and adult ICUs? So I feel as if there might be a really great opportunity, and hopefully not a missed opportunity, to really think about the power of critical care registries. You know, they're invaluable, and they have ICU data sets that just have really allowed us to both establish and validate new definitions and phenotypes. And I think that, you know, they might be considerations for, you know, incorporating precision health. Ways of doing that might look like, you know, us being able to look at these large data sets, make sure that they're valid, they're clean, they're analyzed, stored, transformed, shared, and protected. So you can see that we have to consider these aspects if we're, you know, going forward. And many of the registries that currently exist have all of these considerations in place already. They're dedicated to informatics infrastructure, which is so important. They have that level of expertise already. They are developing bioinformatic platforms that can leverage precision health data, and their data systems support critical care and precision health, particularly from an ICU-specific type of data stream, as well as real-time critical care practices. So how can we think about, you know, actualizing these registries when we think about complex physiologic signatures? And, you know, interestingly enough, this is already being done, and COVID has really allowed us to leverage omic technologies and really connect genetic mechanisms with the virus. And so just, you know, thinking about the importance of this work is really fueled by this really nice study that came out of the GenOmic Genome-Wide Association study of over 2,200 critically ill patients with COVID-19 in the UK, and this is really a consortium of UK ICUs that were able to develop this genetic signature based on leveraging omic technologies. And so I feel that there's a real need for us to think about, well, what are the critical care registries? And I'm not sure if everyone is aware that we have this many, and there might even be more that I didn't capture on this slide, but you can see we have registries that are international, both out of the U.S. and then also across the globe, and, you know, importantly, there are registries that are capturing genomic data. And then we have Discovery, which is a really nice critical care research network that really is fostering collaborative research to improve the health outcomes of critically ill and injured patients. And, you know, I was looking through both the ongoing and newly initiated research studies and, you know, I came across, as one happens to be one in TBI, it's early after TBI, and they're actually including biomarkers within their study. And so I think that, you know, we have the opportunity, and when I mean biomarkers I blood-based biomarkers, to really think about how else can we leverage already existing research network projects that are collecting genomic data or might have the opportunity to collect genomic data. And then I think we need this real cross-pollinization in the ICU and across public health. And the reason I wanted to share this slide is because I think, you know, we have the All of Us project going on in the United States right now, looking to collect millions of genomic samples, as well as overall health and wellness data. And then we've also learned from a very powerful data source, which is the virus registry that came out of SCCM as well, and really the importance of how we came together in a very crucial time to start looking at both safety and effective practices in COVID-19, and then also variations of practice across hospitals. But what would have been, I think, more powerful is if we were also collecting samples at the same time to really better endophenotype these patients. And I think just one more highlight for this registry is if you can look at the number of patients that are enrolled and how much data is being collected, both from pediatric as well as adult data, and really this registry is very robust. So if you think about that registry, you think about the one I highlighted in the UK and the others that were on the slide, there really are some wonderful synergistic opportunities here to start thinking about how we bring omic technologies into the ICU. And then importantly, also for children, we have this really nice platform, Caring for Kids, that comes out of NIH, where they're doing some molecular work as well, particularly more around pharmacogenomics. But importantly, this is a really nice site for those of you who might be interested in pediatric critical care data and maybe getting a better insight into what other research opportunities are occurring within this platform and might actually have an opportunity to start having larger data sets around omics. And then I think, you know, as a summary to this whole conversation, and I can appreciate, I really hit very much the highlights because there's much more granular conversations that have to happen, but could we really think about, you know, multi-omic data, although complex, is very relevant to critical care. I know that there are legal, ethical, and social implications that can't be ignored. I know that we are, you know, in this place where we require infrastructure, we have to accommodate and harmonize large amounts of data, and that really takes true expertise. It takes an amazing amount of financial investment. And then we need to be really clear about, do we have the experts to help us translate that data? And then how do we protect the data? How do we make sure it's valid and reliable? And then how do we share it so we can continue to learn more? And then are the, you know, I would pontificate and position that the ICU registries are invaluable and that, you know, while they require sizable funding and infrastructure support, they do have common data elements, they do have data sharing agreements, and, you know, there may be some that are, you know, investing in looking at omic technologies as also a stream of data collection. And so while I think that there are challenges, I hope that, you know, some of the approaches to how we can use novel omic technologies, perhaps to, you know, develop new therapies or better improve our existing therapies so that they're more tailored to critically ill patients would really be somewhat of a motivating factor for us to start having deep conversations in critical care around the role of genetics and genomics. So with that, thank you so much. I've really enjoyed being able to provide you my thoughts around genetics and genomics in critical care. I hope that if you have any questions, you'll reach out to me. Also, I've provided PMID numbers on the bottom of slides, but as you slide, if you click through the remaining slide presentation, you'll find those references, as well as some internet links for some of the additional resources. So with that, I'd like to, again, say thank you, and I really wish you a good Congress. Great talk, Karen, thank you so much. That was really informative, and I really enjoyed hearing you speak. I did want to mention before we start a discussion, one of the studies you talk about pretty early on, the one entitled Differences in Gene Expression in Immunoparalyzed and Non-Immunoparalyzed Children with Sepsis, that paper is one of our recently released papers to change your practice. So that will be more presented in more detail within that session. And Dr. Farhat was a participant in the related panel discussion. So for our viewers out there, check it out. They're great sessions. The other thing I did want to mention, because you talked a little bit about the virus registry through discovery at SCCM, and I wear another hat within SCCM, and I am current chair of discovery, virus registry is not closed. You can still join. They have ways you can contribute data and use data. So for anyone out there thinking about it, you can still participate in that one. So some questions I had when you were talking, you didn't really talk a lot about disparities, specifically disparities in people of different races, ethnic backgrounds, sexes, and genders. How do you think genetic and genomic information can aid in decreasing disparities and outcomes after critical care? Yeah, that's a great question, right? And I think that we're certainly starting to appreciate the lens of disparity, both from an economic disparity, but also from genetic disparity. We know that there are patients who are disparate just based on the epigenome and their pre-exposures generations ahead, sorry, behind them, right? So we've got really nice data that supports that epigenetics can certainly predisposition you to having higher risk factors. And we might often not capture that type of data in our health histories. I think as we globally, at least I'm going to address this in the United States, when we start thinking about NIH's adoption of being much more forward-thinking around social determinants of health, and then also all of our health systems starting to appreciate that there are unique differences amongst different populations, and that oftentimes these disparate populations really don't have either A, access to this level of type of testing, or B, we are excluding large groups of individuals that need to be better identified to help with how we care for them or how we even prognosticate for them their health. I think we're kind of at the cusp of better, you know, having better conversations around how we do that. But again, disparities, you know, there are so many components to disparity, and we need to get much better, even within just our admission to the ICU, appreciating who is this disparate patient. Because I think there are probably individuals who lean more to very, what I would consider traditional views of what disparity is, but when it comes to genetic disparity, they might not be that obvious. And so, I think that there's this whole area of research, this whole area of really translation is only now starting to really get center stage, and it's time. It really is time that we start thinking about not just disparities and how we care for individuals, but also what is their genetic makeup, and how does that predispose them? Interesting. You know, within my team, I have a geneticist, and we do a lot of, we have a lot of chatting, kind of like you and I are chatting. And we talk a lot about genetic-based ancestry, because there are markers within the genome and certain genetic variants that we can use to sort of determine or identify what region of the world someone's ancestry comes from. And we talk a lot, that really is a much better marker than self-identified race. So, I think that might be something coming. Yeah. And I think that adoption, you know, is something that we're hearing much more now from both geneticists and also from epidemiologists who are, you know, when you think about these large population data sets, you really do need epidemiologists to be part of that team. And so, you know, within my team, I have the wonderful fortune of having a brilliant genetic epidemiologist who works with me, because that's really her talent. And, you know, we often have those conversations about even how do you replicate data? How do you validate data? Can you really validate data across ancestry? And there are real conversations happening that that isn't always the right approach, you know. And so, you know, what works for one ancestry group may not clearly apply to another ancestry group. And thinking that you can just validate any data across any ancestry group is not necessarily good science. Correct. And also, when we look, even if we're doing that with ancestry, it completely misses current cultural influences on health and healthcare, too. So, I'm going to shift gears here a little bit because I'm a nurse and you're a nurse and as two nurses, and we're both doing this genetic genomic research. What spawned your interest in this type of research? How did you get into it? Yeah. So, what I would say is that, you know, as a nurse in the ICU, you know, I think many of us are highly attracted to just the physiology of the human body and how the body responds to different type of diseases and disorders and conditions, but then how we therapeutically affect that. And, you know, I spent many, many years as an ICU nurse, but then also as a nurse practitioner. And one population that I think in pediatrics typically is a pretty generally healthy population is our trauma population. And I've always had kind of a real curiosity around those children that came in who had very similar pre-hospital care after sustaining a traumatic brain injury. We were a very aggressive, you know, TBI group where we were really forward thinking around how we treat these children. And so, we were aggressive across all children. And what would happen is you would see very similar, you know, demographics, very similar predispositions, very similar pre-hospital care, the same kind of ICU care, and then the outcomes were so divergent. And I always felt that there must be more going on that we can't humanly appreciate. Now, is that true of the brain? Yes. The brain is just this amazing organ. And I don't know that we'll ever really truly discover everything there is about the brain. However, what I did come to find is that there were some phenomena that were happening, you know, that were being discovered in adults that we weren't even considering in children. And that happened to be cerebral vasospasm and really the vascular flow within the brain. And so, really, my work started within that, you know, kind of uncovering that phenomena. But what I ended up finding was, you know, then why did one child have it and another child didn't have it? They're both equally severely, you know, had severe TBI, had, you know, very similar, you know, ICU therapies, and yet one would have this progressive vasospasm and another had none. And I'd be like, why is that going on? And so, that really led me to think, you know, are there innate components here I can't appreciate? Is, you know, what are the protein signals? What are the genetic? What is the underlying genetic code here that might be influencing that? And then, partnering with the Summer Genetic Institute at NIH was really my introduction. How do I start looking at incorporating genetics and genomics and other technologies within my body of research in children with TBI? And that's really where I started, but, you know, I've really come to appreciate that, one, I'm a team scientist. I really, truly believe you have to have all the experts at the table and more lenses gives you better ideas and help you think through, you know, just the scientific discovery. And so, I very quickly, you know, reached out and found this amazing genetic epidemiologist who does a lot of GWAS work, a genetic statistician, because that is a whole set of data that looks different than other data that we work with, working with neuropsychologists, and then also working primarily with our ICU team. And so, I've come to appreciate, you know, I've been fortunate in having individuals who are very good at their science want to play with me in my science. You know, I have a physician mentor who's been with me for many years, Dr. Danny Laskowitz, who's done a lot of work in TBI. I think you're familiar with him, Sheila. And he really, truly, you know, as a physician colleague, just really encouraged my love for this type of exploration. And I think he felt that there was enough room for all of us who had an interest and a passion to really, you know, move the science or at least try to move the needle in this field. Yes. I would agree. I think it's so important, like team science, much like team care, it's really the best way to move forward. There's so much, we bring such unique perspectives and different perspectives, but that leads to a better product, a better study, and more relevant results that can really advance practice. So, I'm a big fan of team science. And I think as we translate genetic and genomic into the healthcare practice arena, that's also going to be important. There is a pharmacist at my institution who is really very motivated and very active in looking at pharmacogenomics and some of the real ways we can use that data. Thank you. So, in a perfect world, how do you see genetics and genomics being used in critical care? Way in the future, long past your, my lifespans, when it actually can be used in critical care. I think back to the movie Gattaca, where everyone's genome's been sequenced and that helps determine a lot more life choices than we would like. But I think in the terms of healthcare, if everyone had whole genome sequenced, how would we use that as healthcare teams? Yeah, I think that's interesting because you bring up Gattaca, which has kind of positive and negatives, right? What are the unanticipated downstream consequences that you want to be really mindful of and you want to make sure that there are true protections for patients, as well as us as individuals in our health society? So, in a perfect world, wouldn't it just be brilliant if you're going to go light years ahead? I would tell you that my teenage sons would say, well, we would just have a chip with all of our information encoded and we'd just get barcoded in. And mom, I wouldn't have to tell anybody anything about myself because it'd be right here. And I wouldn't have to go into my chart and try to figure out what tab I'm opening to get my lab results, right? So yeah, I think as a younger generation thinks about it that way, I would say to you, in a perfect world, we might have this kind of genetic information very available. And it would probably need to start at the time of either the early neonatal stage, when a baby is first born, that we're collecting the basic genetic information. We can then have that whole genome available to us. And then as we start better appreciating the child's health, what might be some predisposures. So just coming in from another angle, I'm very mindful of our climate and how our climate and our world is being exposed and how that changes our epigenome. And if you think about children and you think about how they're responding both physiologically and biologically to their environment, that will change over time as it is changing for all of us. So is there a way that that code can be operationalized so that when a child suddenly is presenting with cancer, we might have a better understanding about what those genes are that suddenly were triggered? Or what can we expect would be the right therapies to administer in that child who's been diagnosed with cancer? And then for the same as a child who comes in with septic shock or an adult that comes in with septic shock, do we know, would we have ready, easy gene expression that we could just put up on the monitor and say, boom, this is a patient who sits in the high-risk category or really has a very high prognosis to death if we don't change our therapies right now? And so that would be a really perfect world. But I think we have to first be very, very truthful and honest and say that this type of an endeavor, really health systems bringing in omic technologies is really going to require an immense amount of financial infrastructure, and it will take a lot of really highly developed experts to think through the platforms, the data harmonization, and the ability for us to do this in a safe and protected manner. And I don't know that we're there yet. And I don't know how soon we'll get there. But that's my down, if I could have the perfect scenario. Yeah. And I would agree. We are not there yet. One other thing I wanted to ask you about, you had mentioned the GINA Act, the Genetic Information Non-Discriminant Act, which is a United States of America-based law. And I think in the United States, we have some genetic studies, research happening that might influence care, but how are other countries, are there other countries doing it better? We do have an international audience at SCCM. So what do you see for other countries, are there other countries doing more genetic work? Yeah, I think all of us in the US is a really great first step forward. But I will say that if you look at other countries like the UK, you look at New Zealand, Australia, you look at some of the countries that are in the Netherlands, in that region, they have been so much more proactive and for many years. Some of that might be encompassed in a socialized healthcare system where there are opportunities to have longitudinal data on these individuals across many different health intersects, both from the community into the hospital. But I also think that they've made it a priority to really provide this level of information both to the healthcare sector, but also to the public sector. And so I think it's really how we prioritize the importance of this type of technology. And I think that we get it because we now have all of us, but wouldn't it be nice if there was somehow that the ICUs could intersect to see if there are patients in all of us that are also now in our ICUs? Because those kind of linkages aren't happening, unlike the genomic project in the UK that I described where there are all these, I think there's over 200 ICUs that are collecting genomic data. It's pretty impressive, right? That there's that level of consortium and that kind of commitment. And again, I think we're in a perfect position to do that type of work here in the U.S. as well. And thank you for bringing up the All of Us Research Program. I think it is a really important program in the United States of America. So hopefully we do find a way to capture some of the critical care data for those individuals and really advance our science. I think we are coming to the end of our time, but I would just like to say thank you so much. This has been a wonderful afternoon today, and I've really enjoyed your talk and having a talk with you. So thank you, Karen. Do you have any last words? I don't. Thank you so much. Again, the planning committee really enjoyed that. They really thought this might be a good thought leader session, and I hope it meets the needs of our Congress participants. It's really been a pleasure to be here, and thank you, Sheila, for such a nice job moderating and asking me such great questions.

genetics

genomics

critical care

precision medicine

precision health

patient populations

personalized therapies

data analysis

interdisciplinary collaboration