Not What but Why: Machine Learning for Understanding Genomics | Barbara Engelhardt | TEDxBoston

I have four kids and they all love math and logic puzzles the beginning of the school year I asked him why they love math and logic puzzles so much and my 11 year old answered it's because I'm a detective it's because I'm a problem solver and I love to solve problems about the world and so succinctly my eleven-year-old summed up what I've been feeling my entire career that I have mysteries and problems that I want to solve and the way I'm gonna do it is by learning as much about machine learning as I possibly can so why is machine learning the right tool to solve these mysteries in genomics and biology and medicine well I think in order to think about this we need to first discuss the two cultures in machine learning right now so leo breiman was a professor at UC Berkeley where I did my PhD in statistics and he's well known for building methods and models like a random forests that solve real-world problems in an elegant way he passed away in 2005 and in his obituary he's quoted as saying to students remember that the great adventure of statistics is in gathering and using data to solve interesting and important real-world problems so he was clearly a detective too in 2001 leo breiman wrote a paper called statistical modeling the two cultures and in this paper he describes the two cultures in machine learning one of which I'm going to refer to as the black box which leo breiman was advocating and the other one i'm going to call the open box so when we think about analyzing data in the real world let's say we have an observation X this observation could be a picture on the Internet it could be the fMRI scan from a patient and then we have some Y which could be the label for that observation so the image on the internet might be labeled as cat or the fMRI scan might be labeled as bipolar disorder or healthy so in the black box approach to modeling these data we're going to use something like a decision tree or neural networks to in a brute force way model the relationship between x and y ok because it's brute force because we don't even attempt to model nature it's a black box we can't open it up and we also need a lot of data to be able to model this relationship without surely pretending to model nature the open box approach is quite different so we use very simplified models like factor analysis linear and logistic regression and canonical correlation analysis to try an approximate nature we essentially build a scaffold based on what we think is the relationship between x and y and then fill that scaffold in using data the good news is that it takes a lot less data but the bad news is that we really need to know something about our domain that we're working in to be able to build this scaffold appropriately so if we're using a black box method to try and label pictures on the Internet let's say we start out with a hundred thousand labeled images some of which have cat and some of which don't then when we see a new picture on the internet with high accuracy we can label this image cat so Brad Efron who is a very distinguished statistician wrote a response to the two cultures paper advocating the open box approach and in his response he says the whole point of science is to open up black boxes understand their insides and build better poxes for the purposes of mankind and I think this succinctly encapsulate exactly what I think about this open box approach where we need to open the box model nature and see what's going on inside see what we've learned from the data so now if I apply the open box approach to trying to label images on the internet I might see this image of a cat again and I might say it's a cat and not a hippopotamus because it has a beautiful structure that looks like a cat the nose is exactly a cat's nose the fur is a repeated pattern that is in the shape of a cat it has fuzzy ears it has a tail it looks like a cat so I'm explaining why I'm giving it this label of cat but for this particular problem we don't care why the label is the most important thing the same is not true if you have an fMRI scan of a patient we can't just say this patient has bipolar disorder or not we need to know why we need to know what it is about that fMRI scan that allows us to give this patient a diagnosis so how do we actually open the box then in these biomedical problems well let's say we're studying a rare brain disease and we have maybe 10,000 patients in the world at all with this brain disease that's not enough patients even if we can see them all to be able to use blackbox methods to diagnose these patients just because the signals that differentiate this brain disease from every other brain disease are going to be very very difficult to find so the the open box method instead bills is scaffold of all the possible ways that small numbers of genes and biomarkers and fMRI scan images can maybe be responsible for this label of this disease and by using just a small amount of data and this representative scaffold we can narrow down the causes for this disease very effectively using a few samples a small number of data points so these open box methods allow us to search for causes and mechanisms and patterns in the data and then as detectives we have to look at those patterns open the box and figure out what those patterns represent in terms of biology so how do we do this detective work given that we have patterns that we find patterns in these complex datasets we can now attach each of those patterns to specific processes in the cell that lead to disease and the effects of those diseases back on the cell and once we know these we can start thinking about labeling causes how to draw diagnoses out of early stage patients with a particular disease and then treatments that treat the disease and not necessarily the symptoms so let's go in a little bit deeper to this open box approach for the problem of thinking about gene expression levels so let's say I have 500 patients and gene expression levels for those patients in the 20,000 genes that may be expressed in whole blood so this will be a whole blood sample but instead of gene expression levels I should say we can be talking about genotypes from people across the world or lab and vital signs from patients in a hospital so let's say then that we can also separate our group of patients into those with heart disease and those without to heart disease so the first thing we might do with an open box method is compute the average gene expression levels for those 20,000 genes for the patients with heart disease and the average gene expression levels for those without heart disease and then we can compare those averages very naively to see which genes expressed differently and the heart disease versus the not heart disease patients but in my work we go a step further and if you think about each of these patients none of their gene expression levels will be exactly like the mean the average but those patterns hidden in how the genes vary from the average so in particular now I can think about pairs and groups of genes that differ from the average gene expression levels in a coordinated way and this coordination gives us clues about what's going on in the data so what could these coordinated patterns represent well sometimes it's is biological information that we can use so for example it's possible that some genes vary from the average because there's different proportions of immune cells in those patients which may mean they've started to fight an infection it could be because there's rare genetic mutation in some of these patients that actually upregulate two or three genes in just those patients it could be because there's some cells that have already started a precancerous program and you can already see the evidence of this in the changes in a handful of cells away from the mean differences from the mean could also come about because two samples were run on different machines or actually a different technician in the lab prepared the sample slightly differently these could be representative of biological factors about the patient's like their age their sex or their ethnicity they could even be lifestyle choices so we found genes that vary from the average according to whether the patient was a tobacco smoker or not so this really encapsulates why this open box approach is so powerful in medicine to me because a limited number of samples can find these hidden patterns of variation and then with detective work we can actually put labels name each of those patterns of variation according to their causes and their biological sources so I want to tell you quickly about three success stories about open box science that came out of my group recently so the first one involves a paper that was published last week and the goal of the paper was to describe how mutations in a genome impact expression levels differently across healthy human tissues 44 healthy human tissues and my role in this project was to consider mutations identify mutations in the genome that affected gene expression levels for genes that were not located on the same chromosome as that mutation so we have 23 chromosomes in humans and let's think about what this actually involved so there's four million measurements of mutations in a genome we were thinking across 44 different human tissue types there are 20,000 expressed genes in each of these tissue types so we melted our core by running three point five trillion statistical tests to identify what ended up being only about 500 associations okay so let's actually look at one of those associations and talk about what we did to follow up on this so in thyroid cells we found that there's a mutation that affects the gene expression levels of two genes off of the chromosome and only in thyroid sorry this is a scatterplot of the 44 different tissues and that top one the green one is thyroid this is actually a sample a tissue sample from one of our donors in this projects of their thyroid and we found this association it was very exciting because it turns out that this mutation in previous study has been associated with a higher risk of thyroid cancer so it feels like Rhonda thing here so being a detective we looked around the region of this mutation on the genome and we found that there is a gene really close to this mutation called foxy one so foxy one is special because it's a thyroid specific transcription factor which means it's only expressed in thyroid tissues and that when it's up regulated in thyroid tissues that there's a cascading effect and many other genes in thyroid are also up regulated so this was really exciting again we feel like we're onto something but when we looked at our blackbox statistical methods that throw away all of the variation that can't be explained we couldn't find any association between the mutation and foxy one and all of these genes that it's supposed to affect that's when we open the box we applied these statistical methods that allow us to go in and inquiry what's going on here and not only did we find an association between the mutation and foxy one and many genes downstream but we were able to replicate the signal in a sample of 500 cancer tumor cancer patients with with thyroid cancer which is quite astounding for signals this this small so the second story I wanted to tell you about has to do with the genomics of tissues so for the exact same study that I'm talking about we actually had slides of tissue samples pathology images from about 2,000 of the samples that were matched with gene expression levels so these samples represents tissue samples from a from a donor where they stain them and put them under a microscope and take a photograph of them and that's what you're seeing here these are cerebellum and cerebral cortex samples so what we did by opening the box this time was actually find not just coordinated patterns of variation in gene expression but small sets of genes that were coordinated with image features so in other words when these genes were differential so were these sets of image features and again opening the box we were able to as far as I know for the first time identify a mutation that in individuals with two copies of that mutation have brain tissue that looks one way and zero copies of that mutation have brain tissues that look another way and we were able to do the exact same thing with a muscle mutation for muscle tissue where in with two copies of that mutation had muscle tissue that looked quite different from individuals with zero copies of that mutation so the third story is about open box machine learning to assist doctors so here we're collaborating with doctors at the University of Pennsylvania Hospital and they gave us access to 270,000 patients in their inpatient setting in the hospital setting and our goal in this study was to learn how to recommend to a doctor when to remove a patient from a ventilator from a mechanical ventilator so doctors are conservative when they remove a patient from a ventilator because they they don't want to have to re ventilate that patient understandably but there's actually negative impact to keeping a patient on a ventilator too long they may develop infection or dependency and so of course our machine learning method which was able to look across these 270,000 patients can start giving doctors recommendations but if you're a doctor there's no reason you'd accept a machine telling you what to do because the Machine hasn't been to med school like you have you need some evidence that it's the right thing to do at that time so along with this recommendation our system tells the doctors what signs what vital signs and what lab results what about the patient's take it gives it a reason to recommend that it's time to remove a patient from a ventilator in other words in all the patients that this machine has seen so far how do the signs and symptoms suggest that this patient is going to do well off of a ventilator and then how can I communicate that to a doctor so that they will follow this recommendation and this is a particular example where 40 hours before the doctor removed this patient from a ventilator our recommendation system said it was probably safe to do so so I'm gonna very briefly tell you about two of the methods that I use in open box machine learning one is called sparse factor analysis so this Y matrix is exactly the matrix that I've been talking about where we have samples or patients or donors and 20,000 gene expression levels everything after the equal sign is what we have to learn in this scaffolded model of nature okay and in particular when you think about these the columns of my lambda matrix the K columns each of those are going to be a component the variation in other words they're gonna be a subset of coordinated genes that differ together and the key about that is that there's only gonna be a small number of genes so once I fit this model I can go back and look at each of those K components find those small sets of genes that have coordinated variation and dig into it using my detective work and my understanding of biology to understand what is going wrong with those particular sets of genes so sparse canonical correlation analysis takes us one step further and not only find small sets of genes but also coordinates that with another type of observation in this case we looked at image features and now it's not only finding sets of genes that differ coordinated way but sets of image features that are also coordinated and this allows us to actually pair multiple data types and multiple data sources so that's very exciting so there's two real difficulties in applying these methods to real data problems and the first one is you need to actually know a lot about the domain you're working on or else you can't build this scaffold in the appropriate way and you can't do the detective work in a precise way that I can't solve for you but the other one is that the availability of these methods is not as ubiquitous as for example deep learning is right now so there's a lot of software tools that allow you to do this but not a lot that allow you to do sparse canonical correlation analysis so I'm working with software engineers right now to try and get these methods develop free for use for everyone and I hope that people in science will take me up on it so now I want to tell you about the next question I want to answer the next why I want to find out so last March my mother passed away from complications due to Lewy body dementia LBD is a neurodegenerative disease where you have symptoms that include memory and behavioral problems and parkinsonian like stiffness in your muscles you shuffle Lewy body dementia is impossible to diagnose before death so you have to die and have an autopsy to definitively find this diagnosis and how you find it is that you have a brain tissue like the one you see above with a Lois body in it which is that brown blob the problem is that even if you give drugs to treat Lewy body dementia none of them actually treat the causes because we don't really know the causes of Lewy body dementia and in fact if we treat the symptoms often these drugs are counterindicated so you try and treat the parkinsonian like symptoms the memory and behavioral symptoms get worse and vice-versa so I think we have a lot of the data that we actually need to start putting the pieces together and solving this problem in an open box way so in other words we have mutations that are related to dementia broadly defined not necessarily Lewy body from genome-wide Association studies we understand how mutations affect brain cells and tissues from this work that I told you about earlier and we have a lot of images of post-mortem individuals from autopsies of people with Lewy body dementia so I feel like we just need to build these open box models to be able to put the pieces together and then in an iterative way start building new models new scaffolds of how we might generate new hypotheses from the signals the patterns that we're finding in these data and maybe even go out and produce some enabling data to answer the questions more directly but the implications of doing this of putting these pieces together are gigantic if we can figure out the causes whether they're genetic or environmental of Lewy body dementia if we can diagnose these patients not after death but twelve years before they actually end up dying from Lewy body and if we can treat not just the symptoms but the causes of Lewy body dementia we're talking about solving diseases here which is something I think really important everyone every one of us just by nature of being human is curious and there are specific questions we have about the world and about nature and I hope that you will think next time you have a question that you'd like to solve and a mystery you'd like to address so you think about using the tools in open box science to be able to build boxes for the betterment of mankind thank you [Applause]

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