{"id":521,"date":"2018-12-15T17:46:48","date_gmt":"2018-12-15T22:46:48","guid":{"rendered":"https:\/\/dwan.org\/?p=521"},"modified":"2019-10-25T12:22:19","modified_gmt":"2019-10-25T16:22:19","slug":"letting-the-genome-out-of-the-bottle","status":"publish","type":"post","link":"https:\/\/dwan.org\/index.php\/2018\/12\/15\/letting-the-genome-out-of-the-bottle\/","title":{"rendered":"Letting the genome out of the bottle"},"content":{"rendered":"\n

About eleven years ago, in January of 2008, the New England Journal of Medicine published a perspective piece on direct to consumer genetic tests, \u201cLetting the Genome out of the Bottle, Will We Get Our Wish.<\/a>\u201d The article begins by describing an \u201coverweight\u201d patient who \u201cdoes not exercise.\u201d This man\u2019s children have given him the gift of a direct to consumer genetics service at the bargain price of $1,000.<\/p>\n\n\n\n

The obese person who (did we mention) can\u2019t be troubled to go to the gym is interested in medical advice based on the fact that they have SNPs associated with both diabetes and cardiovascular disease. The message is implied in the first paragraph, and explicitly stated in the last:\u00a0\u00a0\u201cUntil the genome can be put to useful work, the children of the man described above would have been better off spending their money on a gym membership or a personal trainer so that their father could follow a diet and exercise regimen that we know will decrease his risk of heart disease and diabetes.\u201d<\/em>
<\/p>\n\n\n\n

Get it?\u00a0 Don\u2019t bother us with data.\u00a0 We knew the answer as soon as your heavy footfalls sounded in the hallway.\u00a0 Hit the gym.<\/p>\n\n\n\n

The authors give specific advice to their colleagues \u201cfor the patient who appears with a genome map and printouts of risk estimates in hand.\u201d\u00a0 <\/em>They suggest dismissing them:\u00a0\u00a0\u201cA general statement about the poor sensitivity and positive predictive value of such results is appropriate \u2026 For the patient asking whether these services provide information that is useful for disease avoidance, the prudent answer is \u2018Not now \u2014 ask again in a few years.'\u201d<\/em><\/p>\n\n\n\n

Nowhere do the authors mention any potential benefit to taking a glance at the sheaf of papers this man is clutching in his hands.<\/p>\n\n\n\n

Just 10 years ago, a respected and influential medical journal told primary care physicians to discourage patients from seeking out information about their genetic predisposition to disease.\u00a0 Should someone have the nerve to bring a \u201cprintout,\u201d they advise their peers to employ fear, uncertainty, and doubt. They suggest using some low-level statistical jargon to baffle and deflect, before giving answers based on a population-normal assumption.<\/p>\n\n\n\n

The reason I\u2019m writing this post is because I went to the doctor last week and got that exact answer, almost verbatim.\u00a0 I already went off about this on twitter.<\/a>\u00a0 I\u2019m writing this because I think that it may benefit from a more nuanced take.<\/p>\n\n\n\n

More on that at the end of the post.<\/p>\n\n\n\n

Eight bits of history<\/h2>\n\n\n\n

For all its flaws, the article does serve as a fun and accessible reminder of how far we have come a decade.<\/p>\n\n\n\n

I did 23andme when it first came out. I\u2019ve downloaded my data from them a bunch of times.\u00a0 Here are the files that I\u2019ve downloaded over the years, along with the number of lines in each file:<\/p>\n\n\n\n
cdwan$ wc -l genome_Christopher_Dwan_*
\n576119 genome_Christopher_Dwan_20080407151835.txt
\n596546 genome_Christopher_Dwan_20090120071842.txt
\n596550 genome_Christopher_Dwan_20090420074536.txt
\n1003788 genome_Christopher_Dwan_Full_20110316184634.txt
\n1001272 genome_Christopher_Dwan_Full_20120305201917.txt
<\/small><\/font><\/td><\/tr><\/table>\n
\n\n\n\n

The 2008 file contains about 576,000 data points.\u00a0 That doubled to a bit over a million when they updated their SNP chip technology in 2011.<\/p>\n\n\n\n

The authors were concerned that \u201ceven very small error rates per SNP, magnified across the genome, can result in hundreds of misclassified variants for any individual patient.\u201d<\/em>\u00a0 When I noticed that my results from the 2009 download were different from those in 2008, I wrote a horrible PERL script to figure out the extent of the changes. I still had compare.pl sitting around on my laptop, so ran it again today. I was somewhat shocked that it worked on the first try, a decade and at least two laptops later!\u00a0\u00a0<\/p>\n\n\n\n

My 23andme results were pretty consistent. Of the SNPs that were reported\u00a0 in both v1 and v2, my measurements differ at a total of 54 loci. That\u2019s an error rate of about one hundredth of one percent. Not bad at all, though certainly not zero.<\/p>\n\n\n\n

For comparison, consider the height and weight that usually gets taken when you visit\u00a0 a doctor\u2019s office. In my case, they do these measurements with shoes and clothing on \u2013 meaning that I\u2019m an inch taller (winter boots) and about 8 pounds heavier (sweater and coat) if I see my doctor in the winter. Those are variations of between 1% and 5%.<\/p>\n\n\n\n

Fortunately, nobody ever looks at adult height or weight as measured at the doctor\u2019s office. They put us on the scale so that the practice can charge our insurance providers for a physical exam, and then the doctor eyeballs us for weight and any concealed printouts.<\/p>\n\n\n\n

A data deluge<\/h2>\n\n\n\n

Back to genomics: $1,000 will buy a truly remarkable amount of data in late 2018.\u00a0 I just ordered a service from Dante Labs<\/a> that offers 30x \u201cread depth\u201d on my entire genome.\u00a0 They commit to measure each of my 3 billion letters of DNA at least 30 times.\u00a0 Taken together, that\u2019s 90 billion data points, or 180,000 times more measurements than that SNP chip from a decade ago.\u00a0 Of course, there\u2019s a strong case to be made that those 30 reads of the same location are experimental replicates, so it\u2019s really only 3 billion data points or 6,000 times more data. Depending on how you choose to count, that\u2019s either 12 or 17 doublings over a ten year span.\u00a0 \u00a0<\/p>\n\n\n\n

Either way, we\u2019re in a world where data production doubles faster than once per year. <\/p>\n\n\n\n

This is a rough and ready illustration of the source of the fuss about genomic data.\u00a0 Computing technology, both CPU and storage, seems to double in capacity per dollar every 18 months. Any industry that exceeds that tempo for a decade or so is going to experience growing pains.<\/p>\n\n\n\n

To make the math simple, I omitted the fact that this year\u2019s offering -also- gives me an additional 100x of read depth within the protein coding \u201cexome\u201d regions, as well as some even deeper reading of my mitochondrial DNA.<\/p>\n\n\n\n

One real world impact of this is that I\u2019m not going to carry around those raw reads on my laptop anymore. The raw files will take up a little more than 100 gigabytes, which would be. 20% of my laptop hard disk (or around 150 CD ROMs).\u00a0 <\/p>\n\n\n\n

I plan to use the cloud, and perhaps something more elegant than a 10 year old single threaded PERL script, to chew on my new data.<\/p>\n\n\n\n

The more things change<\/h2>\n\n\n\n

Back to the point:\u00a0 I\u2019m writing this post because, here in late 2018, I got the -exact- treatment that the 2008 article recommends. It\u2019s worse than that, because I didn\u2019t even bring in anything as fuzzy as genotypes or risk variants.\u00a0 Instead, I brought lab results, ordered through\u00a0Arivale,<\/a>\u00a0and generated by a Labcorp facility to HIPAA standards.<\/p>\n\n\n\n

I\u2019ve written about Arivale before<\/a>.\u00a0 They do a lab workup every six months. That, coupled with data from my wearable and other connected devices provides the basis for ongoing coaching and advice.<\/p>\n\n\n\n

My first blood draw from Arivale showed high levels of mercury. I adjusted my diet to eat a bit lower on the food chain. When we measured again six months later, my mercury levels had dropped by 50%. However, other measurements related to inflammation had doubled over the same time period.\u00a0 Everything was still in the \u201cnormal\u201d range \u2013 but a fluctuation of a factor of two struck me as worth investigating.<\/p>\n\n\n\n

I use one of those fancy medical services where, for an -additional- out-of-pocket annual cost, I can use a web or mobile app to schedule appointments, renew prescriptions, and even exchange secure messages with my care team.\u00a0Therefore, I didn\u2019t have to do anything as undignified as bringing a sheaf of printouts to his upscale office on a high floor of a downtown Boston office building.\u00a0 Instead, I downloaded a PDF from Arivale and sent them as a message with my appointment request.<\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n

When we met, my physician had printed out the PDFs.\u00a0 Perhaps this is part of that \u201cdigital transformation\u201d I\u2019ve heard so much about.\u00a0The 2008 article is studiously silent on the topic of doctors bearing printouts. I\u2019m guessing it\u2019s okay if they do it.<\/p>\n\n\n\n

Anyway, I had the same question as the obese, exercise-averse patient who drew such scorn in the 2008 article:\u00a0 Is there any medical direction to be had from this data?<\/p>\n\n\n\n

My physician\u2019s answer was to tell me that these direct to consumer services are \u201creally dangerous.\u201d\u00a0 He gave me the standard line about how all medical procedures, even minimally invasive ones, have associated risks. We should always justify gathering data in terms of those risks, at a population level. He cautioned me that going down the road of\u00a0even looking<\/em>\u00a0at elevated inflammation markers can lead to uncomfortable, unnecessary, and ultimately dangerous procedures.<\/p>\n\n\n\n

Thankfully, he didn\u2019t call me fat or tell me to go get a gym membership.<\/p>\n\n\n\n

This, in a nutshell is our\u00a0reactive<\/em>\u00a0system of\u00a0imprecision<\/em>\u00a0medicine.<\/p>\n\n\n\n

This is also an example of our incredibly risk averse business of medicine, where sensible companies will segment and even destroy data to avoid the danger of accidentally discovering facts that they might be obligated to report or to act on.<\/p>\n\n\n\n

This, besides the obvious profit motive, is why consumer electronics and retail outfits like Apple and Amazon are \u201cmuscling into healthcare.\u201d<\/p>\n\n\n\n

The void does desperately need to be filled, but I think it\u2019s pretty terrible that the companies best poised to exploit the gap are the ones most ruthlessly focused on the bottom line, most extractive in their runaway capitalism, and who have histories of terrible practices around both labor and of privacy.<\/p>\n\n\n\n

A happy ending, perhaps<\/h2>\n\n\n\n

I really do believe that there is an opportunity here: A chance to radically reshape the practice of medicine. I\u2019m a genomics fanboy and a true believer in the power of data.<\/p>\n\n\n\n

To be clear, the cure is not any magical app. The transformation will not be driven simply by encoding our data as XML, JSON, or some other format entirely. No specific variant of machine learning or artificial intelligence is going to un-stick this situation.<\/p>\n\n\n\n

It\u2019s not even blockchain.<\/p>\n\n\n\n

The answer lies in a balanced approach, with physicians being willing to use data driven technologies to amplify their own senses, to focus their attention, to rapidly update their recommendations and practices, and to measure and adjust follow ups and follow throughs.<\/p>\n\n\n\n

To bring it back to our obese patient above, consider the recent work on polygenic risk scores<\/a>, particularly as they relate to cardiovascular health. A savvy and up-to-date physician would be well advised to look at the genetics of their patients \u2013 particularly those of us who don\u2019t present as a perfect caricature of traditional risk-factors for heart disease.<\/p>\n\n\n\n

I\u2019ve written in the past about another physician who sized me up by eyeball and tried to reject my request for colorectal cancer screening<\/a>, despite a family history, genetic predisposition, and other indications.\u00a0 \u201cYou look good,\u201d he said, \u201care you a runner?\u201d<\/p>\n\n\n\n

There is a saying that I keep hearing:\u00a0 \u201cArtificial Intelligence will not replace physicians.\u00a0 However, physicians who use Artificial Intelligence will replace the ones who do not.\u201d<\/p>\n\n\n\n

The same is true for using all the data available. In my opinion, it is well past time to make that change.<\/p>\n\n\n\n

I would love to hear what you folks think.<\/p>\n","protected":false},"excerpt":{"rendered":"

About eleven years ago, in January of 2008, the New England Journal of Medicine published a perspective piece on direct to consumer genetic tests, \u201cLetting the Genome out of the Bottle, Will We Get Our Wish.\u201d The article begins by describing an \u201coverweight\u201d patient who…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[37],"tags":[],"class_list":["post-521","post","type-post","status-publish","format-standard","hentry","category-genomics"],"_links":{"self":[{"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/posts\/521","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/comments?post=521"}],"version-history":[{"count":45,"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/posts\/521\/revisions"}],"predecessor-version":[{"id":1133,"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/posts\/521\/revisions\/1133"}],"wp:attachment":[{"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/media?parent=521"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/categories?post=521"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/dwan.org\/index.php\/wp-json\/wp\/v2\/tags?post=521"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}