 To our disparities in genomics lecture, today's talk is Making Precision Medicine Socially Precise. So that's already a great title. I want to just mention that this series of talks has been a production of four institutes at NIH, NHGRI, NIMHD, NIDDK, NHLBI, and the FDA. And so I think that we've gotten some great presentations and hopefully we'll continue this topic. So I'm Eliceo Pérez-Estable, I'm the director of NIMHD and a general internist. My colleague and friend Esteban Gonzalez Bouchard is a pulmonologist and he has been at UCSF 20 years almost at this point. And I'll just say one, he's very accomplished and I'll say a couple of things about his accomplishments. He's actually driven the agenda and taught me about the importance of genetic ancestry in thinking about its role in health disparities and minority health. He learned it in working with Neil Rich and Elad Ziv who was in general medicine or is in general medicine at UCSF, really moved the field at least locally at UCSF in a way that I think would not have been possible under other circumstances, either coming at it from a geneticist, pure geneticist perspective or a pure clinician perspective. So as a well-trained researcher with a public health perspective as well as a clinical one and the knowledge of genetics and epidemiology and statistics I think has really made a big difference in contributions and he'll tell you about some of his accomplishments. Esteban this year was actually recognized by the National Medical Association for his lifetime achievement in addressing issues in minority health and African-American health. So congratulations on that. He was in Orlando earlier in August just last month that received this award. Watch out when you start getting lifetime achievement awards. A signal. But I'll just tell you one quick story about Esteban. I was in my office at UCSF. It was before I was division chief. I was in the corner sitting there on early January and back then I got a phone call from my chair. It was an actual true telephone call and saying I've got a guy in my office. I want you to meet. And they go oh okay well I'm just sitting here you know catching up after the holiday so send him over. And it was this guy. And Esteban at that time was a second year medical resident at the Brigham. He wanted to move to San Francisco. He to do a fellowship and he came and met with legal men and he had been doing some research with Jeff Drazen who is now the editor of the New England Journal on asthma in African-Americans and had was working on the discovery that led to a paper as a resident I think right on a genetic predisposition to severe asthma among blacks. And so that was my story of how I met him and that was 20 years ago roughly. And Esteban has just continued to roll ever since. His work on asthma I think has been visionary. He's put together the largest cohort of minority children looking at not just the genetic and clinical aspects but also environmental and social aspects. And has been very supportive of diversity training among his postdocs and fellows. And so I'll let him tell you his story. Thank you. Thank you so much. Thank you. It's an honor and a privilege to be here. So I'm going to give you an overview of my life's work for the last 20 years. Began way more than 20 years ago and I'll try to describe to you how I woven my personal experiences with my professional experiences or what I call merging academic rigor with personal passion. I'll give you overview some of the highlights in our recent work. Discuss some work that was recently funded by the NHLB and NIMHD that is one of the probably the most exciting papers that we published in the last 10 years on this idea of race. I'll present some work that we just published in March of this past year on pharmacogenetics and whole genome sequencing of minority children. Then I'll launch into where I think we're going for the next 20 years. But before I begin, I want to highlight my team. This is my team. This highlights the diversity of my existing lab at UCSF. And one thing I want you to know is that I came from the product of single parent mother, so I don't like instability. So my lab manager has been with me for 14 years. These are two high school students. Her father is a janitor. Her mom's unemployed. 4.5 GPA. This woman, Una, got her first off the publication before she got a driver's license at the age of 16. She's going off to college. We have three African American MDs, PharmDs, and PhDs. Markita White just became an assistant professor. Kevin Keyes is a Mathematic Latino postdoc. MC Contreras is a postdoc living in the projects. You can see that we have a rainbow diversity here. What you don't see is we call ourselves the Asthma Collaboratory, which means that we only work with nice people. So what's missing from this picture is my long-term colleague, Louisa Burrell, who's the head of epidemiology, has City University in New York. She's a social epidemiologist. Key statistical geneticists, Noah Sightland and Ron Halperin, who together we've developed a lot of the methodologies in ancestry testing before 23am even got started, and also ways to develop techniques to study epigenetics. So we're a very, very, very diverse group. I think it's my responsibility to mentor young people. I've been afforded many opportunities as a young kid for the inner city mission district of San Francisco, and I've been the beneficiary of the kindness of people who are not related to me. And I feel like it's incumbent upon us to return that. So I'm going to discuss Asthma. And Asthma is the most common chronic disease in children worldwide. And when I was a young trainee in Boston from 95 to 98, I was impressed by these data. This is asthma prevalence. These are current data from the sole study, study of Latinos two years ago, showing that asthma prevalence is highest in Puerto Ricans, lowest in Mexicans. And from an epidemiologic point of view, you can argue that perhaps this is a reporting bias, but when you look at death rates, it reflects the same pattern. And I was really impressed by this endeavor. And back in 1997, this data wasn't broken down by ethnic subgroups. It was just broken down by geographic region, meaning that Hispanics in the Northeast had the highest prevalence in mortality. And Hispanics in the West had the lowest. And as Elisale mentioned, we identified a gene that was associated with asthma severity in African-Americans, and it was 40% more prevalent in African-Americans. And at that time, I reasoned that there wasn't issue about being Hispanic, it was an issue about genetic ancestry, given that Puerto Ricans have a higher asthma or a contribution from African-American populations. But when you look across the board, and we published this about two years ago, when you look at all other common diseases, diabetes, obesity, coronary heart disease, and even COPD. Asthma had the largest disparity ratio of any common disease, meaning that if you took the population with the highest prevalence and lowest prevalence, you can come up with a ratio. And you can see that asthma has the highest disparity ratio. It affects a significant amount of the population, and there's tremendous racial differences. Now, I was trained in the medical scientist program in genetics. And so I do come at things from a genetic point of view, although having grown up in an inner city environment, I recognize that probably poverty and socioeconomic status and environmental effects are probably the strongest determinants of health. But I was trained as a basic scientist. And one of the things that really got me upset, and this is a paper we published in nature in 2011. When we looked at all modern genetic studies up until in 2009, with respect to genetics and common disease, we demonstrated that less than 4% of all modern studies published had included non-European populations. And this is problematic because here we are, we're making milestones with the genome project, we're making milestones of the 1000 Genomes Project. We're making tremendous investments, but the results are only being applicable to populations of European population, and I think that this is seminal, we got a lot of press at the time. And recently in 2016, the group out of the University of Washington, Seattle led by Malia Fullerton, demonstrated that the same analysis. Despite the intervening seven years, we have not made as much progress as we like, and when you look at this dark blue bar, which represents African Americans and Hispanic groups, you can see that we've made incremental increases in the diversity. So we have a long, long way to go. And this is important to keep in mind that 47% of the United States is non-European. Less than 14% of the world population are of European origin. And as of today, every child born is more likely to be a minority than a non-minority. So when you look at it from a social standpoint or a taxpayer point of view, the folks that are funding the federal government through taxes are not receiving due diligence. So early on, we created what we call the ethnic collaboratory. We focus on the majority minority populations that are understood and understudied in clinical and biomedical research. And this is what we did. And I started this as a medical resident at the Harvard Brigham and Women's Hospital with the wonderful mentorship of Jeff Drazen and Silverman. We created two study populations, one called Genetics of Aspen, Latino Americans, and the other called the Study of African Americans, Aspen, Genes, and Environments. By reaching out to a cadre of healthcare providers that were serving minority patients. And what we did is we wanted to capitalize on the geographic diversity in the United States with respect to air pollution, socioeconomic status, as well as genetic ancestry. What this meant is that I had to get off my, out of my office and do field visits at every place and working with minority serving institutions. It was wonderful because it was just a handshake and my word and an MOU that will continue to collaborate. And that these investigators will be on every publication that would come out of this. We had sites in Puerto Rico, Mexico, Houston, New York, Chicago, many sites in the Bay Area, San Francisco Bay Area, and collaborations at National Jewish. And together we created more than 11,000 minority children. One of the largest in the United States, all focusing on asthma. But what we did, which was really cool, was we brought in at the outset, social epidemiologists, environmental epidemiologists. And this was born out of a thesis that I did at Berkeley under the mentorship of Ira Tager. We collected a vast amount of data, genomic data, including whole genome sequencing, methylation, very detailed phenotypic information on drug response, detailed questionnaire data on socio-demographic information, perceived discrimination, adverse childhood experiences. And we recruited or collected detailed information on geocoded information on air pollution from the time of birth to the time of recruitment. So if a child was eight years old, we had eight measures of environmental air pollution. If they're 15, we had 15 measures. And the goal here was really to integrate, vertically integrate all these data, recognizing that there's nothing that's gonna be a significant driver of health, nothing like genetics, in abstention of social and environmental factors. So we wanted to identify, what were the determinants of being healthy? What were the determinants of being ill? We've had many successes. This is the who's who publications that came out of my lab or through collaborations, all in high journals. And I like to say this is pretty good for a kid from the Mission District who went to inner city public high school. In fact, I got kicked out of my first public high school. And so I'm pretty proud of this track record. But this is important, but not the end all be all. So in order to recruit our subjects, we couldn't just do an epidemiologic study based on questionnaires. We actually went out in the field and we put our hands on all these patients and children, sorry. And here's an example of a prurigin individual doing what we call spirometry. The top is exhalation, the bottom is inspiration. We had them repeat the spirometry. We gave them a butyrol, which is the most commonly used asthma medication in the world. We repeated the spirometry and the difference between the pre and the post is quantitative measure of drug response. Now, I wanna take a sidebar here and give you an example of how race and ethnicity is used every day in clinical medicine. Whether you like it or not, when you enter a healthcare facility, someone looks at you and it's usually the admin person who's taking your, doing your wallet biopsy in the beginning. And he or she may not be trained in anthropology or sociology, but they assign a racial category to you. And that racial category gets propagated through your medical record. And when I was a young pulmonary fellow at UCSF, I saw a Caltrans worker who was working on the Bay Bridge and he had occupational, inhalational injury. Obviously he wanted to get disability benefits like you or I would, the insurance companies didn't wanna pay. He came and they sent him to me as an independent third party. We performed the test and I was following the technician and the technician compared this patient's results to a standard population average. This is work that was published by NHANES as the population sampling of lung function in the United States. On the left, we have male, on the right, we have female. And I've modified the slide for your convenience. But there are only three reference populations, African American, Mexican and Caucasian. And this is really important because it's one of the seminal inflection points in my life, in my career. Because the patient that I had at the time looked like this. So the question is, is he black or is he white? I know it sounds like a joke. When I looked at the patient, I said, what are you? And he said, I'm half white and half black. And I asked the technician, what is it? And he said, he's black. So we're gonna compare into black patients. Well, that's problematic. Because either way, we're gonna get the diagnosis wrong. If I compare them to whites, I get one comparison. If I compare them to blacks, I get another comparison. To put this in perspective for all you parents who have young children out there, it's like you going to the pediatrician and the pediatrician saying, well, little Johnny's at the 70th percentile for height. Intuitively, you know that that means Johnny's taller than 70% of children, shorter than 30% of children, males. And the question that you don't ask is, who is Johnny being compared to? Is Johnny being compared to whites? Is he being compared to Vietnamese? Or is he being compared to Tongans? So if Johnny is white and being compared to Tongans, his average will be much lower than the size of Tongans, assuming that they're much bigger. If he's being compared to Vietnamese, who tend to be shorter, he might be on the taller side. So the same is true for measures like lung disease, kidney disease, mammograms, prostate levels. And I'd urge you to go look at your kidney function test when you get them from your physicians. There are only two reference values, one for blacks and one for whites. The same thing is for lung disease. And so what we did is my colleagues and I asked the question, do we use self-identified race ethnicity or do we use genetic ancestry? And what was really cool is we found this. This is lung function, so the higher you are, the better. This is your percent increase in African ancestry. All the patients that we sampled, several different healthy cohorts of African Americans. With lung function, we found that African ancestry, as African ancestry increased, lung function worsened. So when we compared that patient, the Caltrans worker I mentioned to our standard reference standards for a 25-year-old male at 172 centimeters, we would have got a predicted equation for whites up here, predicted equations for African Americans here. So the point is, using genetic ancestry, if we focused on President Obama, who's 50-50, we would underestimate the amount of lung disease he had if we used conventional treatments of African, or standards for African Americans. If we used Denzel Washington, who happens to be higher than 20%, 80%, we would overestimate the point. So we published this in a New England Journal in 2010 and demonstrated that by using genetic ancestry, we could approve on the diagnosis of lung disease in African Americans by as much as 15%. We went on to publish this, a follow-up study in the journal Science, looking at Mexicans from Mexico and looking at subcontinental ancestry, meaning the type of Native American ancestry you had also predicted the accuracy of the diagnosis of lung disease. So this long odyssey of identifying a gene in African Americans associated with severity in 1998 and publishing that, the initiation of the Gala study basically became like a Pandora's box and we opened the jar and let the genie out. And I didn't know where it was gonna take us, but it was a pretty successful run. Now, let's talk about epigenetics. And this is work that was funded by the NIHD with support from the NHLBI and some private foundations. We all agree that epigenetics or methylation are driven primarily by social and environmental factors as well as genetic factors. Now, we had hundreds of self-identified Mexicans and Puerto Ricans and other Latinos. We had very detailed measures of genetic ancestry. We had very detailed measures of environmental exposures like discrimination, socioeconomic status, air pollution, SES, maternal education. And we asked a very, very simple question. What proportion of the variance in epigenetics or methylation is driven by genetics or social and environmental factors that covariate was self-identified racist density or what some people call sire? And this is work that we published recently and what we found was really cool. And this is work led by Josh Gallinger, who is a former postdoc of mine currently at Genentech and Noah Zeitlein, who is a statistical geneticist and Louisa Burrell, who's a social epidemiologist. And what we found was that at least within our hands, 75% of the variation in what is driving epigenetic changes was determined by genetic ancestry. And by genetic ancestry, I mean, so for example, I did my 23 and me, I'm 26% Native American, about 8% African and the rest is European. But that's what we call global ancestry, but what really matters is what I am on a gene by gene level. And what we found is that if a particular gene that say is involved in nicotine metabolism, if that gene was of African origin or Native American origin, it was more susceptible to being hypermethylated. What that means in plain English is that the gene is either turned off or on. Now, if you're studying diabetes and we know that diabetes prevalence is higher among Native Americans than it is amongst Europeans, it might make sense to ask the question, is your insulin gene Native American or European? That might influence your risk. So this is probably one of the papers that I'm most proud of in the last 10 years, because in my view, it really pushed the ball down the field with respect to our understanding of this whole idea of race ethnicity, which is a social construct, but it does include factors that co-vary with genetic ancestry, social experiences like discrimination, SES, as well as environmental exposure since we know that low income minority populations tend to be concentrated in heavily polluted environmental regions. And this was one of the first papers, and one of the only ones to my knowledge that really took this factor head on. The key thing that you need to know is it took a whole team of people from physicians, statisticians, to socioepidemiologists, epidemiologists, to basic sciences, biologists to actually address this question, put them all in the same room, agree to disagree, and then just move on. So I think the NIHD and NHLBI should take credit for this work. So going back to lung function and genetic ancestry. Well, we asked the question, remember I said going forward, butyrol is the most commonly prescribed as a medication in the world. Well, one of the publications that we did early on in my career was we brought in children to the same clinical center. We had them withhold their medications and then we did a simple test. How well do you respond to butyrol? On the Y-axis is drug response, the higher you are, the better. And the dotted line we say as a clinician you've had a therapeutically good response to butyrol. And what you could see is that after adjusting for severity and a variety of concomitant covariates that the strongest predictor of drug response in our hands was racial and ethnic background. Puerto Ricans and African Americans had a much lower drug response than Mexicans and Europeans. And this is important because when we look at mortality rates it's highest in Puerto Ricans and Mexicans. So the population with the highest prevalence and highest death rates for asthma also had the lowest drug response. Well, I thought we were the first to publish this and we actually weren't. We were the first academic group to publish this. But a company by the name of Joglaxus Bicline published these data. And before I go on to that slide I wanna show you something that I forgot to take out of my bag but it's quite salient for this. GSK published these data but they published them in a very obscure form. They published them in this piece of paper. This is called the package insert for CERA event. How many people here have read a package insert for a drug that they got from their pharmacy? The whole thing? Okay. Well, this is the package insert. And I'm gonna show you why most people don't read it. But if you read closely, if you read closely, I've highlighted in yellow, circled in red with a giant arrow and I still can't read it even if I take off my glasses. But it basically says if you're an African-American and you take this medication you have a seven-fold increased risk of death. Now, which parent would allow your child to use this medication? So to address some of these questions, in collaboration with TopMed funded by the NHLBI, we took 1,500 asthmatic children or children with asthma and did a whole genome sequencing and looked at the pharmacogenetic determinants of our butyral response. So what we did is we plotted the distribution of drug response in all these children. We took 250 high responders compared to the 250 low responders. We had three racial groups, Puerto Ricans, Mexican-Americans and African-Americans. And this is all done in collaboration with eight universities, 13 individual laboratories. And this is a over 30,000-foot overview of what we identified. We identified pharmacogenetic variants that were significantly associated with drug response. We identified pharmacogenetic variants, rare variants that were racially specific, meaning that they were only found in one population, one racial group and not in another population. These work were just published in March. We identified 27 genetic variants that represent about 10 genetic loci or regions. Then what we did is we took bronchial smooth muscle cells from the airways and we looked for, we did the thing called chip seek and attack seek to look at the non-regulatory regions of the genome. Remember the genome only encodes exons which is about 1% of the entire genome. So that means the other 99% of the genome are regulatory regions, somehow influencing gene expression. And then we took all this information and we prioritized genes related to one biologic plausibility, one the functional variants obtained through chip seek and we prioritized the genes. Now, we were only funded to do this whole genome sequencing and do the analysis. We weren't really funded to take a deep dive, but we prioritized the top gene, which is called NF-Kappa B, and we created a luciferase enhancer, which means that are there genetic variants that are driving the promoter that turns the gene on and off? And then we did RNA seek, which is gene expression in African-American children, and we saw that there are significant clinical or transcriptional differences in the anacapabee gene that we're driving, whether or not an individual would have a good response to drug response or a poor response. What's interesting and which is fascinating is that the gene that was associated with low drug response, and these are pie charts of the distribution in blue is the low drug response gene, is that you see that the gene that was associated with low drug response to albuterol was more prevalent in populations of African origin, which, and then we also saw that in the Caribbean populations, which may help to explain why African-Americans, Puerto Ricans had lower bronchodillate response to albuterol, but also may help to explain why there are differences in ass with prevalence and morbidity and mortality amongst asthma. So it makes a nice story. We just published this in the main pulmonary journal called the American Journal of Restorative Critical Care Medicine in March of this year, and this work was led by two postdocs, Angel Mock and Marquita White from my group. So to summarize the data, we've identified several genes, the 10 that I mentioned, that are all associated with drug response or what we call bronchodillate response. We have identified genes that were also associated with other lung disease-related phenotypes like COPD, allergic response, the beta-2 adrenergic signaling, which is a cascade mechanism where albuterol works with IgE, which is the biomarker for asthma, as well as airway epithelial cells. I'm very proud of this. We have identified common variants that were common to all three groups, and then we also identified racial variants. So because of this, and because of the work that we published in Nature, showing that 96% of all modern studies focus exclusively on European populations, we created the Asthma Translational Genomics Collaborative, or ATGC, which represents the four base pairs of the genome. These are all nice, collaborative people from the United States who have contributed samples to the NHLBI TopMed Consortium. Now the way TopMed works is that you send in your samples, they do the sequencing, they upload it to DVGap, and good luck analyzing them because it's a mess to get them. But what we did is we were funded to do whole genome sequencing on 15,000 individuals. This is on top of another 5,000, so a total of 20,000 individuals of children with and without asthma, African-American, Mexicans, and Puerto Ricans, and of that we have an additional 3,500 RNA-seq samples that we'll use to be able to pair whole genomes to RNA-seq. But given the data that I showed you earlier, we're really trying to address this phenomenon. Why? Why does this exist? Is this due to environmental factors? Is it due to social factors? Or is it due to genetic factors? So, where we're headed now is our studies included a population of individuals between the ages of eight and 21. We're moving now to infants. And why? The reason being these are data from our own data sets is that as an onset, we realized our curves primarily in children under the age of two. This is the number of people, this is the age of onset, and you see that it occurs at a very young age. When we looked across the board at different racial groups, Chicago includes Mexicans, New York is Puerto Ricans, Puerto Rico is Puerto Rico, San Francisco includes African-Americans, Texas includes Mexicans, and this is the age of onset. Puerto Ricans have a very early age of onset. And data from our own group demonstrated that the odds of increasing asthma depend upon whether individuals reported previous infection with one of the most commonly, one of the most prevalent viruses called respiratory syncytial virus, the common cold or any chest ailment illness. You can see that regardless of how we define it, Puerto Ricans had a much higher odds of developing asthma compared to all the other racial groups. That's important because in Puerto Rico, as was not only endemic, I told you it was at 37%, but viral infections that lead to upper respiratory infections of the lung are endemic. And this is work published by the CDC showing the prevalence of RSV respiratory syncytial virus in the mainland United States shown in blue and in Puerto Rico. And what you can see is for this particular year that the lowest rate of prevalence of RSV in Puerto Rico corresponds to the highest rate of RSV prevalence in the mainland United States. So essentially RSV is endemic within Puerto Rico, endemic for respect with asthma. And so here we're going after the population with the highest prevalence of asthma and also the highest risk or highest prevalence of viral infections, whether they be respiratory syncytial virus or human rhinoviruses. So to that end, we created a study called Primero, which stands for first, but it's the first birth cohort study of children in several, several years. It stands for Puerto Rican infant meningenomic epidemiological study of respiratory outcomes. We have not received official work from the NIH or NHLBI, but I think it's going to go forward. And the intent is to recruit 4000 infants in their mothers and follow them longitudinally over time and then to recontact each individual on each successive upper respiratory tract infection. We have a tremendous network in Puerto Rico. We've been working there for 20 years. Our co-PI, Jose Rodriguez-Santana, has the largest pediatric pulmonary and intensive care group in the entire Caribbean. There are 13 hospitals, 85 physicians and 320 staff. And again, we've been working there for the last 20 years. UCSF has been playing a quarterback role in receiving samples, doing all the clinical coordination, doing all the gene expression, methylation work. And my collaborator, National Jewish, was the first to develop the nasal epithelial biopsy given that it's unethical to do percoscopy in children. The next best thing is to do nasal biopsies or brushings of ciliated epithelial cells in the airway. And Max has demonstrated that gene expression patterns in the nose overlap by more than 93% of what gene expression patterns are in the airways. So going back to this, we firmly believe in this vertical integration of biology, social and environmental factors. These are the current data that exist. As I mentioned, these are fresh off the press within the last couple of years by the study of Latino's soul. These are, again, mortality differences. Our goal is to reduce that to this so that there are no differences by race ethnicity with respect to prevalence, morbidity, and mortality. Now, this is a nice collaboration. It's an easy collaboration of individuals working together for the last 20 years. Represent a collaboration between UCSF, National Jewish, and Puerto Rico, or Centro Numilojepe de Yathria. All this sort of work takes a lot of funding. It takes a lot of support. So I want to acknowledge funders, including the folks that sponsored me today, NIMHD, NAEHS, NHLBI, NHGRI. And then UCSF has been a tremendous support to me. And then I'd like to acknowledge key individuals that play the key role here. Within my lab, within Puerto Rico, Henry Ford, U Penn, U Pitt, Picks, Brigham, Harvard, NHLBI, NIMHD, and our colleagues in the Canary Islands. It's 3.45, so it's time for me to end, but I want to thank you for the opportunity to present. It's been an honor and a privilege and I'd be happy to take any questions. And again, I'm going to let my hair down, so feel free to ask me anything you want. But thank you very much. Sure. So I've seen that graph about race-ethnic differences in prevalence and mortality many, many times, and many of you might recognize this. I've used it in other talks. But the mortality excess, once you get the disease, health care comes into play. So what have you heard or known or thought about? Maybe it's a, the mortality disparity is related to access and quality of care of Puerto Ricans in African-Americans with more severe disease for other reasons. Again, I think I started off saying that I think the strongest predictor of health outcomes is SES, which is the parallel of poverty, lack of education, lack of access. Having been grown up with a single mother who was a school teacher, we use the emergency room as our primary care physician, oftentimes at midnight. So I know that there's a huge component of that. Within a closed system like a Kaiser or in Puerto Rico, we could mitigate some of that. And we know that, as you know, much of the work that's been done with Medicare recipients, even in a closed system, we know that there are racial differences and who gets amputation for diabetic ulcers, who gets access to transplants. There are significant disparities to fight the fact that access to care is mitigated. So I wholeheartedly agree that that is probably a big driver. That's why I wanted to focus on the hardcore science by bringing in patients into a clinic, giving them a drug, looking at acute outcomes. To the best of my ability, I showed that there are clinical differences, showing that there are pharmacogenetic differences, recognizing that that's not 100% of the answer. So I'm curious about the nasal samples that you're getting? Yes. So let me form the question. So at Boston University, Avi Spira had taken nasal samples looking at COPD, but eventually he started moving to the mouth also, saying that actually the mouth can also mirror some of the respiratory diseases as well. I'm just curious if you found that to be true, can you take saliva samples or just swabs from the inner cheek and get similar results or do you need the nasal? Well, if you go back far enough to the posterior terminate, you get cells that are ciliated and the most reflective of airway epithelial cells which are ciliated as well. You can't get ciliated cells from the oral samples. What you can get is look at microbiome differences, but what Max Seibold has done is he's been able to use the gene expression patterns from the nasal brushings to not only look at human gene expression patterns, but also viral gene expression patterns. Max published a very eloquent paper on nasal brushing from Puerto Rico in collaboration with our group and Jose's group showing that gene expression patterns from the nose can be used to differentiate patients into different flavors or endotypes like TH2i, TH2lo, and that those patients can be used to identify patients that are more likely to respond to therapy X versus therapy Y. I think OBU is the first to use the nasal samples. I know that we were the first to use them in children and for asthma. Thank you. Hi, as a native San Franciscan that graduated from Galileo High School, I appreciate you coming here and telling your story on your background as well. I'm curious your thoughts on in a community clinic setting where you may not have the ability for your patients especially to get ancestry data, how do you perceive utilization of precision medicine and all these different issues that you've brought up in that kind of environment? So with the all of us initiative, since I was an advisor, it was very important to make sure that we have representation of SES, race, gender, geographic location. A lot of the money was committed to federally qualified health centers. I agree that if you ever been to these federally qualified health centers, precision medicine is not the thing on their mind when they're lacking paperwork and short staffed. Again, if I always got and had to prioritize, I prioritize access to education, clean water, minimize economic disparities that exist. That are getting more pervasive. As a physician scientist, I recognize that all that goes on but I need to be an outstanding scientist and for me to compete at UCSF and nationally, I chose to focus on the basic science coming from the mission district and I went to McIterre. I recognize that we don't operate in the vacuum so I'm very cognizant of that but I'm only one person that I can do what I can do. Thank you. Thank you for coming Esteban and being here today. So I have two questions for you. My first question is related to the work that you're doing in Puerto Rico and the new work that you're now gonna be doing with infants. Are you incorporating some measures to actually look at some of the environmental issues that we may learn from the hurricane last year and the environment from the perspective of what may happen with regards to asthma on that island? So that's my first question. And then my second question really is building on your work that you've done around the importance of ancestral and formative markers with regards to identification of who may be at risk or not in your example with President Obama. Do you think now is the time for us to move away from using race as a population descriptor in genomics research? Okay. Rewarning Puerto Rico, the anniversary of Hurricane Maria is coming up on September 20th. The anniversary of the Framingham study, which really was not representative of the United States is coming up on the 70 year anniversary in October. The opportunity to invest in Puerto Rico is a tremendous commitment from the NIH about building infrastructure. We will hire hundreds of workers in Puerto Rico to address this. The U.S. history with Puerto Rico has been wonderful in the beginning. We thought Puerto Rico shot down 30 German subs. It is the easternmost military outpost for the United States. It plays a strategic role, but over the last couple of years and recently it's become a very adversarial relationship. It's an island, it's in deep water. There are lots of sharks. Difficult to get to. But we have very talented people there. Our history of research in Puerto Rico has been quite negative. We've done the equivalence of Tuskegee's there. So we just got word about the birth cohort. So we need to be mindful of getting really talented Puerto Rican investigators that are gonna be Dr. Eliseo Perez and Stubbley and I talked about this a few minutes ago about bringing in top scientists who are there. As you know, I published on this. We don't like to do what's called Safari research where we just parachute into a community, take stuff and leave. We need community engagement, not only on the community level, but on the scientific community level. Your second question was? Should we stop using race? Ah, never, okay. Never, that'll never go away. Race is a social construct. Race is my views like a shopping cart. It includes information about genetic ancestry. It includes information about your social experiences, your demographic experiences. The example I like to use is when insurance agencies try to make a decision on what they're gonna charge you for car insurance. The actuarials use information on your, let's say for teenagers when you're first about to get car insurance. Okay, male or female? Your age? Your zip code? Your GPA? And if you ask me the question, what's the likelihood of a young boy, teenager, adolescent, lifespan in Ferguson, Missouri? I would ask male or female? Black or white? That has nothing to do with biology, but it pretty clearly has biologic consequences, meaning like life or death. So the whole construct of race ethnicity is never gonna be a way because it's what we call an epidemiologic proxy for all this other information. Recently in Milwaukee, the basketball player who played on the professional team, I don't know if you saw that. It was like a week ago. Parking violation, turning him to being tased. That has nothing to do with his genetics. He was African-American. Then he played the NBA game the next day. He had a visible footprint on his face by the police. So if we don't capture that information, we'll never get away with it. Ward Connerly tried to do away with collection of race ethnicity at the University of California. So we didn't know the denominator of who was getting into Berkeley and who was not or to the UC system. From an epidemiologic point of view, and I was trained in epidemiology, it's never gonna go away. And as a clinician, we're never gonna hang our hat on one variable but it's another to make a diagnosis of heart disease. I see Dr. Valentine here. We're never gonna say, just because you have this biomarker, you're doomed. We use a whole constellation of clinical signs, symptoms, and markers to make a clinical decision. Race is never gonna be the one thing, but it's something that's very important and it'll never go away. Well, thank you very much. It's an honor and privilege to be here.