
Launch HN: Probably Genetic (YC W19): At-home DNA testing for every gene - astroH
Hi Hacker News, We’re Harley and Lukas from Probably Genetic (<a href="https:&#x2F;&#x2F;www.probablygenetic.com" rel="nofollow">https:&#x2F;&#x2F;www.probablygenetic.com</a>). 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.<p>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.<p>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&#x27;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.<p>About the test:<p>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.<p>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 exome sequencing test rather than a genotyping array, which allows us to cover all of the genes in a person’s DNA. We often get the question, why not do whole genome rather than whole exome? Right now it simply comes down to accessibility. For most consumers, whole genome sequencing is still too expensive and the additional gain in terms of coverage of pathogenic mutations doesn’t necessarily warrant the significant price increase. That being said, if you are interested in clinical-grade whole genome sequencing, we can soon offer this as well.<p>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&#x27; data without explicit consent and we are more than happy to both delete our users&#x27; data and destroy their sample if requested.<p>Interestingly, we often have the opposite problem where we receive inbound requests of people trying to share their data with us to see if we can help them. Out of the more than 10,000 rare diseases, over 95% do not have an FDA-approved treatment, which is why the rare disease community is so motivated to leverage their personal insights. We have started a waitlist to provide such services and are actively seeking ways to help these people and integrate them into our community, even if they have not had sequencing through us.<p>Finally, how much does it cost? A single test right now costs $899 on our website, but we try to offer the test in trios where we sequence both the patient and two family members as this often gives a higher diagnostic yield. The latter option is $1,799. We expect that the test price will decrease significantly with time as the cost of sequencing drops and more of the analysis can be automated. We don’t currently accept insurance; however, in our experience, using more traditional channels to access this kind of testing can result in bills of &gt;$10,000, not all of which may be covered. Many insurance providers don’t even cover this kind of testing, except for very specific purposes, despite more and more of the medical literature recommending exome sequencing as a first-tier diagnostic for specific indications. Ideally, we would make the product so affordable that it simply makes sense to use us rather than billing insurance for the test plus the numerous doctor and specialist visits needed before and after it’s ordered. We are currently offering the test at cost, as we aim not to profit off of the patients that need it most, and this is sustainable because, with the consent of the patients, we can leverage our data asset for drug discovery, clinical trial recruitment, and drug repurposing.<p>Consumer genetic testing is growing rapidly as an industry and nearly doubling every single year. What is missing from this market is accessible physician-ordered testing that can genuinely help those with complex symptoms and undiagnosed genetic conditions. This is what we hope to provide. If you have any questions or feedback, we would love to hear it and please check us out at <a href="https:&#x2F;&#x2F;www.probablygenetic.com" rel="nofollow">https:&#x2F;&#x2F;www.probablygenetic.com</a>.
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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.

------
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.

~~~
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.

------
selimthegrim
So you're monetizing what these guys are doing for free?

[https://stanfordcehg.wordpress.com/2017/06/22/feature-
interv...](https://stanfordcehg.wordpress.com/2017/06/22/feature-interview-dr-
plavi-mittal-in-depth-diagnostics-seattle-wa/)

~~~
text70
Not to mention: [https://nebula.org](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.

------
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...](https://www.invitae.com/en/physician/category/CAT000168/#exome-
faq-panel-ordering)

~~~
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.

------
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.

------
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...](https://support.illumina.com/bulletins/2016/04/fastq-files-
explained.html)) (2) The BAM, which contains sequence alignment data (you can
learn more here:
[https://software.broadinstitute.org/software/igv/BAM](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...](https://www.mayoclinic.org/diseases-
conditions/adrenoleukodystrophy/symptoms-causes/syc-20369157)).

------
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.

------
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.

------
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.

------
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.

------
aloukissas
"we will never share your data without your consent" \- bravo to you guys for
not going the route of 23andme etc.

~~~
aroch
In fairness to 23andme, they also don't share your data without your consent (
Individual Data Sharing Consent : [https://www.23andme.com/about/individual-
data-consent/](https://www.23andme.com/about/individual-data-consent/) and
population-based Research Consent:
[https://www.23andme.com/about/consent/](https://www.23andme.com/about/consent/)).

It just so happens that when they do share your data it may be with a
Pharmaceutical company

------
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).

~~~
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!

------
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!

------
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.

------
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.

------
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...](https://us.dantelabs.com/collections/advanced-dna-
tests/products/whole-genome-sequencing)

~~~
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.

------
CodiePetersen
Great explanations. Hope you guys do well. I do like the fact you delete and
destroy data and samples.

~~~
lukasl
Thank you!

------
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.

------
p9s
Congratulations on your lunch, we do hope you will take data privacy
seriously.

~~~
lukasl
Thank you!

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spease
Can this test detect repeated sequences, eg as in Huntington’s disease?

~~~
astroH
Our test won't detect Huntington's unfortunately.

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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.

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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.

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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/](https://www.probablygenetic.com/)

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

~~~
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.

