Author Archives: Katie Stoll

ACMG Carrier Screening Guideline: The Hypothetical “Tier 3” Panel

This post was modified on 3/30/2022 with input presented by some DNA Exchange readers.  First – the original post did not account for the fact that ELP1 is reported out as IKBKAP by Natera, SEMA4 and Quest. Table and graph were updated to reflect this. 

While the list of labs surveyed for this post was not intended to include all labs that offer carrier screening, it has been noted since this was initially posted that Fulgent does offer a carrier screening panel based on the ACMG Tier 3 recommendation. A paragraph has been added to reflect Fulgent’s test offering.

In July 2021, the American College of Medical Genetics and Genomics published a new carrier screening guideline, Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). The gist of this recommendation is that all individuals who are considering pregnancy or who are pregnant should be offered a carrier screening panel inclusive of 113 specific genes. In a prior post, Bob Resta and I shared our concerns regarding ethical issues and the ways in which this panel was designed.

With this post I have a practical question regarding implementation: How does one order a carrier screening panel of these ACMG-recommended genes when such a panel does not exist?  

A quick recap of the ACMG carrier recommendation. The guideline defines 4 tiers of carrier screening:

Carrier Screening Tiers defined in the ACMG Practice resource, Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG).

The carrier frequencies utilized are based on the public database gnomAD and represent carrier frequencies for any subpopulation that makes up at least 1% of the United States total population. 

The goal of this ACMG recommendation was to define a standard panel that could be offered to all patients. The guideline recommends that all patients who are pregnant or are considering pregnancy be offered the “Tier 3” panel, and that reproductive partners may also be offered the Tier 3 panel simultaneously. This panel is inclusive of 113 genes, 86 of which were derived from the gnomAD data as having a carrier frequency of 1 in 200 or higher; 11 additional genes were  “highly represented in one or more patient populations and have potential to be underrepresented in gnomAD”; and 16 genes associated with X-linked conditions with a prevalence of 1 in 40,000 or higher.

ACMG recommends against using the Tier 1 or Tier 2 panel for any patient. Further, it states that the Tier 4 panel be reserved “for consanguineous pregnancies (second cousins or closer) and in couples where family or medical history suggests Tier 4 screening might be beneficial.”

A huge problem with this recommendation is that the Tier 3 panel, as it is described by ACMG, does not exist as an orderable test through most labs. I have surveyed several labs, and those with the biggest commercially available panels do not provide coverage for somewhere between 25 and 49 genes of the 113 that are outlined by ACMG for the Tier 3 panel.  

Analysis of carrier screening labs performed on March 24, 2022. For a full list of genes by lab, see Table below. 

Some of the labs I have highlighted in this analysis have published press releases and sent emails to their client base in enthusiastic support of these guidelines that call for expanded carrier screening, even though NONE of them actually offer what ACMG currently recommends. The Industry lobbying group for Myriad, Natera, SEMA4 and ThermoFisher, the Access to Equitable Carrier Screening Coalition “applauds American College Of Genetics And Genomics” on this new recommendation that none of these labs can currently fulfill.  

One lab, Fulgent Genetics, offers a panel that is based on the Tier 3 recommendation, along with several caveats and limitations for some of the recommended genes that have common variants that may be missed or are expected to escape detection by their platform. While the Fulgent panel includes  all 113 ACMG-recommended genes, these caveats and limitations demonstrate that sensitivity across the genes included can vary dramatically and may be low in cases where the common mutation is a trinucleotide repeat, inversion or other alteration not reliably identified through next generation sequencing.  For example, Fulgent reports including FXN analysis on their panel with the caveat that their analysis will only detect sequence variants  which account for <5% of pathogenic  variants in this gene (the vast majority of FXN pathogenic variants  are due to GAA repeat expansion.)

Perhaps Fulgent along with other labs that are working to develop a panel that meets the ACMG requirements and will be able to identify most pathogenic variants in the 113 gene set.  It may be difficult to do this and keep the cost of testing down as there are technical challenges to assessing some of the genes that ACMG recommends. For example, the most common mutation in the F8 gene is a gene inversion. With PLP1 the most common mutation is a gene duplication. Rearrangements are common with the OCA2 gene. These technical variations present a challenge to labs as they expand their carrier screening panels. From the marketing perspective, adding 50 genes to their currently existing platform may seem more impressive than adding a small handful of more technically difficult ACMG-recommended genes.

Do obstetrical care providers recognize that when they are ordering an expanded panel that it may include hundreds of genes that are not recommended while missing several genes that are part of this ACMG-produced panel? What does this mean for our liability as providers when we cannot order a test that is recommended by our professional society? 

In a future post I plan to focus on carrier screening for cystic fibrosis and some of the harm seen from reporting practices on expanded carrier screening. But for now I would like to reflect back to the time when we first considered screening for cystic fibrosis, the rollout of which was not without challenges. Before guidelines were issued by the American College of Obstetricians and Gynecologists and the American College of Medical Genetics, there was significant preparation for implementation. Care was taken to determine whether we knew that the variants included on the CFTR panel cause disease. We thought we were clear about this but even with great scrutiny, the original 25 mutation panel included a variant that we eventually learned did not cause disease. There were standards written for laboratories regarding how to do the testing and what should be included in the report. There were educational resources developed for patients and providers. There appears to be much less care and preparation with these current guidelines in spite of the recommendations for testing for many more as well as increasingly complex conditions.

In today’s world of carrier screening, we see both the 113 gene Tier 3 panel recommended by the ACMG as well as commercial laboratories in constant competition to expand the size of their carrier panels. Yes, labs are expanding their genetic carrier screening offerings, but it does not appear (regardless of their marketing materials) that the recommendations from ACMG are the reason why. Even some of the biggest panels available don’t include 22-43% of the genes recommended by the ACMG while providing coverage for numerous genes that are not included in the recommendation. Data regarding performance characteristics of screening for many of these genes both within and beyond the panel are lacking. As a result, pre and post test counseling our patients regarding carrier screening and the downstream challenges are just going to become increasingly more complex.  

ACMG Tier 3 Panel
Labcorp / Integrated Inheritest® 500 PLUS Panel
SEMA4 Expanded Carrier Screen (502 Genes)
Natera Horizon™ 421
Myriad Foresight®
Invitae Comprehensive Carrier Screen
Quest QHerit(R) Extended
ABCA3
ABCC8
ABCD1
ACADM
ACADVL
ACAT1
AFF2
AGA
AGXT
AHI1
AIRE
ALDOB
ALPL
ANO10
ARSA
ARX
ASL
ASPA
ATP7b
BBS1
BBS2
BCKDHB
BLM
BTD
CBS
CC2D2A
CCDC88C
CEP290
CFTR
CHRNE
CLCN1
CLRN1
CNGB3
COL7A1
CPT2
CYP11A1
CYP21A2
CYP27A1
CYP27B1
DHCR7
DHDDS
DLD
DMD
DYNC2H1
ELP1
ERCC2
EVC2
F8
F9
FAH
FANCC
FKRP
FKTN
FMO3
FMR1
FXN
G6PC
GAA
GALT
GBA
GBE1
GJB2
GLA
GNPTAB
GRIP1
HBA1
HBA2
HBB
HEXA
HPS1
HPS3
IDUA
L1CAM
LRP2
MCCC2
MCOLN1
MCPH1
MID1
MLC1
MMACHC
MMUT
MVK
NAGA
NEB
NPHS1
NR0B1
OCA2
OTC
PAH
PCDH15
PKHD1
PLP1
PMM2
POLG
PRF1
RARS2
RNASEH2B
RPGR
RS1
SCO2
SLC19A3
SLC26A2
SLC26A4
SLC37A4
SLC6A8
SMN1
SMPD1
TF
TMEM216
TNXB
TYR
USH2A
XPC
As of March 23, 2022

Quest Diagnostics QHerit™ Extended

Myriad Foresight® Carrier ScreenUniversal Panel

Invitae Comprehensive Carrier Screen

Labcorp / IntegratedInheritest® 500 PLUS Panel

SEMA4 Expanded Carrier Screen (502 Genes)

Natera Horizon 421 (from printed materials provided by Natera)

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FDA Approval of Voxzogo – An Unmet Medical Need?

Last week, the U.S. Food and Drug Administration announced approval of Voxzogo (vosoritide), a drug developed by BioMarin for the purpose of increasing growth in children with achondroplasia. The drug is approved for children five years of age and older who have achondroplasia and open epiphyses, and is administered by daily injection. Voxzogo was approved by the European Commission (EC) in August of this year and marketing authorization reviews are currently in process in Japan, Brazil, and Australia.

This drug was developed specifically to target the effects of the FGFR3 mutation that causes the fibroblast growth factor receptor 3 to be overly active in people with achondroplasia, which prevents normal bone growth. The FDA cited this trial as the reason for the approval: a year-long, double-blind randomized trial (RTC) that showed an increase in growth (a mean of 1.57cm per year) in participants who received the drug. While some suggest that other health complications may be ameliorated by the use of vosoritide, that is purely speculation at this point. The FDA approval was based on the trial’s primary endpoint, “change from baseline of annualized growth velocity.”

The study reports:

“This study is limited in that direct evaluation of the effect of vosoritide treatment on final adult height and how this relates to functionality, quality of life, and activities of daily living in people with achondroplasia cannot be evaluated at this time. In addition, whether treatment with vosoritide will ameliorate the medical complications associated with achondroplasia and decrease the need for surgical interventions is unknown.”

Vosoritide was given the Priority Review designation by the FDA meaning that the review will be completed within 6 months. According to the FDA website, the priority review designation exists to “direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.”

While a spokesperson from the FDA proclaims that this approval “fulfills an unmet medical need for more than 10,000 children in the United States”, this drug is controversial among people living with achondroplasia and other types of dwarfism. Many believe that the approval of this drug based on the ability to only increase growth is centered on corporate interests to bring a high-cost commercial drug to market without evidence that health outcomes are improved and that this approval represents deep prejudice against people of short stature. 

Vosoritide was approved under the Accelerated Approval Program, which arose from the 21st Century Cures Act, signed into law in 2016. This accelerated approval program lowers the bar for what evidence is required for FDA to approve drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. Proponents of this accelerated program say that it will help bring important treatments to patients faster. Many have expressed concern though, that these speedy approvals are putting patients at greater risk of harm given that the long term safety of these drugs is not known. With the accelerated approval process, the FDA can require additional post-approval studies. In the case of vosoritide, the approval is conditional on post-marketing study that will assess final adult height. This means that the primary justification for the drugs approval has always been increased height (not reduction in health concerns associated with achondroplasia) and that BioMarin will be able to profit off the sale of vosoritide for many years before we are certain that the drug actually increases final adult height.  

An important question up for debate here is whether a drug’s ability to increase the height of people with achondroplasia by 6-8 inches is meeting an unmet medical need. Considering the potential health effects secondary to the bone growth changes in achondroplasia such as sleep apnea and spinal compression, we won’t likely have the answer to that for some time.

Is short stature in and of itself a “serious condition” or “unmet medical need”? Maybe the answer to that question depends on whether you are viewing it through a medical model of disability lens or a social model. The medical model would hold that the condition of the person causes disability and that medicine should aim to “fix” the condition of the person. The social model would hold that it is systemic barriers in society and discriminatory views that cause disability – it is the condition of our society that needs fixing.

There is reasonable concern that the FDA’s enthusiastic support to celebrate the approval of this expensive drug to increase height can only further support discriminatory views that medical providers have had towards people with disabilities by validating that short stature in and of itself is a medical problem that needs a cure. 

The CEO of BioMarin, Jean-Jacques Bienaimé, seems to have a medical model perspective on achondroplasia judging by this quote: “It’s the difference between being able to drive a car or not, reaching stuff in closets, being able to take care of your hygiene. It would make a huge difference for those patients. There’s no question about it.”  

Daily injection of this drug is not necessary to allow people with achondroplasia to drive a car, reach the items they need, or take care of their own hygiene. Of course people with achondroplasia perform these activities all the time with assistive devices and inclusive design. This statement from BioMarin’s CEO may represent ignorance about the capabilities of someone with achondroplasia or, perhaps more likely, may be a misrepresentation to hype the importance of vosoritide.  

The stakes are high for BioMarin here. The drug is priced at $320,000 per year for the treatment, and the stock value surged with news of the FDA approval of what is being called the company’s new blockbuster product. FDA approval is linked to insurance coverage for drugs. Medicaid and Medicaid have very limited ability to decline drug coverage for FDA-approved drugs. Private insurers also must cover FDA approved drugs, although there may be more financial burden put on patients with cost-sharing arrangements. 

I have been thinking a lot about this FDA approval and the bigger system we are now in with so much interest (and money) in drug development for rare disease. There is a lot to be hopeful about for people living with rare conditions, but pervasive discriminatory views against disability in combination with massive corporate interest to rush therapeutics to market is of great concern. 

The use of vosoritide and similar drugs is likely to expand in the years to come. Studies are currently underway looking at vosoritide use in infants, and also the use of vosoritide for children with other genetic conditions that cause short stature. I would imagine fetal therapy trials may not be long in the future. The increase in therapeutics for genetic conditions will of course also fuel the diagnostic industry. I predict that as the approval of vosoritide therapies expands to younger ages, genetic testing companies will use this as a selling point for testing. Companies such as Natera and Baylor Genetics have been promoting a prenatal cfDNA test that screens for achondroplasia and other single gene conditions, and the companies have been trying to make the case that this test could result in better outcomes for families by learning about a diagnosis earlier. Having a treatment that could be started in infancy or even earlier could help make this case. 

When news of this FDA approval broke, I first learned about it on this twitter thread by Dr. Joseph Stromondo, professor of Bioethics and Disability Studies at San Diego State University. In it he says, “Did anyone ever doubt this outcome, though? There is never a moment any of us leaves our house that we aren’t greeted with ridicule and hostility. Our bodies are regarded as public spectacle just for existing in the world. How could this outcome be any different? Of course someone would find a way to profit off of these stigmas and the fears they produce in average height parents. This was inevitable. I think the more critical questions surround our response to the drug, as a community of dwarf adults and allies. What do we do now?” He concludes, “we need to find new ways to live with dwarf pride and help families see what is possible for their LP [Little People] kids. We need to come together and focus on creating a space that celebrates our lives and bodies in an otherwise hostile world.”

The development of the drug, and now the FDA approval of vosoritide has been controversial among people with achondroplasia. While some see the development of these drugs as an attack on their very existence, others are celebrating the approval with hope of the possibility of health benefits that result from use of the drug. 

Little People of America (LPA), a nonprofit support organization for people with dwarfism and their families, seems to be trying to navigate the differing viewpoints on drug development. From this FAQ on LPA and Pharmaceutical Company Engagement they state, “We have long celebrated dwarfism as a valuable contribution to human diversity. LPA also values diversity within our own community and respects the choices of its members regarding medical intervention. While LPA has never actively promoted medical research aimed at treating or curing dwarfism, LPA is not opposed to medical research if it holds the potential to improve quality of life by treating symptoms that can range from uncomfortable to lethal.” More recently in a position statement on the FDA approval of vosoritide, the LPA states that “they strongly believe that a focus on growth velocity is a search for a pharmaceutical solution for a societal problem. We want to reframe priorities in research to the most meaningful ones for our members, such as reducing spinal stenosis, sleep apnea, and the need for corrective surgeries, as well as supporting other improvements in quality of life.”

The availability of vosoritide will present parents with a decision that will be difficult for many. How do you make a choice about treatment when the potential for health benefit and the possibility of risk are impossible to quantify? While people who themselves have achondroplasia have differing views on vosoritide, it is fair to say that people with lived experience will likely have more background information from which to draw on to make a decision about whether to consent to treatment for their children with achondroplasia. While I can imagine there will be enormous pressure towards use of the treatment by healthcare providers, with most babies with achondroplasia being born to parents of typical stature, they may not even be presented with the consideration that declining the treatment as a reasonable option.

Pharmaceutical companies that profit from drug sales (and also those companies that make the tests that diagnose the conditions) have an interest in selling their products. That is the role of a company, and their primary duty is to their shareholders: to profit on products they produce. These priorities are not unexpected, and the current regulatory framework encourages it. It is expected that the information coming from BioMarin and their partners (who will also profit from this endeavor) will highlight the positive, hopeful aspects of the drug and downplay the uncertainty and potential risks. We can expect to see mass marketing of this drug that promises hope of more healthy futures for people with achondroplasia, even though we don’t yet have proof that this is the case. BioMarin projects $1 billion per year at its commercial peak in sales from vosoritide. Their chief commercial officer, Jeff Ajer recently stated that the company has teams “in place and well-prepared for what could be BioMarin’s largest brand yet.” It is likely that the perspectives and voices of those with concerns about vosoritide will be drowned out by the mountains of money that will be used to promote these drugs. 

As genetic counselors we are often the ones who will be sharing information about what life with a genetic condition could look like for a family who is hearing of a diagnosis for the first time. As new medications targeting genetic conditions are developed, we will be at the forefront of supporting our patients in navigating information about new treatments. With this privilege, we also have a tremendous responsibility. It is crucial that we are clear and honest about the limitations and unknowns. I hope all of us will take great care in evaluating the complexities of new and emerging treatments. I hope we will critically evaluate the sources of the information we are sharing with our patients. I hope we will listen to the critiques and concerns from people with lived experiences with the conditions that we are counseling our patients about. We will better serve all of our patients when we are prepared for discussions about the ethical debates surrounding treatment and people with disabilities as a historically marginalized population. 

As we consider the growing options families will have to face when considering whether or not to treat their children with new pharmaceuticals, for which the long term outcomes are still unknown, I hope that we will check our own biases and do our best to provide a nuanced assessment of the options and the concerns. And in balancing the messaging that may be coming from the big money that drives so much of this, I hope we will also seek out and share perspectives from people whose voices may be harder to hear amongst the hype.

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An offer too good to be true? Might be a kickback.

Consider this imaginary scenario from three perspectives:

#1 You are an administrator for a large healthcare system in your community that is facing a greater demand for mental health services than ever before. Qualified mental healthcare providers are in high demand leading to psychiatrists and counselors demanding higher wages; yet reimbursement from Medicare and Medicaid haven’t kept up.

A well-known pharmaceutical company approaches you with a new program which includes a computer program that will interface directly with the healthcare system’s electronic medical record. This program has a suite of tools that will provide patient education, screen patients for depression and other mental health concerns and can make recommendations for treatment based on chatbots and pre-programmed algorithms. The program also allows for ease of ordering and delivery of medications, directly to the patients that are identified as possibly benefiting them. The system will check insurance benefits, handle billing, and provide education to the patient making the whole process seamless and burden-free for your clinical staff and providers. And the pharmaceutical company will provide direct access to mental health counselors and psychiatrists to take care of your patients when there are needs beyond what the chatbot and videos can provide. This is all offered to your healthcare system free of charge. This is a departure from how mental health services have been offered previously within in your healthcare system, however you are convinced that this program it would increase access to care that is desperately needed and greatly benefit your budget as well.  

#2 You are a psychiatrist that has worked in a community health practice for many years. The work is taxing and not well supported. When you were recruited by a pharmaceutical company it felt like an easy choice. The pay that was offered was nearly double what you were paid when working for community health and the perks, benefits and hours allow for a much-improved work-life balance. And with so many tools for efficiency and support, you believed that more patients would be reached in the system through access to medications than you could have ever reached through traditional clinical care.

#3 You work in business development for a pharmaceutical company. Integrating into healthcare systems with tools to boost clinic efficiency and support health care providers like free electronic mental health screening questionnaires and algorithms for treatment recommendations means that more patients will be reached, and more prescriptions will be sold. Direct access to patient information input into company tools, such as the questionnaires, as well as control over the tools and their internal algorithms mean that the company can engineer the tools to make recommendations for prescribers that will garner the highest payment from insurance payers. This direct access is solid gold in the pharmaceutical business. The salaries of psychiatrists and mental health professionals are easily paid for by a fraction of the increased revenues in prescription sales. And the opportunity to have psychiatrists and mental health counselors on the pharmaceutical company staff, to interact directly with healthcare system providers and staff as well as patients has shown to be a powerful sales tool that gives healthcare systems the confidence to utilize the company’s platform.

Could this scenario happen? If so, is there a problem with it?

Let’s first consider the positives:

  • Improved patient access for a needed service.
  • Earning potential for expert healthcare providers.
  • Pharmaceutical company is making a healthy profit (as a successful business should)

And the negatives?

  • The pharmaceutical company is essentially monopolizing prescribing for the healthcare system.
  • In the interest of profits, the pharmaceutical company is incentivized to influence prescribing to maximize reimbursement.
  • Excessive prescribing practices may result, that are not necessarily in the best interest of the patient and may incur great costs for the payers and broader health system.
  • The healthcare system is allowing sensitive patient information to be shared with the pharmaceutical company which may also raise patient privacy and data sharing concerns.

Such a scenario is ethically murky and likely would be problematic given state and federal anti-kickback statutes. While patient access to services may be increased, there is a risk that the profit interests of the pharmaceutical company would be prioritized over the best interests of the patients and the healthcare system.

The anti-kickback laws are intent-based, criminal statutes that prohibit intentional remuneration, whether monetary or in-kind, in exchange for referrals or other Federally funded health care program business.

From the Office of the Inspector General (OIG): The types of remuneration covered specifically include, without limitation, kickbacks, bribes, and rebates, whether made directly or indirectly, overtly or covertly, in cash or in kind. In addition, prohibited conduct includes not only the payment of remuneration intended to induce or reward referrals of patients but also the payment of remuneration intended to induce or reward the purchasing, leasing, or ordering of, or arranging for or recommending the purchasing, leasing, or ordering of, any good, facility, service, or item reimbursable by any Federal health care program.

Further the OIG  states that remuneration to encourage referrals in health care can lead to:

  • Overutilization
  • Increased program costs
  • Corruption of medical decision making
  • Patient steering
  • Unfair competition

The above imaginary scenario could be especially problematic given the involvement of healthcare providers, psychiatrists and mental health counselors. The practice of using physicians or other health care professionals involved in direct marketing activities has been termed, “white coat” marketing. See OIG Advisory Opinion No. 11-08: “White coat marketing is closely scrutinized under the anti-kickback statute because physicians and other healthcare professionals are in an exceptional position of public trust and thus may exert undue influence when recommending health care-related items or services…Given the nature of these relationships, when physicians or other health care professionals market items and services to their patients, patients may have difficulty distinguishing between professional medical advice and a commercial sales pitch.”

How does this connect to genetic counseling?

Currently, throughout the United States, genetic testing laboratories are approaching physician clinics, hospitals, and healthcare systems with proposals to help streamline genetic services. These laboratories promise a bi-directional interface with the local EMR to ease test ordering and reporting. They provide screening tools to identify patients who meet clinical guidelines for genetic testing and videos to provide information to support pretest consent. They provide insurance authorization and billing follow-up. And they provide genetic counseling support to patients who use their tests. Furthermore, the labs are often making big claims about the potential for downstream revenue that could be generated from more genetic testing in the system in terms of imaging, risk reducing surgeries, procedures, etc. that may be recommended once high-risk patients are identified.

Could any of these complementary services, in exchange for genetic test orders, be considered an illegal kickback or remuneration? Could the complementary genetic counseling services provided to patients be considered “white-coat” marketing? 

The answer to that question may depend on if there can be a monetary value assigned to provision of genetic counseling services. And, since genetic counselors aren’t recognized under federal CMS as reimbursable, it is possible that there is no clear assignable value for genetic counseling services that would be considered a remuneration by CMS.     

Genetic counselors are often leaving clinical positions for higher paying positions with industry, and healthcare organizations are finding it increasingly difficult to maintain their own locally hired staff. This taken with the fact that healthcare systems have difficulty getting reimbursed for independent genetic counselors who are on staff with their organization, offers of complementary lab-provided genetic counseling bundled up with ease in test ordering are appealing. Labs see marketing by genetic counselors as a powerful sales tool to increase genetic test orders and offer genetic counselors attractive positions in terms of pay and other benefits. And then labs make deals with hospitals, clinics, and healthcare organizations to offer full service genetic healthcare solutions by labs that want to be the one stop shop. With companies that have an interest in selling more and more tests, and healthcare systems having a hard time retaining genetic counselors or getting reimbursed for their services, we will likely see automated processes constructed by the labs to make recommendations about test orders.

I believe genetic counselors can offer excellent services regardless of who employs them. I know that many lab-employed genetic counselors are working hard and taking great care of their patients. And I believe that the tools that the companies provide do have the potential to expand access to genetic testing. What worries me though is that this expansion of testing may not ultimately be what is best for patients and will cost the healthcare system (and thus all of us) greatly. As this landscape continue to shift, with genetic counseling being offered as an incentive to promote test orders of specific test brands, the practice of independent genetic counseling services as we have known them may soon vanish. Our ability to provide unbiased counseling that allows patients to make informed choices about what is best for them (which may not always be a genetic test) and our ability to select that best test, regardless of testing laboratory, will be a thing of the past.

Legislation has been introduced that would allow for genetic counselors to be reimbursed by Medicare, Access to Genetic Counselor Services Act of 2021 H.R. 2144 and S.1450. Medicare recognition of the genetic counseling profession is crucial to ensuring access to independent services. Please consider contacting your representatives and senators to voice your support of these important bills. Learn more here.

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ACMG Carrier Screening Guidelines: Falling Short On Equity and Inclusion

by Katie Stoll and Robert Resta

The American College of Medical Genetics and Genomics (ACMG) recently published a new Clinical Practice Resource that they proclaim recommends an “equitable approach for offering carrier screening to all individuals during pregnancy or preconception.”

We recognize the drawbacks of a screening program based solely on reported ancestry or ethnicity. And we understand that ensuring the same standard of carrier screening is available to all patients regardless of race or ethnic background addresses an important equity concern. However, the ACMG guidelines fall short in several areas: 

  • Addressing the benefits of carrier screening
  • Questionable criteria for determining the severity of the included conditions
  • A limited definition of inclusivity
  • What choice patients should have in which conditions are or are not included in their personal screening.

The ACMG guidance is broad, calling for offering sequence-based population carrier screening for 113 genetic conditions to all patients who are pregnant or considering pregnancy. The rationale for expanded carrier screening according to the guideline is to allow for informed reproductive decisions. Specifically ACMG states that “reproductive decision making is the established metric for clinical utility of population-based carrier screening.” 

Five reproductive options are described in the guidelines: 1) In vitro fertilization with preimplantation genetic testing for monogenic conditions 2) Use of donor gamete/embryo, 3) Adoption 4) Prenatal diagnosis using chorionic villus sampling or amniocentesis followed by a decision to either prepare for an affected child including special care after birth or to terminate the pregnancy. 5) A decision not to have children. We would add a sixth option –  choice of reproductive partner, though perhaps this is more likely in situations of arranged marriages, such as with the Dor Yeshorim program.

Of these potential options, only one – prenatal diagnosis – is an option for those who undergo carrier testing during pregnancy, a fairly common occurrence. For most of the 100+ conditions included in the list, there is at best sparse evidence that prenatal preparation offers concrete medical benefits or that such knowledge enhances emotional preparation and psychological adaptation to having a child with one of these conditions. For a significant portion of patients who participate in carrier screening – those who are screened while pregnant – the only immediate benefits are either pregnancy termination or carrying to term. Therefore, the guidelines should also strongly recommend research into the specific ways that prenatal knowledge of any condition included in the panel either do or don’t enhance obstetric/neonatal management and/or parental emotional preparation and adaptation to having a child with the condition. Particularly for parents who would not consider termination or alternative reproductive pathways, we should be able to offer compelling evidence that carrier screening has measurable benefits for them and for their children if we are to claim that preparation is a benefit of screening.

ACMG states that they used “published definitions”’ to define the severity of genetic conditions considered for inclusion. The published definitions they are referring to come from one single study, published by Counsyl (now Myriad Genetics), a lab that was among the first to offer expanded carrier screening. In this study conducted in 2013, Counsyl surveyed people for whom they had emails in their internal database (presumably customers and/or staff) and asked respondents to provide their ratings of severity for five conditions that they felt represented a spectrum of health and developmental concerns. The outcome was responses from 192 genetic counselors and physicians. The opinions of these respondents is what ACMG is basing  recommendations for a mass population carrier screening program. 

The Counsyl study grouped severity into the following categories:

  1. Profound: shortened lifespan during infancy or childhood, intellectual disability; 
  2. Severe: death in early adulthood, impaired mobility or a [disabling] malformation involving an internal organ; 
  3. Moderate: neurosensory impairment, immune deficiency or cancer, mental illness, dysmorphic features. 

It is concerning that this study puts conditions that are associated with intellectual disability in the same group as those that are associated with death in infancy/early childhood. Also, if we look across the lifespan, many, if not most of us will experience some features that could be counted in the Severe and/or Moderate buckets. 

We cannot assume that this limited survey of healthcare providers is representative of the viewpoints of the US population. This survey did not include the perspectives of people who themselves have lived experience with the conditions included on the ACMG panel, or even people outside of the medical genetics community.

A condition that comes up frequently with expanded carrier screening is related to GJB2-related DFNB1 nonsyndromic hearing loss. GJB2 is included on the recommended ACMG panel on the basis of population frequency (second only to CFTR on the basis of current US-wide population frequencies) and in that it is considered of “moderate” severity based on the Counsyl study. Many in the Deaf community do not consider hearing loss a disability or disease, and we imagine many people who are homozygous for GJB2 mutations would not classify their hearing loss as a moderately severe condition.

We need to recognize that as much as we might try to avoid bringing our own biases into the way we counsel patients, or how we define the severity of a condition, the mere act of offering a prenatal test is not value neutral. There are negative associations implied for any condition we are including on a prenatal testing panel that by definition has a clinical utility metric of influencing reproductive decisions. We need to recognize our responsibility in that it is us in the medical genetics community who determine what is included on genetic screens, and we are also who defines what these conditions are in how we describe them to patients (be that in how we write a summary on a lab report or counsel people in clinic).

Stakeholder perspectives beyond the genetics community should be involved in development of these guidelines including what is included on screening panels and how we define these conditions for our patients. Perspectives from people with intellectual disabilities, the Deaf community and those living with cystic fibrosis, sickle cell anemia, spinal muscular atrophy, and other conditions being considered for inclusion on a carrier panel should have their voices included.

ACMG has been called to task previously on the issue of not including patient voices in the development of guidelines; see Nothing About Us Without Us: Guidelines for Genetic Testing.  And the National Council on Disability specifically recommended that “Professional standards of care for offering NIPS and other prenatal genetic tests should be established through consensus negotiations that include genetic counselors, obstetrics and gynecology care providers, and representatives from affected disability communities.”

Another concern not addressed in the guidelines is whether patients have a choice to not include certain conditions in a screen. For example, someone may wish not to screen for a specific condition given historical negative experiences of racial stigma and bias (see this interview and article to learn more about  problems encountered when carrier testing for sickle cell was introduced in the 1970s). Someone may wish to limit screening only to conditions for which we have a high degree of certainty of outcome, or only to conditions for which death in infancy/childhood is expected and for which there are no effective treatments. As Lisa Dive and Ainsely Newson point out in a recent thoughtful paper on reproductive carrier screening, some may find screening for life-limiting conditions to be acceptable and prefer not to screen for all conditions on a panel. If the goal of carrier screening is to support informed and autonomous choices, patients should be able to decide what is included on their screening.  

Concerns regarding how conditions were defined and about the lack of diverse stakeholder perspectives, including those with disabilities and genetic conditions, were raised with ACMG during the development of this guideline and no actions were taken to address them. In ACMG’s email announcement to members about the new Practice Resource, lead author Anthony R. Gregg, MD, MBA was quoted as saying, “The benefits of carrier screening are clear. The greatest benefits can be achieved by accepting the challenge that all women be offered carrier screening not during pregnancy, but as they move from being pediatric patients to patients requiring well-women care. Professional organizations must respond to this call.” At the same time, ACMG is pushing state legislatures to not allow genetic counselors to order genetic testing. For many patients, genetic counselors are a common point of contact in preconception planning and during pregnancy. It is hard to see how such a policy enhances equity and access to testing if a genetic counselor cannot order a genetic test.

We will be waiting to see how professional organizations respond to this call. While it is too late for change to come with ACMG’s publication, other professional organizations including the American College of Obstetricians and Gynecologists (ACOG) and the National Society of Genetic Counselors (NSGC) can do better and demonstrate a genuine commitment to advancing equity and inclusion for all people by including diverse stakeholder voices, including those with genetic conditions and disabilities, in the development of guidelines related to carrier screening.  

As the healthcare providers charged with the responsibility of guiding care, it is imperative that we do the important work of inviting all marginalized stakeholder populations to the table, hear their concerns, and address them before releasing guidelines that shape policies that will affect all of us. Equity extends beyond access to health services. As explained by Dr. Richard Besser at the Robert Wood Johnson Foundation:

Health equity cannot be achieved without actual lived experiences informing and advancing policies, regulations, laws and initiatives that address disability rights, accessibility and inclusion.

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Filed under Katie Stoll, Robert Resta

Bob has retired. What are the Resta us going to do now?

A few months ago, Robert Resta shared his plans to retire with the DNA Exchange author group. Retirement announcements have felt more bitter than sweet during these strange times of Covid-19 when we cannot gather to recognize the moment and celebrate the incredible careers of our friends and mentors. And what a remarkable career Bob has had. Following completion of his genetic counseling training at UC Irvine in 1983, Bob started work at Swedish Medical Center in Seattle, WA. He worked at Swedish for 37 years, first as the director of genetic counseling in the perinatal clinic and then founding the hereditary cancer clinic in 2006. It is pretty remarkable in this day and age when genetic counselors move jobs so frequently that Bob dedicated nearly four decades to one institution. In addition to counseling thousands of patients over the years, Bob has contributed much to the genetic counseling profession. He was on the editorial board for the Journal of Genetic Counseling for 10 years and Editor-in-Chief from 1995-2001. He has contributed to numerous books and has authored dozens of peer reviewed publications. And, to date, he has authored 117 essays for the DNA Exchange. 

While I had known he had been edging towards retirement for a while now, I had hoped that he would continue to provide his unique form of wisdom on DNA Exchange for years to come. He has said that he doesn’t think he’ll have much to contribute to the blog in his retirement and he encouraged us to think of bringing in new voices to this forum.

Although I wish him the very best in his retirement I hope he might speak up now and then. We have so much more to learn from him. Of course I understand that now that he is no longer working in a clinic, we will not see funny, thought-provoking, touching posts about patient interactions. And he may not keep up with what is happening with this lab or that lab to be able to offer his commentary on changes in the industry and how it is affecting patients.

I have appreciated every piece Bob has written, however what has been most important to me have been those that provide historical perspective. He has a remarkable gift for using a historical lens to provide context for what is happening today. And he has a unique gift for shining a light on even the darkest corners of our profession’s formative years with wit and wisdom that allows us to take in uncomfortable truths. We need to keep reflecting on this history as the field progresses.

If indeed Bob no longer feels inspired to write for the DNA Exchange (or even if he does) it is worthwhile to go back to the DNA Exchange archives and read his prior publications.

Fun Fact: the number one most popular post of all time on the DNA Exchange is, “And Bob’s Your Uncle: A Guide To Defining Great Aunts, Great-Great Grandparents, First Cousins Once-Removed, and Other Kinfolk.” This essay has topped the charts nearly every day since it was published, garnering over 189K views at the time of this post.

Some other fan favorites of Mr. Resta’s posts include:

p + q = Solved, Being the True Story of How the Chromosome Got Its Name

Why “H.R.3235 The Access To Genetic Counselors Services Act” Makes ACMG Feel Threatened By Genetic Counselors (Again)

Facts, Figures and Fictions in Genetic Counseling

What Do We Mean By “Psychosocial” in Genetic Counseling?

While many of his short essays provide historical context for genetic counseling he also has several that predict the future of the field. I will admit that I have lost sleep over some of these posts, at least the ones that I dislike his predictions. Perhaps this is because he’s been right so many times. It’s as if he has the power to set our destiny by putting words on the internet.

Work Shift: A (Wrong?) Prediction

Who The Hell Do We Think We Are? 12 Questions About The Future Of Genetic Counseling

Are We There Yet?

Will the DNA Exchange fade away without Bob? If asked, he might predict this would be the case. After all, he has written more than 40% of the content for this blog and has been our steadiest contributor since it was founded in 2009. But despite Bob’s facility for predicting the future, the fate of the DNA Exchange is really in our hands. This is a call to those of you among our genetic counseling who want to contribute and share your unique and diverse perspectives on the field we love. We need to hear from you!

The best tribute we could offer Bob is to help new voices keep alive the forum he helped to build. A new generation of genetic counselors has much to tell us.  I hope that some of you will choose to share those stories here, in the tradition of Bob Resta, the cranky and wonderful sage of genetic counseling. 

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Orig3n of the Specious

While the world grapples with a global pandemic with enormous cost of lives and livelihoods, some companies are finding an opportunity to make a quick buck from this crisis. One such company is the direct-to-consumer genetic testing company, Orig3n, Inc. DNA Exchange readers may recall that I wrote about Orig3n a couple of years ago when I sent a swab from my dog and tap water from the kitchen sink to Orig3n for their Child Development DNA test. In both cases, Orig3n issued test reports, failing to recognize that they were not human specimens. Given this experience as well as issues raised by numerous others, I was deeply troubled when I learned that the FDA had granted Orig3n accelerated authorization for a nasal swab based RT-PCR Covid-19 test. And unfortunately, I wasn’t surprised when news broke that Orig3n is failing in their Covid-19 testing

Last Friday it was reported that Orig3n miscalled several hundred Covid-19 tests for residents and staff at multiple long term care facilities throughout Massachusetts. Upon retesting by Orig3n and by the Broad Institute, 383 tests have been determined to be false positive. Previously, the Massachusetts Department of Public Health (DPH) specifically recommended Orig3n to long term care facilities and has required rigorous and widespread testing for staff and residents in order to qualify for a Covid relief funding. As of August 8th, the Massachusetts DPH has halted Orig3n from performing Covid testing citing the laboratory director’s failure in providing management and the lack of quality control measures in testing. According to Robin Smith, CEO of Orig3n, “We’re currently working with the state of MA to finalize steps that will enable us to resume testing in our Boston lab,” in a statement to the Boston Globe.

Orig3n did not only perform testing for long term care facilities in MA. They have also been lauded by public health officials for providing tests to unhoused people in the greater Boston area and have been contracted by State public health systems, schools, and long-term care facilities throughout the country. Orig3n’s Chief Executive Officer reports that the lab has processed tens of thousands of Covid-19 tests over the past 90 days. This news out of Massachusetts  may be just the beginning of the test failure story. Keep an eye on North Carolina where the state department of Health and Human Services contracted with Orig3n to provide Covid testing, setting up more than 300 test sites to increase testing access for African American, LatinX/Hispanic and American Indian communities. In early August there were reports of a Covid surge in NC. A few days after the uptick in Covid cases was reported there, there was a news report that test results sent to Orig3n would be delayed due to “unforeseen circumstances” and that the State lab would now be performing these tests.

The fact that Orig3n has become a major provider of Covid-19 tests despite numerous prior concerns is a massive public health failure. While we desperately need access to testing, it is imperative that this testing is reliable and from a trusted source. There were significant limitations and gaps in regulation of laboratory testing prior to Covid, and the hopes that oversight of laboratory tests would improve have been dampened by a recent decision from the current administration and the United States department of Health and Human Services that premarket review by the Food and Drug Administration (FDA) for laboratory developed tests will no longer be required. 

In 2018, after Orig3n released a test report for my dog and water from my kitchen sink for the Child Development genetic test, I filed official complaints about Orig3n with both the FDA and with the Centers for Medicare & Medicaid Services (CMS) – Clinical Laboratory Improvement Amendments (CLIA) Region 1. In these letters I outlined concerns related to the laboratory’s technical proficiency and professional oversight, the lack of clarity of how Orig3n would store and use collected biological samples, and the bioethical issues related to direct-to-consumer genetic testing marketed for children. I received responses from both agencies. From the FDA ,“We take such reports seriously, and we will evaluate this matter to determine what follow-up action is appropriate. The type and extent of any follow-up is dependent upon the nature of the problem, the possible impact on the public health, and the availability of our resources.”  And I was assured through multiple correspondence that the Massachusetts Department of Health and CLIA-Region 1 were investigating my concerns. It should be noted that I have not been alone in reporting concerns about this lab – for an excellent summary of the pre-Covid concerns, see this Businessweek article.

How is it possible that despite the many public concerns raised, Orig3n could be fast-tracked by the FDA and recommended by the MA DPH as a vendor for testing so important as Covid-19 – the same agencies that have been investigating these issues? Certainly, questions of false results should have risen to the surface as possibly “impacting public health” when the FDA was considering authorization for Covid-19 testing, right? I can only assume that in the end, FDA and CMS just did not have adequate available resources or the authority to fully investigate and consider this and other concerns raised over the years.

Orig3n has had a troubled history, but I fear that this lab’s story is just the tip of the iceberg, especially as there are really no barriers to entering the Covid-19 testing market short of being a CLIA certified laboratory (and sadly, that seems to be a pretty low bar). Today there is a long and growing list of commercial labs throwing their hats in the Covid testing arena. Many of these once focused solely on direct to consumer testing are now pivoting their focus to on the more lucrative Covid-19 testing. I am sure genetic counselors out there recognize some of the names on this list of tests who have received Emergency use Authorization by the FDA Covid-19 testing. Although all of these labs have been granted authorization, I am certain the quality of the testing among these labs is not equal. From my discussions with friends and family who have gone through Covid-19 testing, it seems that the lab that is performing a Covid-19 test is not usually made transparent to the patient. When you put your trust in your healthcare provider, school system, long-term care facility, employer, or public health officials – you may never know what lab is performing the test.

False positive and false negative tests are a possibility with any screening test. While the issue that came to light with Orig3n was false positive tests, false negative tests are also a problem with testing for Covid-19 and issues with false negative tests are probably more difficult to recognize by laboratories and public health officials given that most tests are negative. (Side note: this story highlighted a horrible situation of two women’s real health concerns being dismissed by the medical system because of false negative tests). The algorithm published by many labs is that if your test is positive, it should be treated as positive regardless of whether or not you have symptoms. But if your test is negative and you have symptoms, you should seek a second test. But is there any way you can make sure your test goes to a trustworthy lab? As a patient, is there anyway to even know for certain, what lab is performing your test?

While we are in desperate need of testing for Covid-19, we need to ensure that the available testing is reliable. Public trust in our health system and in science itself is already incredibly fragile and fast-tracking any lab that wants to get into the Covid-19 testing business will do more harm than good in the fight against this virus. We need more resources for, and empowerment of, our regulatory bodies, at both the state and federal level, to allow for review, oversight and consumer protection of laboratory testing. With time, this Covid-19 crisis will end, but the need for this type of oversight across all types of laboratory testing, including genetic testing, will not. Orig3n’s Covid-19 testing errors are a good example of the type of harm that will constantly occur without it.

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Is There A Doctor in The House? Physician-Mediated DTC Genetic Testing

23andMe has received a lot of attention as well as significant criticism from the medical community for their ever-expanding direct to consumer (DTC) genetic test offerings. While I share many concerns about 23andMe, it is worth noting that of the hundreds of tests that are directly available to consumers these days, 23andMe is the only lab that has received marketing authorization by the FDA for DTC testing. The only one.

These days anyone can easily order testing online directly from a number of companies, for themselves or their children – from pharmacogenomic testing to whole genome sequencing. How is it possible that so many labs are offering testing when only 23andMe has been given the green light by the FDA to offer DTC health risks tests?

One answer is so called ‘Consumer-Initiated, Physician-Mediated’ testing. With this flavor of DTC testing, laboratories can offer testing directly to consumers and bypass the need for FDA approval. So long as a qualified healthcare provider is involved in ordering the test, the FDA will continue to exercise their enforcement discretion and not get involved.

“As a matter of policy, the FDA generally does not review some types of tests, called laboratory developed tests (LDTs), that are created and performed in a single laboratory, if they are offered to patients only when prescribed by a health care provider. These tests typically do not have the FDA’s independent assurance of the analytical validity, clinical validity, or clear communication of test results.” FDA Website Updated 12-20-2019

I gotta’ say that I am baffled that consumer-initiated, physician-mediated testing is expanding so rapidly without any regulatory checks or balances. It seems like every other day there is a press release about a new partnership that enables labs to offer complex genetic tests, direct to consumer, with a physician’s order.

The biggest DTC genetic testing lab in the world by the number of samples, Ancestry.com (more than 15 million samples tested according to their website), recently announced that they are entering the health testing space and will be providing customers with some results related to hereditary risk for cancer, cardiovascular disease and more. And with their partner, Quest Diagnostics, Ancestry.com plans to release full exome data to customers later this year. However, unlike their main competitor, 23andMe, they are not offering this testing DTC with blessing from the FDA. Instead they have partnered with PWNHealth, LLC, so that their tests will be “physician-ordered” and thus escape the regulatory authority of the FDA. With this model, a test is selected and paid for online by the consumer, and then the lab requests a  physician at PWNHealth to authorize the test order.  

Ancestry.com isn’t alone in the decision to market complex medical tests directly to the public; PWNHealth also counts Invitae, Flugent, Sema4, Lineagen, Pathway Genomics, OneOme, Color Genomics, Ambry Genetics, and others as their partners. Just this past year, mega labs Quest Diagnostics and LabCorp launched new patient-initiated, physician-mediated lab testing, both partnering with PWNHealth. While PWNHealth seems to be a major player in this area of physician-mediated testing, the physicians working for PWNHealth aren’t the only ones signing test orders for consumer-initiated tests.

I know this from my personal experience of initiating one of these genetic health risk tests for myself. It was remarkably easy to order an extensive genetic test for hereditary cancer susceptibility. Ordering the test did not require me to provide health or family history information that would allow a physician to determine if this test was medically appropriate for me. In fact, all that was required for the test order was my credit card number and mailing address so that the lab could ship me a test kit. I returned my DNA-containing spittle never having talked about it with my own doctor, or any other doctor for that matter. Several weeks later, I received my results with a physician’s name and address on the report listed as the “Ordering Physician,” which Google Maps shows me is a UPS Store in a strip mall in Colorado (1,400 miles from my home state of Washington). This doctor was not a name I recognized from ordering the test, and I had no communication with him prior to, or in the time since my testing. Interestingly, I was able to find him LinkedIn where under Experience he lists: “PHYSICIAN OF RECORD (POR) services provided for DIRECT-TO-CLIENT laboratory testing.”

Consistent with this, while recently tuned into a webinar hosted by a lab offering a new consumer-initiated genetic testing product, a representative of one of the companies that provides physician “oversight”  stated that the physicians signing off on these genetic test orders do not have any expertise in genetics and at the company, “genetic counselors are considered the experts and the physicians approve or reject orders based on the genetic counselor recommendations.”

My sense is that the companies promoting and selling these consumer-initiated tests are getting a free pass for now because they provide genetic counseling along with the test results. Advocates of these consumer-initiated tests say that any pathway that allows people access to their own health information is a positive, and physicians that sign off these orders as well as the genetic counselors involved may feel that they are doing more good than harm by improving access to this information.

But the idea that a physician will, in exchange for payment, sign off on test orders for people who are not under their care is quite troubling to me. If these labs were billing CMS, such arrangements, which essentially pay physicians a fee in exchange for referral to the laboratory, may be seen as illegal kick-backs. In fact, the regulatory gaps that allow for consumer-initiated, physician-mediated genetic testing are the same ones that allowed one of the biggest Medicare fraud schemes of all time to take place.

What does the movement towards a growing number of these types of DTC testing options mean for the field of medical genetics?

Perhaps people will have greater access to genetic testing. But will the information received through these tests improve people’s health? Or will they lead to people receiving inaccurate, incomplete or misunderstood information? What are the downstream costs to our healthcare system to follow-up these results for tests that were never indicated in the first place?

What does it mean when the very same doctors are signing off on genetic tests that provide information such as results of pathogenic variants in genes for which we have proven interventions to improve health outcomes (e.g. BRCA and Lynch syndrome) are also signing orders for tests that make such evidence-less claims such as to design a DNA-based weight loss plan or to personalize your cannabis experience? Could this blending of evidence-based applications of genetics with snake oil damage trust in all of the work that we genetic counselors do? 

We are at an important crossroads where regulation and policy are needed to ensure responsible implementation of genetics in medicine. With this quickly evolving field there is an urgent need to address regulatory shortcomings with regards to genetic testing to reduce fraud and to ensure that people have access to high quality genetic tests and information. If medical tests are to be available directly to consumers, we need mechanisms to ensure that such tests have a high analytical and clinical validity and results must be comprehensible by those receiving them. Given the FDA’s current enforcement discretion of LDTs, we have no regulatory body accountable to see that this is the case. 

If the FDA continues to turn a blind eye to physician-mediated DTC lab testing, individual states may need to exercise their regulatory authority over the physicians who inappropriately order medical tests for people not under their care. In 2017, healthcare attorney and physician, Kimberly Lovett Rockwell, MD, JD  suggested in a JAMA Viewpoint article that state medical boards should consider sanctions against practitioners who work for DTC testing companies and order testing for any consumer without a medical history or examination, regardless of testing utility. Imagine all of the Medicare fraud that could have been prevented had such actions been taken a couple of years ago!

Lastly, one of the most important actions that will improve access to quality genetic healthcare and reduce inappropriate genetic testing would be CMS recognizing genetic counselors as healthcare providers (#supportH.R.3235 – Access to Genetic Counselor Services Act of 2019). Such recognition would allow reimbursement for genetic counseling services that are not tied to selling genetic testing products. Lack of fair reimbursement for independent genetic counseling has contributed tremendously to the shift of genetic services out of the traditional healthcare setting and into the consumer marketplace. CMS recognition would ensure the public that genetic counselors are subject to the same fraud, waste, and abuse laws and regulations as other healthcare providers and thus less likely to be unwitting parties to supporting DTC test schemes.

It is sadly ironic  that genetic counselors are faced with opposition to CMS recognition given the opinion by some that ordering and interpreting genetic tests is engaging in the “practice of medicine”, and should only be performed by licensed physicians. Yet at the same time, so many genetic tests are being ordered by licensed physicians outside of what is considered the standard and accepted “practice of medicine”.

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Guest Post: If Gay Means Happy, Then Why am I so Sad?

By Austin McKittrick

Austin is a genetic counselor for Genetic Support Foundation, a non-profit genetic counseling group, where he provides telehealth genetic counseling from his home base in Vancouver, WA. He a first time blogger, long time reader of the DNA Exchange.

 

A study recently published in Science sought to answer the age-old question: Where’s the ‘gay gene’? As a member of both the genetics and LGBTQ+ community, this headline naturally piqued my interest. I’ve always thought that this question is inherently a double-edged sword: by ‘proving’ that non-same sex attraction is in some way genetic, the whole ‘it’s a choice’ argument can finally be put to rest. But finding a scientifically detectable ‘cause’ for non-heteronormative behavior naturally brings up an equal (if not greater) level of concern.

The intentions of researchers are often not what is embodied by the products of that research. I honestly don’t think that the creators of genetic testing for ancestry thought that this testing would one day be used by the Canadian government to try to sort out where migrants to their country are ethnically from. But maybe they should have.

Even when we think we understand the genetics of a trait, the outcomes often aren’t as straightforward as we once believed. Particularly for a trait such as ‘nonheterosexual behavior’, where social, religious, family, and political influences also strongly affect one’s beliefs and how they may choose to reconcile those beliefs with their lifestyle. Genetics is leaping forward faster than the majority of us had probably anticipated, and we’re getting a real lesson about putting the cart before the horse.

There are some issues with how the study was conducted, as sexual identity is very complex and some of the questions have been viewed as being too binary and focused on behavior rather than sexual orientation. The researchers categorized people into two buckets: those who have EVER had ONE or more same-sex sexual experience are categorized as ‘nonheterosexual’ while those who have never had a same-sex sexual experience are categorized as ‘heterosexual’. They do make an attempt later in the study to outline that sexuality is a spectrum, but that assertion is buried amongst other extrapolations.

The data sets for this study were collected from the UK Biobank, as well as direct-to-consumer testing company 23andMe. Companies such as these encourage their customers to consent to having their DNA used for research, promising that their selfless contribution will further the field of genetics and healthcare. In all actuality, it appears that this data is being sold to entities that are using it for less medically noble endeavors. Aside from individuals not fully understanding that their data could be used for such ‘research’, they may actually unknowingly be participating in research that could potentially lead to discrimination and other harms against them in the future.

The authors of the ‘gay gene’ study determined that ‘like other behavioral traits, nonheterosexual behavior is polygenic’. There you have it folks: it’s not ONE gene. It’s LOTS of genes! Is that better? Worse? Depends on what you do with that information…

Enter GenePlaza, a company that boasts that it can take the DNA information that you’ve received from companies like 23andMe and Ancestry.com and use its internal apps to tell you things like how smart you are or how good you are at math (in case your grades in school didn’t tell you already). With data taken from this new study, GenePlaza proposed that for $5.50 they could tell you exactly how gay you are.

Backlash to the announcement of the app was swift, and a petition was quickly announced in an effort to get the app shut down. Although at the time of this publication it not yet reached its goal of 2,500 signatures, it appears to have been effective as there is no sign of the app now on GenePlaza’s app site.

It’s tempting to want to give GenePlaza the benefit of the doubt. ‘Oh they just thought it would be a harmless app’ or ‘They probably just thought it’d be a good party trick’. However, the revelations that the app’s developer, Joel Bellenson, is based full-time in Uganda paired with the news that this year Uganda is announcing plans that would make the death penalty punishment for homosexuality makes it seem that something more nefarious may be at play.

As the authors of the study said, we should resist ‘simplistic conclusions because the behavioral phenotypes are complex, because our genetic insights are rudimentary, and because there is a long history of misusing genetic results for social purposes.’

Some have raised concerns about the motivation of such research studies. But once something like this is out of the bag, it’s very difficult to put back in. No matter the motivation, this is another shining example that when it comes to genetic technology, we regularly need to be asking ourselves not only ‘Can we?’, but ‘Should we?’.

 

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MUTYH: Who should be screened? How should we screen? Who decides?

As recently discussed on the DNA Exchange, general population screening for any health condition has both risks and benefits, and sound health policy should weigh all of these factors to ensure that we are doing more good than harm. But the debate about what, who, and how we should be screening for hereditary cancer risk seems to be mainly an academic exercise practiced by some in the clinical genetics and public health communities. While we continue to debate the merits of population screening, the commercial laboratories keep pushing forward, making these tests readily available to the general population through direct to consumer (DTC) testing products.

Often the cancer genetic test isn’t the main product that the customer is seeking, but rather may be a bonus of sorts provided along with ancestry and other DTC tests. Such is the case for the new health reports for MUTYH variants that 23andMe began releasing this past summer. Individuals who inherit one MUTYH pathogenic variant may have a slightly increased risk for colon cancer. Individuals who inherit biallelic pathogenic variants have a very high risk for colon polyps, colon cancer and other cancers and are said to have MUTYH-Associated Polyposis syndrome, or MAP.

Earlier this year, 23andMe received clearance from the FDA to release information about two variants in the MUTYH gene that are common in individuals of European ancestry – G396D and Y179C. The basis for this 510(k) approval is that it is substantively equivalent to the 23andMe BRCA test (which evaluates for three founder mutations most common in individuals of Ashkenazi Jewish ancestry). The company recently reported that they have over 10 million customers, with approximately half of those accessing the health portion of the testing (in contrast to ancestry alone). And considering that about 80% of those customers are of European ancestry, I estimate that of the approximately 4 million people received the new new MUTYH Genetic Health Risk report. Through this report. I estimate that about 250 people may have learned that they have MAP and about 60,000 customers learned that they are carriers for one of these two MUTYH variants. 

So who should be screened for MUTYH variants? If you ask 23andMe the answer would be everyone. How should we screen? According to 23andMe, screening should be done by a two variant genotype panel. And who decides who is screened? From what I gather, this new health report was not driven by customer demand, nor were healthcare providers calling for more access to MUTYH testing. Generally our guidelines recommend MUTYH testing only in very specific circumstances, such as when a patient has multiple adenomatous polyps, or if they have a sibling who has been diagnosed with MAP. But it is not the healthcare providers or guidelines directing who is screened. Presently it would seem that 23andMe decides who gets screened for MUTYH variants, and with the blessing of the FDA. I am curious to know how my genetic counselor colleagues are handling or are likely to handle such cases. What would you most likely offer to a patient that comes for genetic counseling with a heterozygous positive DTC MUTYH variant report, and no family history concerning for MUTYH polyposis or other hereditary cancer syndrome?

 

My hunch is that most genetic counselors would offer follow-up clinical testing, and that this will usually be at a minimum a full analysis of MUTYH. I certainly can see the benefit of identifying patients who have biallelic MUTYH variants to allow for earlier and more frequent colonoscopy screening and prevention of some cases of early onset colon cancer for those who may not otherwise have known that they were at increased risk. Since the announcement of the new health reports by 23andMe I have been curious about how many individuals with MAP could be identified through this stepwise screening, first with 23andMe and then follow-up clinical testing of the entire MUTYH gene for all of those who first have one or two variants detected through 23andMe.

Staying with the estimated 4 million 23andMe customers of European descent who opted for the health reports, I estimate that there are about 390 total people out of the 4 million who have MAP, and of these about 250 would be identified through testing the two common variants alone (homozygous or compound heterozygous for Y179C/G396D.  (My calculations and assumptions are all available here.) Through this stepwise screening of sequence analysis only for those who are first found to have at least one common variant, we would identify approximately 374 of the total 390 people with MAP, while missing about 16 people who carry two less common MUTYH variants. The cost per MAP case identified depends on the cost of follow-up genetic testing. Publicly available pricing suggests that single gene analysis of the MUTYH gene through a clinical lab is typically between $500-$1,500 per test for complete single gene analysis, although clinical testing may be priced as low as $250 to more than $2,000 per test. Thus, through this stepwise process (full gene analysis for those with one or more common variants first identified) the cost for clinical genetic testing would be somewhere on the order of $42,000 – $378,00 per MAP case identified. Given that general population guidelines recommend colon cancer screening should begin at age 50 and because approximately 75% of colon cancer in individuals with MAP occurs in patients under the age of 50, this genetic screening approach, and initiation of colonoscopy screening at an earlier age than typically recommended, could prevent as many as 94 cases of early onset colon cancer in this 23ndMe screened group, with cost per case prevented in the range of $168,000 to 1.5 million. It is important to note that this only considers genetic testing. A more complete economic analysis may include genetic counseling costs, additional cancer screening costs, as well as the estimated cost for genetic testing in other family members.

23andMe isn’t the only company that has an interest in MUTYH screening. Several labs offer DTC, or the close relative of DTC testing, the so called “patient-initiated, physician-mediated” testing in which an individual may request testing themselves, and a physician contracted by the lab signs off on the test order to bypass the need for FDA scrutiny (a discussion for another post). MyHeritage, who previously offered only ancestry testing recently began offering a “health” component which includes four variants in the MUTYH gene (including the two common European variants). Color Genomics and  Invitae  both consumer-initiated, physician-mediated tests as well as clinician ordered tests that provide a more complete analysis of MUTYH and other cancer susceptibility genes. 

Is more comprehensive testing such as full gene sequencing better when it comes to MUTYH testing in the general population? It depends on how better is defined. I can certainly appreciate that detecting those additional 16 individuals with MAP (and being able to prevent about 4 cases of early onset colon cancers) that would have been missed in our 23andMe population of 4 million people would be one benefit to more comprehensive testing. But what’s the trade off? 

At the recent American Society of Human Genetics meeting in Houston, Invitae presented data reviewing MUTYH variants found in analysis of a cohort of 270,806 patient samples that were submitted for multigene hereditary cancer risk panels. They reported that through a more complete analysis of MUTYH they discovered 5,929 patients with pathogenic or likely pathogenic variants in MUTYH, of which 1,377 (23%) of these patients carried one or more variants other than G396D and Y179C. That’s no surprise – in fact it fits well with our current understanding of the population frequencies for these genetic variants as well as our appreciation that about 80% of variants detected through MUTYH testing in a population of mostly individuals of European Caucasian ancestry are the G396D and Y179C variants.

The presented statistic that is getting the most attention in the news since the meeting is Invitae’s assertion that 40% of individuals in the cohort with biallelic mutations would have been missed by the targeted variant testing. But the necessary context that is missing here is that about 90% of those that would be “missed” in that 40% would have one of the two common variants paired with a second other, undetected variant. Through a stepwise approach in which only individuals with one or more of the common variants on first screening through 23andMe had follow-up clinical sequence analysis, approximately 96% of the total MAP cases would be identified. That means there would be only about 4% of individuals who would have biallelic variants that both would have gone undetected by a stepwise approach that begins with a two-variant screen.

If we were to ask Invitae who should be screened, I believe they would likely agree with 23andMe that everyone should be tested. Where they differ is in how the screening should be done, with Invitae advocating for more complete next generation sequence analysis for all people rather than targeted SNP panels. I can appreciate the logic in this argument that this strategy would detect more cases of MAP, especially in people who are not of European ancestry. But how would the cost of testing compare for the number of cases detected? The devil is in the details of how this testing is done and who pays for it. Invitae currently offers a patient-initiated, physician-mediated cancer gene panel for $250. If people elected this test and paid for it on their own instead of having 23andMe, given that it is considered a clinical test and no follow-up studies would be needed, then we would not see the additional cost in follow-up clinical testing (although we may see more downstream costs with follow-up for variants, including variants of unknown significance in other genes on the panel). My sense though is that people seek out tests like 23ndMe for reasons other than to know there MUTYH or other cancer gene status. So if we are considering the total cost of clinical testing for all people rather than just for those who present with at least one of the common mutations on a screening DTC test we would see quite a dramatic increase in the cost to identify a case of MAP as well as the cost to potentially prevent a case of colon cancer before the age of 50 (61-fold increase over the stepwise approach).

What is difficult to tease out in these analyses is that most tests that include MUTYH are not ordered with a high suspicion or concern for MAP. In most cases, it is included as part of a bigger panel, and MUTYH is not the primary reason for testing. In the case of 23andMe it comes along as part of a bigger ancestry, traits and health screen. In the case of Invitae it usually comes along as part of a multigene cancer panel for which the primary indication is usually for evaluation of genes other than MUTYH. So should we consider that extra information provided by the MUTYH analysis in patients a bonus or a burden? As DTC and consumer-initiated testing becomes more common, and as clinical testing panels more often include MUTYH, are we spending more time counseling patients about MUTYH results that are unlikely to significantly affect health outcomes or screening recommendations for the patient or their family members? I worry that patients may put too much value on these results as a possible explanation for their cancer, when it may unlikely be the case. And I feel conflicted about how much we should be advocating for family member testing when there is such a small chance that their care and outcomes will change as a result. 

The focus right now seems to be on the question of how we should be screening for MUTYH. I think we are engaging in the wrong discussion here – I think we should go back to the heart of this and really take a close look at why we are doing this testing?  What is driving adoption of expanding genetic testing to include analysis of genes such as MUTYH? And how should we integrate these technologies into practice in a way that will help the most people and cause the least harm. We need to critically consider the statistics that are presented and carefully weigh the costs versus the benefits of expanding testing. 

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Given that we are just a week away from the annual NSGC conference, I’d like to make a plug for the 3rd annual ‘GC’s Got Talent’ hosted by Genetic Support Foundation on November 6th from 7-10 pm. The event will be Emceed by the ever engaging and talented DNA Exchange blogger, Bob Resta. In addition to storytelling, dancing, singing and comedic acts, a silent auction will showcase the artistic and creative talents of GCs. It’s not too late to sign up to share your talent and we are seeking storytellers for the themes: “Confessions of a Genetic Counselor” or “Most Awkward Moment in my Career”…Contact  info@geneticsupport.org for additional info.

2016 talent show

 

 

 

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Mind Games

As is the case with many topics in genetics, I learn the most in my time away from the office, researching questions for friends and family. And the genetics questions du jour are almost all related to pharmacogenomics (PGx) testing. More specifically, PGx testing for psychiatric medications. Maybe you are getting these questions too? For me, they usually go something like this:

Are these genetic tests that promise to tell you what

antidepressant medication will work best for you a real thing?

And if they are, why isn’t everybody taking them?

I have witnessed friends and family members struggle with medication management for depression, anxiety and mood disorders. People in these situations are often desperate for help and quite vulnerable. I can fully appreciate the hope that a simple genetic test could provide the answers to ease the journey. But as we find with many things in genetics, the reality is much more complicated than the hopeful answer we wish we could give. Ultimately, I know my position on this will disappoint many who are looking for that silver bullet. While there are a handful of applications for pharmacogenomics in specific situations related to psychiatric medications that have evidence to support their use, there is little evidence that multigene panels in this area lead to better outcomes. There is concern that harm may come because of the use of this unproven information to guide important decisions with prescribing and dosing of psychiatric meds. 

My conclusions regarding these tests are in part based on critiques from reputable sources on the current state of commercially available PGx psychiatric panels, including the American Psychiatry Association Workgroup for Novel Biomarkers and Treatments. This workgroup performed a detailed review of several commercially available tests and concluded that there is a lack of sufficient evidence to support the widespread clinical use of the proprietary combinatorial pharmacogenomic models used by these labs. There are many publications that highlight issues with existing studies about these tests including concerns related to conflict of interest and problematic study design. The financial sector is also following this topic closely given much has been invested based on the promise of these testing products being adopted broadly. Recognizing the strong commercial drivers at play here also causes me to view laboratory claims with a dose of skepticism. 

But when it comes to the general public, I think the commercial push to see these tests more broadly adopted is drowning out the voices of the experts who are urging caution. It seems that since many in the field of psychiatry aren’t convinced that these tests are ready for prime time, the labs have decided to bypass the most relevant specialty, and go straight for patients and primary care providers. Additionally healthcare payers are banking on the promise that these PGx tests will more than pay for themselves by allowing for better precision in prescribing of expensive medications. Payer support is helping to move psychiatric PGx testing to the mainstream.

New pharmacy-laboratory partnerships are emerging to promote these tests. Last year, PGx lab Genomind®  announced a partnership with Albertsons Sav-On, Jewel-Osco and Acme Sav-On pharmacies: pharmacists can discuss PGx testing with patients and, if the patient consents, the pharmacists will directly contact the prescribing provider to “suggest the Genecept® Assay. ” The  sample can be collected right in the pharmacy. Last month, Myriad Genetics, Inc. announced a similar program with Kroger Prescription Plans to promote GeneSight®  genetic tests in Kroger pharmacies. From the GeneSite® press release: “pharmacists at more than 2,300 Kroger stores will provide counselling about GeneSight® to eligible employer group members and facilitate testing with their prescribing healthcare professionals.”

Pharmacists are now direct marketing genetic testing to patients. And while members of the pathology and clinical laboratory space are taking some issue with this, there hasn’t been much public concern raised by the broader medical genetics community about this proposal to have pharmacists providing “genetic counseling” and facilitation of genetic testing.   

It will be interesting to see how these programs evolve with greater attention from regulators. With several years of push and pull between labs marketing these tests and clinicians raising concerns about their clinical utility and safety, the FDA has recently started to flex their regulatory muscles in this space. In Oct 2018, the agency published a Safety Communication, warning patients not to change management based on PGx results without first discussing with their healthcare provider and to be aware that claims made by genetic testing laboratories about PGx tests are not supported by sufficient clinical evidence. The FDA cautions healthcare providers in the use of these tests and directs providers to FDA-approved drug and genetic test labels. Lastly, the communication advised test manufacturers not to include specific drug information that is inconsistent with FDA-approved drug labeling. In April, the FDA sent a letter to Inova Health System with concern that the clinical validity of their PGx tests had not been established for the reported intended uses. Shortly after this letter was issued, Inova elected to cease offering their MediMap® tests. The FDA has been in communication with several other laboratories and stated that “most firms addressed the FDA’s concerns by removing specific medication names from their labeling, including promotional material and patient test reports.”

Some of the critiques I have heard about the FDA’s engagement in regulating these tests is centered around whether or not the FDA should be the authority on the evidence required to support the relationship between certain variants and drug metabolism. A frequently referenced pain point is the difference between the PGx genes/variants that make the cut per FDA drug labeling and the evidence grade rating per the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC). In looking at most of the commercially available PGx tests on the market today though, it is clear that many of the variant-drug connections included on lab reports are not consistent either with the FDA-approved list or with CPIC guidelines

For example, the sample GeneSight® report available online as of the day of this posting, under the category of “Mood Stabilizers” shows three drugs in the red bucket, “Significant Gene-Drug Interaction” and no drugs in the green, “Use As Directed” bucket. Top of the red list is lamotrigine (Lamictal®), which has a footnote that reads “Use of this drug may increase the risk of side effects.” The justification given in the Gene-Drug Interactions table is a variant in the UGT1A4 gene. Search of the CPIC database gives the UGT1A4 – lamotrigine pair a “D” level rating. According to the website, the CPIC D Level is defined as follows: “There are few published studies, clinical actions are unclear, little mechanistic basis, mostly weak evidence, or substantial conflicting data. No prescribing actions are recommended.” How might this report affect a person with bipolar who is struggling to find the right medication? One can imagine that it may be difficult for both the patient and the prescribing provider to feel comfortable with a treatment plan when not supported by this genetic test report.

For the same GeneSite® sample report, under the “Antidepressants” heading, there are a total of 22 antidepressents for which analysis is available, with only three in the “Use as Directed” green bucket. Top of that long list of 22 drugs in the red, “Significant Gene-Drug Interaction” bucket is bupropion (Wellbutrin®). Bupropion is a medication commonly used to treat depression and has been approved by the FDA for use since 1985 with a generic version of this drug readily available. There is no data in the CPIC database to support the assertion made my GeneSight® of a “Significant Gene-Drug Interaction” with bupropion. And interestingly, the only three antidepressant medications that made it to the green “Use as Directed” category are expensive drugs for which no generic version is available: levomilnacipran (Fetzima®), desvenlafaxine (Pristiq®), and vilazodone (Viibryd®). If I received this report and didn’t know better, I might assume that these drugs would be worth the high price tag if they are genetically the most likely to treat depression without the potential for side effects. There is no gene-drug information in CPIC about any of these three preferred medications, and I didn’t have to look very far beyond the GeneSight® report to see the long list of side effects and contraindications associated with each of these medications. But imagine the difficulty a prescribing provider might have in convincing a patient to consider forgoing the expensive new drugs in the green bucket to consider a more affordable medication with a longer history of success in treatment from the red bucket. Lab reports are not often looked at as one piece of the puzzle, but rather as the *truth* by patients. And as I have previously written on a different topic, it is incredibly difficult to convince a patient that an expert assessment may be more trustworthy than what is printed on a test report. 

Regulation of genetic testing is a big and thorny issue, and I don’t claim to have easy solutions for improving these challenges. But what I do hope to do is to begin a conversation with my fellow genetic counselors on what role we should have in the dissemination of information regarding PGx testing. I feel it is our professional obligation to understand, to the best of our abilities, the evidence or lack thereof when counseling our patients, consulting with other healthcare providers and discussing these tests with friends and family. When people first started asking me about these tests, my initial feeling was one of hope and optimism. Of course it would be wonderful if a simple genetic test could provide a clear path towards the best medication for those who are suffering. Now, after having spent hours down the rabbit hole to try to better understand the current state of this field, I remain hopeful that these tools may someday provide real benefit for the masses. Unfortunately, it seems to me that at the present time, this wild west of the competitive genetic testing marketplace has resulted in bigger but not necessarily better panels, including information that is often not evidenced-based. I worry that these reports could lead people down a wrong, and potentially dangerous path.

So for now when my loved ones ask me, “are these genetic tests that promise to tell you what antidepressant medication will work best for you a real thing?” I will give the more cautious and complicated answer. While this technology holds promise for the future, the evidence we have at this point does not support that these tests will help guide better care and lead to better outcomes for most people. And I will continue to do my best to support them on the journey forward, wherever the bumpy and winding road may lead.

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