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Launch HN: Probably Genetic (YC W19): At-home DNA testing for every gene

109 points by astroH ↗ HN
Hi Hacker News, We’re Harley and Lukas from Probably Genetic (https://www.probablygenetic.com). We built an at-home physician-ordered DNA test that covers all genes and looks for pathogenic variants related to thousands of rare genetic conditions.

Why rare genetic conditions? It may seem like a niche problem but there are ~400 million people worldwide with a rare genetic condition, half of which are currently undiagnosed. To put this into perspective, it’s estimated that 1 in 10 Americans has a rare condition and while each of the individual ~10,000 conditions is rare, the population that suffers such conditions is larger than cancer and HIV combined. Furthermore, for the patients that have been diagnosed, it takes on average 8 years for doctors to identify their conditions. You’ve already heard of rare genetic conditions, you might just not be aware of it. Remember the Ice Bucket Challenge for ALS? Most of these diseases initially look like more common conditions, such as autism, chronic pain, ADHD, or even the flu, before patients get worse. This diagnostic odyssey can be extremely costly for patients and in our experience, some are spending more than $30,000 and seeing more than 10 doctors before they get access to the right specialists and testing.

We have seen this problem first-hand. Lukas is a rare-disease expert and worked on the world’s largest rare disease project (the 100,000 genomes project) as a PhD candidate at Oxford University in the UK. I am trained as a theoretical computational astrophysicist and during my PhD and fellowship at Cambridge University and Oxford University, I spent my spare time working with National Healthcare Service doctors developing and publishing medical diagnostics with machine learning. Our original idea was actually slightly different from what we have now. We spent a lot of effort on developing a symptom checker specifically for rare conditions with the idea to comb through existing medical records and flag patients with potential rare genetic conditions because, unsurprisingly, WebMD and others aren't really great for this purpose. As we were building this, we realized that for the patients we worked with, even if their symptoms were suggestive of a genetic condition, access to clinical-grade genetic testing was extremely difficult for many as it was either too expensive because insurance wouldn’t cover the cost, or they couldn’t find a doctor that would order it. Thus, we decided to use our expertise to both find these patients more efficiently and built up a service to drastically reduce the time and cost to access clinical-grade genetic testing.

About the test:

Just like most DNA tests, you can do this from home and it’s noninvasive, all we need is a little saliva. Unlike most DNA tests, ours is physician-ordered, sequenced in a CLIA-accredited and CAP-certified lab, the results are signed out by a licensed clinical lab director, all users have access to genetic counseling, and we try to incorporate as much phenotypic data as possible into the analysis. Our product is a whole-exome sequencing test with 100x coverage and covers all of the more than 20,000 genes, where 85% of known disease-causing variants occur.

People always ask, how are you different from 23andme? Looking for a rare genetic condition is kind of like trying to find a typo in a novel. Using a 23andme (or similar) test to look for such a condition is like trying to find a typo in the first Harry Potter novel and stopping after 75 words. Those tests are just not meant for this purpose. Most are based on genotyping arrays that look for very specific variants at predetermined locations in the genome. However, the variants that cause rare diseases can occur anywhere. For example, there are over 1,700 different mutations in the CFTR gene that can cause cystic fibrosis. Approximately 85% of the known pathogenic mutations occur in the protein-coding regions of DNA called the exome. Our test is a whole exom...

81 comments

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thrwaway69
That's pretty interesting. Where I can read more or check your products?

Found the site: https://www.probablygenetic.com/

Doesn't seem like it's available for india or outside US.

astroH
Thanks for adding the link! Probably forgot the most important thing but just added the website :)
astroH
Yes, right now, we offer only in the US in all states except NY.
otoburb
That's a bummer. Is NY on the roadmap or is this due to an intractable regulatory gate?
astroH
Ideally, it will be. They have different regulations as you are alluding to which makes it difficult for us at the moment.
ampdepolymerase
What about federal lab requirements to store genetic samples?
astroH
Great question. We use a CLIA-certified and CAP-accredited lab, and we must keep the specimen through the completion of the testing and result reporting. If there is any sample remaining after testing, we will hold onto it longer in case we need to run a validation or other tests as recommended, but we will, of course, have it destroyed at the request of the patient. It's recommended that we keep them for as long as they are stable.
blue_eyes1978
is the actual basepair sequence shared with the patient? How much of the chromosomal sequence is actually mapped? I'm interested in how this may be incorporated into a patient's chart to fully flush out future diagnoses as sub-clinical symptoms progress down the pathophysiologic maturation chain.
lukasl
Great question! In addition to the result report, we share three different types of files with the patient:

(1) The FASTQ, which contains the read data from the sequencer (see https://support.illumina.com/bulletins/2016/04/fastq-files-e...) (2) The BAM, which contains sequence alignment data (you can learn more here: https://software.broadinstitute.org/software/igv/BAM) (3) The VCF, which contains the variants present in the patient as compared to the human reference genome

We map all >20,000 genes in the human genome, which covers 85% of all known disease-causing mutations. Genes make up about 2% of your DNA.

Regarding integrating this into ongoing healthcare for patients: continuous re-analysis of a patient’s genetic data is important, for two reasons: (1) we discover 100-150 new disease-causing genes every year, which means we can return results today that we couldn’t a year ago, and (2) a patient’s symptoms change over time, which matters because we analyze the patient’s DNA for what’s causing their symptoms. Plus, a lot of diseases have a late-onset, which means you might be perfectly fine until your thirties, and all of a sudden you start developing a condition that you didn’t know about. Adult-onset ALD is an example of such a condition (https://www.mayoclinic.org/diseases-conditions/adrenoleukody...).

elektor
Harley and Lukas, this looks like a very promising start-up and especially timely for Rare Disease Week. Congrats on the launch!

My question to you: You've made a comparison of your service to 23andMe in your post, can you provide some similar insight as to why your service would be preferable to Dante Labs? They claim to provide a "Whole Genome Sequencing Full DNA Test (30X)" [1]

Thank you!

[1]https://us.dantelabs.com/collections/advanced-dna-tests/prod...

astroH
Thanks so much for the comment! In order to offer this testing and give back a result report that can really be used by a doctor, it should be physician-ordered, processed in a CLIA-certified and ideally, a CAP-accredited lab, have the lab report signed out by a clinical lab director, and ideally (for ethical reasons) offer genetic counseling to patients. From the bioinformatics perspective, the bioinformatician should be trying to take in all of the medical information we know about the patient and apply this to the analysis. This is what we offer. In contrast, with Dante labs, you basically send them your sample and get back raw data and some very basic reports. If you bring these to a doctor, the recommendation might be to just get another genetic test via a lab that follows all of the procedures as stated above so a person may end up doing it twice if they go that route. Ours offers the complete end-to-end solution that you would get in the healthcare system while Dante labs is really just a way to access your raw DNA.
blue_eyes1978
But do your results also allow a user/customer/patient to access their raw DNA, as well? And how much of the DNA is mapped?
astroH
Yes, we do allow users to access their raw DNA. We will make VCF, BAM, and FASTQ files available if requested. We map the entire exome at 100x coverage which covers all genes.
rootusrootus
Actually delivering results would make them extremely preferable. I've been waiting on Dante Labs since May of 2019. After complaining to them later in the year about the lengthy delay, my status magically changed to 'sequencing started' and has been there for a few months now.

I have given up on ever getting results from Dante Labs, and I'm unsure if I would even trust the sequencing results either way. I recommend anybody else considering them do their own due diligence before making a purchase.

astroH
Out of curiosity, would they be preferable because of pricing or simply because it fits your needs better?
rootusrootus
Just delivering anything at all would be preferable. Dante Labs still hasn't sequenced my DNA, and they've had my kit for almost a year.
all2
> Patient privacy is a huge concern for us and something we think about all the time. Quite simply, we will never share any of our users' data without explicit consent and we are more than happy to both delete our users' data and destroy their sample if requested.

This should be the default rather than a user-requested option. I would consider auto-deleting user data (ensuring privacy for anyone's data outside some window of time) to be akin to auto-opt-in organ donation: most people don't know or care enough to change the default and will go with whatever is on the form (which is why organ donation is 99ish% of some populations in Europe and drastically lower than that in the United States - we should ignore the moral implications of choosing for people and focus on the outcomes of choosing a 'sane' default action). If you want an iron-clad guarantee sequences will never fall into the hands of bad actors (anyone who has delusions of genocide, for example) deletion/destruction is the way to go; perhaps even two or three passes of bit-by-bit overwrite.

Consider a future where such sequences will allow bad actors to engineer viruses against family units, regions of peoples, and so on.

astroH
I think that's a really good point. In fact, for many lab tests where the results are completely "cut-and-dry", this suggestion totally makes sense. For us, one thing we consider is that the diagnostic yield for these types of sequencing tests is only ~40%-50% in the best case. We know from the literature that if we perform a reanalysis 6 months-1 year, the chances that we find something in patients that don't have a result increases quite substantially as does how we interpret known variants. Thus, continual reanalysis is very important to many of the patients that we work with. Unfortunately, it's too expensive to resequence every time we need to run such a reanalysis algorithm.
est31
> it's too expensive to resequence every time we need to run such a reanalysis algorithm.

You can also send hard disks to customers with the exome on them and ask them to either send them to you for a, idk 20 USD reanalysis that you recommend doing every year, or you can even have it done on the customer's computers themselves with a program that you provide that downloads the latest database of variants from the internet and then performs the analysis completely off-line without sending any info on which disease chances the patient has to you.

astroH
Both good suggestions. The hard-drive idea is totally doable and something we have considered. In terms of the analysis, it's not quite a program that you can run on your own computer. You can rank variants this way but you need a trained bioinformatician to interpret them which is why it has to be done on our side.
rkagerer
I'm interested in more detail on your privacy policy, and reading any contractual language on this subject in your Terms of Use (or whatever other fine print forms the agreement between you and your customers).

I stay far away from services like 23andMe because of their user-hostile terms (at least that's the impression I got when I last scrutinized them a few years ago).

To me the ideal DNA test would be one I process myself at home, without sending anything to the cloud. I recognize that's not viable since most of us lack home laboratories.

Next best option would be one where the sample is submitted anonymously and results accessible under a system-generated ID code. That would alleviate some of the risk if you or your partners screw up in terms of privacy and security (it's naive to ignore that possibility - look at how many Fortune 500's have been breached or suffered human error).

A user could "opt in" to share identifying information (ideally only to the extent they're comfortable - e.g. I might be willing to submit coarse data like racial background, age, etc. while withholding my name and address).

In all cases I would still expect to see very strong, binding language in both your agreements with me, and those with the labs you subcontract out to, assuring that my data will be kept confidential and all traces deleted (including from all backups!) when I request.

Regarding re-sequencing and long-term storage for privacy concerned users: give me the option to download the raw data (compressed and encrypted?) and delete it from your platform. I can re-submit to you in a few years for an updated analysis. That avoids the cost of re-sequencing while, for privacy-conscious users like me, minimizes the window in which you storing my data could cause me harm.

astroH
I think this is really well put and something that we haven't considered (letting users download their data and then re-upload later). As long as we could ensure the data hasn't changed it could work. Unfortunately, we can't do anonymous testing because it is physician-ordered. I should say that some of this identifiable information is super important for the analysis.
astroH
Just to elaborate on this, by analysis I mean understanding which mutation in the genome is pathogenic.
est31
Also that way the data are safe if the company gets acquired by someone like 23andme or pivots away from this path themselves. The statement that they care about privacy is really great, but it's harder to actually live it.

Anyways, wishing them lots of luck in building a company that actually respects privacy and doesn't just claim it.

astroH
Thanks for the comment and we totally agree. The only way to prove we care about privacy is to live it and be as transparent as possible.
mattparmett
Congrats on the launch! I'm a VC that's invested in this space and I think you are hitting on an important distinction between physician-ordered and consumer-directed testing (we often call the latter "medical tourism").

Another very important part of the testing process, particularly in the rare disease space, is the pre- and post-test genetic counseling. I see that all users have access to genetic counseling, which is great - just curious about how you are handling that part of the process?

astroH
Thanks so much for the comment. That's a really great way to describe the distinction! In terms of genetic counseling, for post-test purposes, we won't release positive results until the patient has booked a session with one of the genetic counselors where the results are released. In the case of negative results, we give the patient the option to discuss with a counselor but do not make it mandatory. In both cases, the counseling is included in the cost of the service. For pre-test counseling, the way it currently works in our service is that when users request a test, they have to fill out a detailed medical intake questionnaire which is then reviewed by both a genetic counselor and a physician. Right now, it is up to the discretion of the genetic counselor that reviews the information whether they feel like they should reach out to the patient and discuss how this may impact them or whether they have requested the appropriate test. If demand increases significantly for pre-test counseling, this is definitely something we will able to add moving forward.
mattparmett
That all makes sense. My question was more from a business logistics perspective - are you employing the counselors, or outsourcing to a third party? There is a lack of supply in that market and depending on growth, you may find it difficult to hire a large group of counselors. If you are outsourcing, be cognizant of who you are using as a vendor.

My fund's investment is in the genetic counseling space so I'm biased, but one of the issues to consider is using a lab-affiliated counseling group vs. truly independent counseling group. Another issue is, some counseling companies are focused on physician authorization (pre-test approvals to increase test volume) while others are focused on return of results, ongoing counseling etc. (the latter being more expensive).

Anyway, all things to think about. I also echo some of the other comments here around competing vs Invitae, Color, etc. They are all-in-one shops with scale and can be formidable - but also a potential exit opportunity if you've developed any unique/defensible IP.

Happy to chat more over email if you'd like.

astroH
At the moment, we are currently outsourcing genetic counseling. We simply don't have the capacity at the moment to bring that in-house. Very happy to discuss further over email (harley@probablygenetic.com). One thing to consider is that for many of these other companies that are doing genotyping or panels, a lot of the analysis can be automated. For exome and genome testing, this is not currently the case and there is plenty of space to develop IP in that regard.
jcims
Can you expand a little bit on the physician-ordered aspect then? Was this purely a policy decision that your team made or did you arrive at it through regulation or related externalities? If the former, was there any particular concern that drove the decision?

Sorry, one additional question. Is your company willing to do testing on pathology samples (i.e. from a biopsy) as well or just from the collection method that you ship to the customer?

astroH
It sort of determines how the FDA chooses to regulate. This was one of the issues that came up with 23andme in the beginning. The FDA chooses not to strictly regular physician-ordered lab-developed tests and thus the physician-ordering is sort of a key piece. Right now, we only accept saliva (and soon a cheek swab) that's sent in via one of our kits. Unfortunately, at the moment, we are not exploring doing sequencing on other samples.
jcims
That makes sense. I don't know if you're expecting customers to find a doc that will be willing to order or if you're curating a list of docs that customers can select from, but in my experience the latter is much simpler to navigate.

My wife was in a situation where she was in the ragged edges of a common disease that made her eligibility for various trials and therapies suspect. She had a somatic mutation that would be nice to be able to fully catalog. There is a trial going on right now (MATCH [0]) that does selective testing for mutations and deficiencies in cancer patients that have some associated trial therapy. This is fine but outcomes are of course going to vary and developing a catalog that can be mined after the fact might help identify other areas to focus on.

Best of luck to you and your company!

[0] - https://www.cancer.gov/about-cancer/treatment/clinical-trial...

astroH
Really appreciate it! As a quick comment, we work with a physician network that has physicians licensed in all 50 states and they review the medical information of all of our patients. This way we don't put the burden on our users.
jcims
Nice. That's way better. Especially in the situation with rare maladies (or a combination of them) it doesn't take long for the layperson to know more about it than their local GP will. Trying to convince them to order a $900 lab for you would be an uphill battle in many cases.
ac29
> The FDA chooses not to strictly regular physician-ordered lab-developed tests and thus the physician-ordering is sort of a key piece.

Does this mean you will be able to offer the sort of "you are X% more likely to get disease Y" information that the FDA prohibited 23andme from providing? If not, what information can you provide?

astroH
Great question and something that I should have clarified. We look for mutations that are either considered pathogenic or likely pathogenic under the guidelines of the American college of medical genetics and genomics when considered with the other medical history of the patient. This is what we return to patients. This is considerably different than a "risk score" as you have pointed out. Other companies, like Color, use the physician ordered model to offer that sort of information for cancer risk and cardiovascular conditions. We focus on primarily on mutations associated with rare conditions. In principle, we could offer these other things as our test captures much of that information and we are looking to add this to the analysis in case patients are interested.
quantguy11959
Thanks for the comparison against 23 and me but I’d be interested in how you plan to differ from Invitae/Fulgent/Myraid aside from the D2C aspects.
astroH
Great question. Right now the major difference is the D2C (patient-initiated, physician-ordered) aspect. Invitae is starting to offer this to some extent but they mainly seem focused on cardiovascular and cancer. Unlike those companies, we don't consider ourselves a testing company. For most patients in the rare disease space, understanding the underlying genetic cause is really only the first step in the process and then most need tons of help navigating the healthcare space afterwards. We started with the test, mainly because of the access and affordability issue patients were having. Many of our patients have requested tools for longitudinal phenotypic data collection, connections with all of the relevant advocacy groups, further genetic counselling, efficient ways to test family members, and detailed, patient-readable information content about their variant. We try to provide everything these patients need (aside from medical advice of course) as the healthcare system isn't currently set up to help rare disease patients.
zmmmmm
How thoroughly have you compared yourselves to existing options like Invitae? They appear to offer pretty much what you are describing for a similar (slightly higher) price [1].

I feel like you may be underestimating both the maturity of the existing market and the complexity of doing what you are proposing at scale. Are you issuing clinical reports for your results? If so, who is doing that as neither of you sounds like you would meet the normal requirements for that.

[1] https://www.invitae.com/en/physician/category/CAT000168/#exo...

astroH
Invitae is definitely one of the most impressive companies in the entire genetic testing space. There are many companies that can offer exome testing, but as far as we are aware, in almost all other cases, you still need your own physician to order and you would be surprised how many patients struggle to get their doctors to order genetic testing, especially because in many cases insurances are not reimbursing. Our test is in CLIA-certified and CAP-accredited lab and is physician-ordered. It's important to note that we do not make medical diagnoses we simply provide the report that you can take to your doctor and have them interpret in the context of your other medical history and information. In essence, it's a very similar service but in our case patient-initiated. The report is signed out by a clinical lab director in connection with our sequencing and bioinformatics partners.
kian
Where are you located? I was under the impression that many states in the US mandate that you hold on to the genetic data for them, and thus that you can never truly delete or remove it.
cflyingdutchman
SF
kian
23AndMe, which is located in California, claims on their website that they are required to maintain any information from genetic tests indefinitely. How is Probably Genetic able to 'destroy samples and data' on more than a soft-delete basis?
astroH
Apologies for not getting to this earlier. Our in-house GC is est fit to answer this; however, as far as I am aware, CLIA only requires that we keep samples until the analysis is complete and results are returned to patients. They recommend that one keeps this as long as possible. The other thing is the difference between a report and raw data. I believe that we are supposed to hold onto reports for 21 years, some states have slightly different regulations but that's different from raw data. We are also a physician-ordered LDT while 23andme is FDA approved so there are differences there as well.
aloukissas
"we will never share your data without your consent" - bravo to you guys for not going the route of 23andme etc.
cflyingdutchman
I read your FAQ but still couldn't tell if you test for Scheuermann's Disease Orpha:3135.
astroH
So it's important to note we don't test for diseases but rather variants which may be the etiology. I'm not an expert in this condition by any means but a quick search says we still don't know the candidate genes for this and many have been excluded which would be problematic for our test.
the_watcher
Do these tests qualify for FSA/HSA/MSA reimbursement? If so, you should highlight that, particularly in November/December when people are making their elections for the next year (or in the case of an FSA, trying to figure out how to make sure they use their entire balance).
the_watcher
As an anecdote, the first year I had an FSA, I didn't fully realize that it was use it or lose it and ended up spending $1500 on things like sunscreen, contact solution, and first aid kits.
astroH
Really great suggestion. We haven't tried accepting this yet but naively, I would imagine they should be. I wish I could give a more concrete answer but I will further look into the details and ask our in-house GC.
the_watcher
If it turns out that you can, I'd also recommend preparing a document you can send to purchasers verifying that it qualifies, as FSA providers don't always get this right by default.
astroH
Very much appreciate the advice!
ablekh
Congratulations on your launch and good luck! I'm curious about your participation in YC accelerator and would very much appreciate if you could reflect on it (interview, pros, cons, impressions, etc.). I'm especially interested in this due to my current (passive) work on a deep tech (science-based) startup, albeit in a totally different domain, and it would be great if you could reflect on your YC journey from a deep tech startup's perspective.
astroH
YC was immensely helpful for us in a lot of ways. Definitely happy to go into more detail offline but two things I really liked were that there are so many companies in the healthcare space now that have come out of YC and regulation is a hugely scary aspect of the field and getting advice from them on how to navigate many things saved me so much time and headache. YC also very much redefined how I personally think about an MVP and it's usually a lot more minimal than I initially realise. As the community grows bigger, a lot of this will become even better. I almost wish we were slightly further along when we started as a lot of the prolems that companies in our batch were facing are starting to affect us now that we're not in set-up mode. The key thing for me is that we have to make sure we do right by patients above all and I have to integrate that with all of the other advice that sometimes conflicted in my head.
ablekh
I greatly appreciate your prompt and very helpful feedback. The aspects that you mentioned are certainly interesting and, while the regulation aspect is not a significant issue in the domain I'm concerned about, the MVP aspect is certainly very much applicable. Thank you as well for your kind offer to connect offline; I would love to chat. Please send me a quick e-mail (aleksandr.blekh@gmail.com) and I will be happy to connect.
neil_s
So glad to see this service exist. While Shkreli is out jacking up prices for rare disease drugs, you guys are making help more accessible by providing doctors trained to order these tests, running the tests at certified labs, and being super transparent with data sharing.

Cheering for you to succeed!

astroH
Thanks so much for the kind words and support!
gavinray
This is incredibly cool, really amazing to see full-genome sequencing versus the very limited number of SNP's that other players in the space are doing.

I am working with a team of people at the moment building a product around genome analysis and insight for people who have existing sequences - sort of like Promethease but more accessible to the average person.

If you are open to it, I would love to get in contact with your team and learn more about what you're doing. Is the email address contact@probablygenetic.com the best place to reach out?

astroH
A service like that is definitely needed! Please feel free to get in touch via the contact address.
gavinray
Amazing! Will 100% reach out later tonight, look forward to speaking with you all.
p9s
Congratulations on your lunch, we do hope you will take data privacy seriously.
spease
Can this test detect repeated sequences, eg as in Huntington’s disease?
astroH
Our test won't detect Huntington's unfortunately.
Real_S
This is a great product. Where is the sequencing done?
astroH
Very much appreciate the comment. The sequencing is done at a lab in Maryland.
selimthegrim
So you're monetizing what these guys are doing for free?

https://stanfordcehg.wordpress.com/2017/06/22/feature-interv...

lukasl
That's a really interesting post! I hadn't heard of them and just had a look at the website. I think the focus is here is more to first collect survey data on patients and, once sufficient survey data is collected, run a research study on specific diseases, but I might be wrong. That's different from our service. We're providing a fast and easy-to-use genetic testing service, not a research study. I also couldn't find an option on their website to actually get testing, but I'll keep an eye out!
text70
Not to mention: https://nebula.org

Whole genome, not just the protein coding regions, which can catch more clandestine promoter, and non-coding SNPs, etc.

astroH
Nebula isn't a physician-ordered test, nor does it come with the bioinformatics pipeline needed for rare conditions or genetic counseling. It's quite simply a different product for a different purpose.
chaostheory
why not have an option for a blood test?
lukasl
Patients generally prefer less invasive sample collection methods, which are also easier to use at home. That said, we are considering launching a blood-based collection method, too.
chaostheory
Personally, I'd rather have accuracy than convenience especially at this price point.
lukasl
Both saliva collection and cheek swab are reliable methods for whole exome sequencing. The combination of sample collection, sequencing and variant calling have to comply with CLIA and CAP, it's a binary cut-off. We wouldn't be able to (and wouldn't want to) report back results for which we can't assure quality.
colsandurz
Would you ever be able to test two potential parents to see if they're both carriers for genetic diseases? Or, is that a completely different type of test?
astroH
Yes, we could test two potential parents to see if they are carriers. Depending on what you're looking for though, if it's a specific mutation, there might be a slightly cheaper option on the market as our test is very broad spectrum.
CodiePetersen
Great explanations. Hope you guys do well. I do like the fact you delete and destroy data and samples.
aaauaucuggaa
Super exciting launch! Always good to see more bio companies in YC. I applied for an engineering position and would love to know more about what challenges are being tackled on the software/bioinformatics front.