Hi Michelle,

Counsylor here! Nice to meet you. Just wanted to note a few things in response to your great post.

1) Full list of mutations: First, the full list of mutations and details on what we're doing is available on the Medical Professionals page, along with a paper by Harvard, Stanford, Yale, and Counsyl scientists that has been made available on Nature Precedings in advance of publication:

https://www.counsyl.com/medical/publications/
http://precedings.nature.com/documents/4192/version/1

2) Tay-Sachs enzyme vs. DNA testing: Second, regarding the Tay-Sachs enzymatic testing issue, we are absolutely sympathetic to and aware of the NTSAD's reasoning on this point.
http://www.ntsad.org/events/NTSAD_Position_Statement.pdf

As you probably know, others like Professor Bach have supported DNA based screening:
http://www.ncbi.nlm.nih.gov/pubmed/11170098

I think all parties agree that enzyme testing is certainly more sensitive, as it catches a portion of carriers that do not register on genotyping based assays. However, (as you note) there are tradeoffs involved in enzyme testing, as such testing involves blood and can't easily be multiplexed with other assays. What this means in practice is that the extra incremental cost required to identify the remaining set of carriers with a Tay Sachs enzyme test is substantial. Combining an enzyme assay with a universal carrier screen may nevertheless be desirable if the goal is the most complete screen possible.

That said, in the near future the obvious way to resolve this impasse is to move to a sequencing based assay for TSD, to cut the Gordian knot. We will have an announcement on this soon :)

3) The at-home carrier test is a sequel to the at-home pregnancy test. Third, we believe the at-home carrier test is a clear and natural successor to the at-home pregnancy test. If you think about it, both tests are for otherwise healthy people. In both cases, most people test negative, and a positive result is a life-changing event that can necessitate significant medical followup.

Importantly, society has already established that at-home testing is an issue of reproductive freedom. That is just as true for the at-home carrier test as it is for the at-home pregnancy test. Many people are comfortable with taking a pregnancy test in a clinical setting. Others, however, do not want their doctor (however well meaning) to know their pregnancy status. Similarly, people should have the choice of whether they want to take a carrier test in a doctor's office or in the privacy of their home.

4) The mechanics of sample acquisition (at-home vs. clinical) are orthogonal to the fundamental issue of disease etiology (Mendelian vs. complex)

As noted in our paper, it is of crucial importance to separate the logistics of test provisioning (at-home vs. office visit) from the molecular etiology of the disease (Mendelian vs. complex). An attempt to predict complex disease susceptibility from genes will fail regardless of whether a test is obtained over the internet or in a clinical setting because the requisite signal is simply not present with today’s technology.

By contrast, the signal for predicting Mendelian disorders is quite binary and does not change as a function of whether a sample is collected at home or in the clinic. The only question is the narrow technical issue of whether mailing a saliva sample significantly degrades signal vs. sample collection in a clinical setting; both internal data and external references indicate this is not the case, in that saliva samples are as reliable as blood for the purposes of genotyping .

5) As NIH Director Francis Collins notes, in order to get from the status quo of 0 genes to a personalized medicine future of 22000 genes, we must go through the 100 gene universal carrier test.

From the Language of Life, pages 45-50:

If I were younger and about to start a family, I would want to test myself and encourage my wife to do the same - not just for CF but for a long list of recessive diseases...
Short of having complete genome sequences for all couples prior to starting a pregnancy, are other carrier screening tests being contemplated in the near future?

Debates about the appropriateness of carrier screening will be likely to change in character in the coming few years, as more and more individuals will have complete DNA sequences of their entire genome determined, revealing all of their carrier status risks and providing an opportunity for couples to know about those risks prior to initiating a pregnancy. It is likely that within a few decades people will look back on our current circumstance with a sense of disbelief that we screened for so few conditions. They will also be puzzled and dismayed, as I am now, that our health care system put so many couples in an unnecessarily difficult position, by not identifying their carrier status until a pregnancy was already underway.

Here is Collins again in the NEJM: 

Most single-gene conditions are uncommon...However, the total effect of monogenic conditions is substantial, from both the individual patient's and public health perspectives

In essence, we have already spent billions on the personal genome, on the concept that every person will soon have their own genome sequence on a USB key.

Now, in order to make this sequence useful, society must invest in personal genome education for every citizen to be an informed and empowered user of their genome. This is the "last mile" problem, where the scientific infrastructure must now be accompanied by social and educational infrastructure. Harvard's Personal Genome Education Project is a worthy first step in this direction.

Please note that this ambitious educational goal might seem infeasible till we remember the computer revolution. With the advent of the personal computer, everyone has become a little bit of a computer scientist, and computer literacy has boomed. Similar, the advent of the personal genome is going to make everyone a little bit of a medical geneticist, and genetic literacy should -- must! -- likewise boom. 

Importantly, the number of system administrators and computer scientists grew exponentially over the course of the personal computer revolution. We expect the number of genetic counselors and medical geneticists to experience a similarly rapid rise during the personal genomic revolution. In other words, personal genomics is only going to increase the demand for the unique services of the Chicago Center's people! :)

Colleen-
Thank you for your response. I looked at the medical professionals section again and I still do not see the listing of mutations or more specifics on the technology you use. I see the link to the Nature Preceedings paper, but it would be very helpful to have the information directly on your website, rather than having to weed through a 49 page document!

While I agree that this may be the direction testing is going in general, I'm not sure that I'm comfortable comparing it to a home pregnancy test. I'm not concerned about the positive results, as I would assume that most people would go to their doctor for follow-up, as they would with a positive pregnancy test. With a pregnancy test, however, a woman may receive a negative result but would follow-up with her doctor if she still had suspicion that she was pregnant. With carrier testing for Mendelian disorders, most people are likely to accept a negative result as an absolute negative, without understanding the residual risks, and therefore may not see the need to talk to their doctor or a genetic counselor.

It would be wonderful if everyone could be educated in this area, as you mentioned, but we're certainly not there yet. I appreciate your comparison to computer literacy, and agree that it's amazing how far we've come. While this is important, it doesn't quite have the same impact as personal genetic information. If you can't send an email, you can get by. If you don't understand the genetic risks for your children, the implications can be much more serious.

Thank you again for your thorough response.

Thank you Michelle for your valuable insight and well written blog posting.

Hello Michelle,

Ah, didn't mean to make you dig! :) A lot of physicians wanted us to present all the data together in a pdf rather than spreading it over the website...that was feedback that we received. Basically, people who want to know the technical details of panel content are usually interested in other details as well, so the full context of the paper is useful.

But to be very precise, the full list of variants with performance statistics and clinical references is available in Tables 6 and 7 in the manuscript.

With carrier testing for Mendelian disorders, most people are likely to accept a negative result as an absolute negative, without understanding the residual risks, and therefore may not see the need to talk to their doctor or a genetic counselor...If you don't understand the genetic risks for your children, the implications can be much more serious.

I absolutely agree with the thrust of your argument, but would add one key thing: the current status quo (i.e. no preconception testing & no carrier status education) guarantees that vast numbers of carrier couples receive a false negative result due to total lack of testing.

Wouldn't you agree it's better to reduce the percentage of false negatives from ~100% for many diseases (the status quo) to something considerably less than that (by offering genetic counseling & universal carrier testing to all couples planning a pregnancy?).

Colleen -

I find it interesting that you seem to be stating that a lack of testing is a false negative. These are two completely different concepts. From a logistical standpoint, a false negative cannot occur outside the context of attempting to find a positive result. With regard to the discussion at hand, the untested couple's perceptions of their pregnancy risk is not the same as the potential misconceptions of a couple who has a negative panel. The untested couple has no reason to think that they have reduced their risk to zero, whereas the couple that takes a Counsyl test may have this misconception, as we have been discussing. Combining these concepts certainly allows you to increase the impact of your statement, but it is inherently inaccurate.

Sara Cherny MS CGC

Hi Sara, I really appreciate your comment because I think it gets to the heart of the matter.

The untested couple has no reason to think that they have reduced their risk to zero

We respectfully disagree. Here is what two parents who had a child with a genetic disease told us:

My wife and I never thought our kids would develop a genetic disease. We’ve always been healthy people. During her pregnancies, my wife followed doctor’s orders to the letter.

In other words, the parents had a reasonable expectation that they had a "clean bill of health" after their consult with a physician before pregnancy. This contrast between expectation and result is particularly pronounced for parents who were not offered testing for common conditions like SMA. As the cost of genome sequencing continues to fall, the standard of care in this area is only going to rise.

Moreover, the courts have generally sided with the parents on this kind of issue. Failure to test means failure to diagnose and has lead to large damage awards in related cases:

http://www.phgfoundation.org/news/2476

The Ohio Supreme Court in the US ruled this month that parents may sue on the basis of medical malpractice in the event of negligent genetic counselling or the negligent failure to diagnose a severe or fatal condition...negligently performed and interpreted the diagnostic tests and that they were negligent in their failure to recommend further tests that would have revealed Matthew’s genetic abnormality

http://www.cbsnews.com/stories/2007/07/24/national/main3092290.shtml

In what is being called a "wrongful birth" case, a jury awarded more than $21 million Monday to a couple who claimed a doctor misdiagnosed a severe birth defect in their son, leading them to have a second child with similar problems....Had the disorder been correctly diagnosed, a test would have indicated whether the couple's second child also was afflicted and they would have terminated the pregnancy, according to the lawsuit. Instead, Kousseff, a specialist in genetic disorders, told them they should be able to have normal children in the future.

As this CME course notes, malpractice judgments have been awarded for failing to perform carrier tests for Canavan's disease, thalassemia major, and fragile X. In some of these cases, the physician did not take a family history to determine if screening was indicated.

As genome sequencing becomes more and more routine, a positive family history will no longer be necessary to screen for all conditions before pregnancy. To quote the NIH Director again from the Language of Life:

If I were younger and about to start a family, I would want to test myself and encourage my wife to do the same - not just for CF but for a long list of recessive diseases...
Short of having complete genome sequences for all couples prior to starting a pregnancy, are other carrier screening tests being contemplated in the near future? Debates about the appropriateness of carrier screening will be likely to change in character in the coming few years, as more and more individuals will have complete DNA sequences of their entire genome determined, revealing all of their carrier status risks and providing an opportunity for couples to know about those risks prior to initiating a pregnancy. It is likely that within a few decades people will look back on our current circumstance with a sense of disbelief that we screened for so few conditions. They will also be puzzled and dismayed, as I am now, that our health care system put so many couples in an unnecessarily difficult position, by not identifying their carrier status until a pregnancy was already underway.

And as the former head of NSGC wrote presciently in 2007:

http://www.springerlink.com/content/v062153362074r28/fulltext.html

As the number of genetic carrier screening tests grow, it will inevitably become impractical or even impossible to continue to use the traditional model of genetic counseling as a prelude to obtaining informed consent. We anticipate a point in time when meaningful prescreening counseling about all of the available carrier screening tests will become impossible, making the counseling process either misleading or meaningless (Simpson and Elias 2003). Key issues are the capacity for health care professionals to convey the information, and more importantly, that patients may not be able to integrate the information in a rational way (Rodwin 1993), reflecting the limits of human decision-making ability.

To address these concerns, the concept of “generic” consent for genetic carrier testing was first proposed by Elias and Annas (1994). Generic consent emphasizes broader
concepts and common-denominator issues in genetic screening, such as the type of information sought, limitations of screening, the possible need for follow-up tests to
establish a definitive diagnosis, the reproductive options that might have to be considered, the costs of screening, and social issues, including confidentiality and the possibility of
social stigmatization. A key concept is that detailed information about any specific test or disorder (other than one used as a “generic” example) would be given only if a
condition was detected, although patients would still have the opportunity to receive more detailed information by requesting it at any time. The concept of “generic consent” for genetic carrier testing reflects a modification of the role expectation of the physician and patient in the face of the expanding number of genetic tests available and a decision to concentrate on what these tests have in common, rather than on what makes each of them unique. In the context of a large number of screening tests, this is more likely to be general information to help the patient to make an informed decision and try to prevent information overload that makes a reasoned decision impossible (Simpson and Elias 2003).

Lack of Awareness of Genetic Carrier Testing Prior to Pregnancy

Repeated statements by individuals attending the focus groups included the following: (1) that they had not been aware of genetic carrier testing in advance of our focus groups, (2) that they could not recall if they had undergone carrier testing, and (3) among those who had known of genetic carrier testing, the first time they learned of it was during pregnancy. Women in particular commented on how learning about genetic carrier testing during pregnancy changed the way they responded to the information. Specifically, that they were more likely to want to directly proceed with any test that was available based on their own anxiety about the health of the baby.

I’d like the information. Firstly, I’m confused why it’s only done when someone is pregnant. This information should happen in a physical exam. We should know this information about ourselves well before we’re even pregnant.... The second part to that, for me, once I was pregnant that mother instinct kicked in and I wanted to know everything. If there were a way they could make sure that the child has ten fingers and ten toes, I want that test done. Just any test—you can test me. I don’t care if it’s for white, black or Hispanic. ... Test me. Give me that test, so I can knock that off the list. Whether it’s a huge risk or not, if it runs the gamut of different diseases, I’m assuming that most women would want to know and would take it, especially if it’s a simple blood test. That’s what it is, correct? (African American Female <35 years old).

When the vendor discusses the sensitivity and specificity of Counsyl, is it for the alleles or SNPs which each "assay" is designed to find (ie, analytic validity) or is it for detection of the presence or absence of each disease/disorder (ie, clinical validity)? It is likely the values satisfying these different definitions of S&S are immensely different.