The issue is with the model, not precision!

The Wirecutter has a thorough review of direct-to-consumer ancestry testing services. Since I now work at a human personal genomics company I’m not going to comment on the merits of any given service. But, I do want to clarify something in regards to the precision of these tests. Before the author quotes Jonathan Marks, he says:

For Jonathan Marks, anthropology professor at University of North Carolina at Charlotte, the big unknown for users is the margin for error with these estimates….

The issue I have with this quote is that the margin of error on these tests is really not that high. Margin of error itself is a precise concept. If you sample 1,000 individuals you’ll have a lower margin of error than if you sample 100 individuals. That’s common sense.

But for direction-to-consumer genomic tests you are sampling 100,000 to 1 million markers on SNP arrays (the exact number used for ancestry inference is often lower than the total number on the array). For ancestry testing you are really interested in the 10 million or so (order of magnitude) markers which vary between population, and a random sampling of 100,000 to 1 million is going to be pretty representative (consider that election year polling usually surveys a few thousand people to represent an electorate of tens of millions).

If you run a package like Admixture you can repeat the calculation for a given individual multiple times. In most cases there is very little variation between replicates in relation to the percentage breakdowns, even though you do a random seed to initialize the process as it begins to stochastically explore the parameter space (the variance is going to be higher if you try to resolve clusters which are extremely phylogenetically close of course).

As I have stated before, the reason these different companies offer varied results is that they start out with different models. When I learned the basic theory around phylogenetics in graduate school the philosophy was definitely Bayesian; vary the model parameters and the model and see what happens. But you can’t really vary the model all the time between customers, can you? It starts to become a nightmare in relation to customer service.

There are certain population clusters that customers are interested in. To provide a service to the public a company has to develop a model that answers those questions which are in demand. If you are designing a model for purely scientific purposes then you’d want to highlight the maximal amount of phylogenetic history. That isn’t always the same though as the history that customers want to know about it. This means that direct-to-consumer ethnicity tests in terms of the specification of their models deviate from pure scientific questions, and result in a log of judgment calls based on company evaluations of their client base.

Addendum: There is a lot of talk about the reference population sets. The main issue is representativeness, not sample size. You don’t really need more than 10-100 individuals from a given population in most cases. But you want to sample the real population diversity that is out there.

10 million DTC dense marker genotypes by end of 2017?

Today I got an email from 23andMe that they’d hit the 2 million customer mark. Since they reached their goal of 1 million kits purchased the company seems to have taken its foot off the pedal of customer base growth to focus on other things (in particular, how to get phenotypic data from those who have been genotyped). In contrast Ancestry has been growing at a faster rate of late. After talking to Spencer Wells (who was there at the beginning of the birth of this sector) we estimated that the direct-to-consumer genotyping kit business is now north of 5 million individuals served. Probably closer to 6 or 7 million, depending on the numbers you assume for the various companies (I’m counting autosomal only).

This pretty awesome. Each of these firm’s genotype in the range of 100,000 to 1 million variant markers, or single nucleotide base pairs. 20 years ago this would have been an incredible achievement, but today we’re all excited about long-read sequencing from Oxford Nanopore. SNP-chips are almost ho-hum.

But though sequencing is the cutting edge, the final frontier and terminal technology of reading your DNA code, genotyping in humans will be around for a while because of cost. At ASHG last year a medical geneticist was claiming price points in bulk for high density SNP-chips are in the range of the low tens of dollars per unit. A good high coverage genome sequence is still many times more expensive (perhaps an order of magnitude ore more depending on who you believe). It also can impose more data processing costs than a SNP-chip in my experience.

Here’s a slide from Spencer:

I suspect genotyping will go S-shaped before 2025 after explosive growth in genotyping. Some people will opt-out. A minority of the population, but a substantial proportion. At the other extreme of the preference distribution you will have those who will start getting sequenced. Researchers will begin talk about genotyping platforms like they talk about microarrays (yes, I know at places like the Broad they already talk about genotyping like that, but we can’t all be like the Broad!).

Here’s an article from 2007 on 23andMe in Wired. They’re excited about paying $1,000 genotyping services…the cost now of the cheapest high quality (30x) whole genome sequences. Though 23andMe has a higher price point for its medical services, many of the companies are pushing their genotyping+ancestry below $100, a value it had stabilized at for a few years. Family Tree DNA has a father’s day sale for $69 right now. Ancestry looks to be $79. The Israel company MyHeritage is also pushing a $69 sale price (the CSO there is advertising that he’s hiring human geneticists, just so you know). It seems very likely that a $50 price point is within site in the next few years as SNP-chip costs become trivial and all the expenses are on the data storage/processing and visualization costs. I think psychologically for many people paying $50 is not cheap, but it is definitely not expensive. $100 feels expensive.

Ultimately I do wonder if I was a bit too optimistic that 50% of the US population will be sequenced at 30x by 2025. But the dynamic is quite likely to change rapidly because of a technological shift as the sector goes through a productivity uptick. We’re talking about exponential growth, which humans have weak intuition about….

Addendum: Go into the archives of Genomes Unzipped and reach the older posts. Those guys knew where we were heading…and we’re pretty much there.

Direct-to-consumer genomics, it’s back on!

The past three and a half years, and arguably longer, there has been something of a dark night passing over direct to consumer (DTC) personal genomics. The regulatory issues have been unclear to unfavorable. If you have read this blog you know 23andMe‘s saga with the Food and Drug Administration.

It looks like 2017 DTC is finally turning a regulatory corner, with some clarity and freedom to operate, FDA Opens Genetic Floodgates with 23andMe Decision:

Today, the U.S. Food and Drug Administration told gene-testing company 23andMe that it will be allowed to directly tell consumers whether their DNA puts them at higher risk for 10 different diseases, including late-onset Alzheimer’s disease and Parkinson’s.

The decision to allow these direct-to-consumer tests is a big vindication for 23andMe, which in 2013 was forced to cease marketing such results after the FDA said they could be inaccurate and risky to consumers, and that they required regulatory approval.

I still agree with my assessment in 2013, this won’t mean anything in the long run. DTC is here to stay, and if the decentralization of medical testing and services don’t happen in the USA, they’ll happen elsewhere, and at some point medical tourism will get cheap enough that any restrictions in this nation won’t be of relevance. But, this particular decision alters the timeline in the grand scheme of things, and matters a great deal for specific players.

It’s on!