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2019 February 17

Full-genome sequencing pricing

Filed under: Uncategorized — gasstationwithoutpumps @ 12:23
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In the comments on Dante Labs is a scam, there has been some discussion on pricing of whole-genome sequencing.  There are a lot of companies out there with different business models, different pricing schemes, and subtly different offerings—all of which is undoubtedly confusing to consumers.  I’ve been trying to collect pricing information for the past year, and I’m still often confused by the offerings.

Consumers buy sequencing for two main purposes: to find out about their ancestry and to find out about the genetic risks to their health.

For ancestry, there is no real need for sequencing—the information from DNA microarrays (as used by companies like 23andme or ancestry.com) is more than sufficient, and those companies have big proprietary databases that allow more precise ancestry information than the public databases accessible to companies that do full sequencing.  The microarray approach is currently far cheaper than sequencing, though the difference is shrinking.

The major, well-documented risk factors for health are also covered by the DNA microarrays, but there are thousands of risk factors being discovered and published every year, and the DNA microarray tests need to redesigned and rerun on a regular basis to keep up. If whole-genome sequencing is done, almost all of the data needed for analysis is collected at once, and only analysis needs to be redone.  (This is not quite true—long-read sequencing is beginning to provide information about structural rearrangements of the genome that are not visible in the older short-read technologies, and some of these structural rearrangements are clinically significant, though usually only in cancer tumors, not in the germ line.)

For most consumers mildly interested in ancestry and genetic risks, the 23andme $200 package is all they need.  If they are just interested in ancestry, there are even cheaper options ($100 from 23andme or ancestry.com—I have no idea which is better).

My interest in my genome is to try to figure out the genetics of my inherited low heart rate.  It is not a common condition, and it seems to be beneficial rather than harmful (at any rate, my ancestors who had it were mostly long-lived), so the microarrays are not looking for variants that might be responsible.  Whole genome sequencing would give me a much larger pool of variants to examine to try to track down the cause.  To get high probability of seeing every variant, I would need 30× sequencing of my whole genome.  If I thought that the problem was in a protein-coding gene, I could get 100× exome sequencing instead.

The problem with whole-genome sequencing is that everybody has about a million variants, almost all of which are irrelevant to any specific health question.  The variants that have already been studied and well documented are not too hard to deal with, but most of them are already in the DNA microarrays, so whole-genome sequencing doesn’t offer much more on them.  Looking for a rare variant that has not been well studied is much harder—which of the millions of base changes matters?

The popular, and expensive, approach in recent genomics literature is to do genome-wide association studies (GWAS).  These take a large population of people with and without the phenotype of interest, then looks for variants that reliably separate the groups.  If there are many possible hypotheses (generally in the thousands or millions), a huge population is needed to separate out the real signal from random noise.  Many of the early GWAS papers were later shown to have bogus results, because the researchers did not have a proper appreciation of how easy it was to fool themselves.

Earlier studies focussed on families, where there is a lot of common genetic background, and each additional person in the study cuts the candidate hypothesis pool almost in half.  To narrow down from a million candidate variants to only one would take a little over 20 closely related people (assuming that the phenotype was caused by just a single variant—always a dangerous assumption).  I can probably get 4 or 5 of my relatives to participate in a study like this, but probably not 20.  I don’t think I want to pay for 20 whole-genome sequencing runs out of my own pocket anyway.

I have some hope of working with a smaller number of samples, though, as there has been an open-access paper on inherited bradycardia implicating about 16 genes.  If I have variants in those genes or their promoters, they are likely to be the interesting variants, even if no one has previously seen or studied the variants.  Of course, the size of the region means I’m likely to have about 80 variants in those regions just by chance, so I’ll still need to have some of my relatives’ genomes to narrow down the possibilities, but 8 or 9 relatives may be enough to get a solid conjecture.  (Proving that the variant is responsible would be more difficult—I’d either need a much larger cohort or someone would have to do genetic experiments in animal models.)

How expensive is the whole-genome sequencing anyway?  It can be hard to tell, as different labs offer different packages and many require more than the advertised price.

A university research lab like UC Davis will do the DNA library prep and 30× sequencing for about $1000, but not the extraction of the DNA from a spit kit or cheek swabs.  That is a fairly cheap procedure (about $50, I think), but arranging for one lab to do the extraction and ship to another lab increased the complexity of the logistics, to the point where I don’t think I’d ever get around to doing it.  Storing the sequencing results (FASTQ files), doing the mapping of the reads to a reference genome to get BAM files, and calling variants to get VCF files adds to the cost, though cloud-based systems are available that make this reasonably cheap (I think about $50 a year for storage and about $50 for the analysis).  Interpreting the VCF files can be aided by using Promethease for $12 to find relevant entries in SNPedia.

Fullgenomes.com offers packages from $545 to $2900, with an extra $250 for analysis.  The most relevant package for what I want would be the 30× sequencing package for $1295, probably without their $250 analysis, which I suspect is not much more than consumer-friendly rewrite of the results from Promethease (which can be very hard to read, so most consumers would need the rewrite).  Their pricing is a little weird, as the 15× sequencing is less than half the price of 30×, while the underlying technology should make the 30× cheaper per base.  I’ll have to check on exactly what is included in the $1295 package, as that is looking like the best deal I can find right now.

BGI advertises bulk whole-genome sequencing at low prices for researchers, but never responded to my email (from my university account) trying to get actual prices.  A lot of other companies (like Novogene) also have “request a quote” buttons.  My usual reaction to that is that if you have to ask the price, you can’t afford it.  Secret pricing is almost always ridiculously high pricing, and I prefer not to deal with companies that have secret pricing.

Dante Labs advertises very low prices, but does not deliver results—they seem to be a scam.

Veritas Genetics offers a low price ($999), but that does not include giving you back your data—they want to hang onto it and sell you additional “tests” that cost ridiculously large amounts.  I believe they will sell the VCF file (but not the BAM or FASTQ files it is based on) for an additional fee.

Most of the other companies I’ve seen have 30× whole-genome sequencing priced at over $2000, which is a little out of my price range.

 

2019 February 15

Why do I write?

Filed under: Circuits course — gasstationwithoutpumps @ 19:56
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O Why Do You Write? Charles French asks

I have a question for all you out  there who write, and that includes writers of books, poetry, plays, nonfiction, and blogs. If I left out any kind of writing, you are included also.

Why do you write?

I wrote my textbook Applied Analog Electronics because I was creating a course for which I could find no suitable textbook. I wanted a college-level introduction to electronics that was focused on designing things, not on applied math. I don’t have an objection to math (there is plenty in my textbook), but I wanted it to be there to solve a particular design problem, not just with sterile exercises. The central theme of the book had to be iterative engineering with design, construction, and debugging of interesting circuits, with almost everything else as support for that activity.

All I could find on the market either delayed design until the third or fourth course (which seems to be the standard approach in EE departments) or was very hand-holding—telling students exactly what to wire and leaving no electronics design to the students.

When I started the book writing, I already had a fairly thorough set of lab handouts and felt that the book would be a simple rewrite with a bit of additional material. Boy, was I wrong!

The book has taken over much of my life (when I’m not teaching the course from it or grading student work) for the past few years. I had a “finished” draft at the beginning of January, but students in my class have pointed out about 170 problems with it, and they are only halfway through the book. A lot of the problems were tiny copy-editing things (commas, spaces, spelling errors), but some were substantive. I have about 50 to-do notes accumulated for me to work on this summer.

I think that this year’s students have been motivated to find errors by the token amount I pay for each error found (25¢) and by the “leaderboard” on Piazza, where I keep track of what I owe each student. To encourage more feedback, I try to be generous in allocating the quarters—something doesn’t have to be a real mistake, if I agree that the wording can be improved or something needs to be rewritten for clarity or completeness.  Students can ask questions about something they don’t understand, and if that triggers a specific idea for a change to the book, I give credit for that also.  (Having question-triggered corrections means that even students at the bottom of the class can get credit for book corrections.)

The question of why I write on this blog is a harder one.  Sometimes I am trying to share something I learned, sometimes I’m asking for help finding a solution to a problem, sometimes I’m motivating myself by making something public (like my weight and exercise records), sometimes I’m just thinking out loud (like many of my posts about the design of my course).  I’d like to say that I blog for the social connections, but so few people respond to my posts that I can’t really pretend even to myself that I am having a conversation.

I think that a few of my posts have been valued (at least Google thinks enough of them for people to come to them with searches), so I have some incentive to keep on writing.

2019 February 1

Thirty-third weight progress report

Filed under: Uncategorized — gasstationwithoutpumps @ 20:08
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This post is yet another weight progress report, continuing the previous one, part of a long series since I started in January 2015.

Starting teaching again, with the daily commute up the hill and skipping lunches has helped start bring my weight back down.

I still have about 10 pounds to lose to get back to the weight I want—where I was a year ago.

My exercise for January included about 4.44 miles/day of cycling, and I’m now doing 2km every other day. That’s not going to get me to my goal of eventually running a marathon, but it should keep mr from injuring myself again, while maintaining enough muscle and flexibility so that I don’t have to start all over next summer.

My speed is not great (equivalent to an 8–8:30-minute mile), but I’m not exhausted at the end of 2km.

2019 January 23

Mediocre experience at the local bike shop

Filed under: Uncategorized — gasstationwithoutpumps @ 11:24
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My bicycle was in need of some care this past weekend (bald tire, worn brake blocks, worn chain), so I decided it was time for a tune-up.  I usually do all the work on my bike myself, but the closest bike shop to me (now called CycleWorks, previously Sprockets) has changed hands repeatedly in the past few years, and I am a bit worried that they may not last long.  So I decided to spread the wealth a bit and pay for a tune-up.

I called them up to see if they could do a tune-up over the weekend—I wanted the bike for commuting on Tuesday (Monday was a holiday).  They said that they were closed on Monday, but if I brought the bike in on Saturday, they could have it ready by Sunday, unless it needed some part they didn’t have.

I brought the bike in on Saturday shortly after they opened at 9 a.m. and explained what I wanted.  The only unusual request was that I wanted the packing grease removed from a new chain and replaced with a dry lube like White Lightning or T9.

Early in the afternoon on Saturday, they called me and said that the bike was ready.  The promptness of service was quite pleasing, and they did seem to have used dry lube on the new chain.  I ran a few errands on Saturday, and found that the brakes were not well adjusted—the cables were loose enough that I was almost bottoming out the brake levers before the brakes engaged.  I could fix it with the barrel adjusters, but I used up almost the full travel on one barrel (which should be reserved for wear on the brakes, not the initial adjustment).

Tuesday morning, on my way up the hill, I shifted into my lowest gear and the chain came off into the spokes.  It turns out that they had the rear derailleur adjustment off by a full index step and they hadn’t set the stops on the derailleur correctly.  This is the sort of problem I would expect of an amateur or a new trainee, but not from a professional bike mechanic I was paying an $80 labor fee for.

This morning I took half an hour of my time to adjust the brake cables and the rear derailleur correctly, also doing a little truing of the rear wheel to keep the rim from rubbing on the new brake blocks.

I won’t be going back to CycleWorks for a couple of years—time to give them a chance to hire or train competent staff (or go out of business).  I’ll have to try the next closest bike shop, which is 0.2 miles further away.  (Santa Cruz is blessed with an abundance of bike shops, which makes it fairly easy to find one that meets your needs and your tastes and is within walking distance—for years Sprockets was a good match for me, but CycleWorks doesn’t seem to be.)

2019 January 21

More typos than expected

Filed under: Circuits course — gasstationwithoutpumps @ 16:53
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When I released my textbook in December, I offered 25¢ for each typo or other mistake found in the book.  I expected, based on how much material was new, to have about 50 typos in the book.

My students have already found 42 errors, and they are only up to about page 200, so I’m having to revise my error estimate upward to about 100 errors.

This year’s class seems to be pretty sharp—they have done much better on the first two quizzes than last year’s class did, and in two weeks they have already found about as many typos as last year’s class did over two quarters.

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