Unprofitable Genetic Testing Labs – The Size of the Loss, The Reasons for the Loss, and What It Means for Genetic Counseling and Genetic Counselors

By Katie Stoll, MS, Jessie Conta, MS, and Michael Astion, MD, PHD

Genetic counseling is a critical part of the genetic services process, beyond just coordination and ordering of a genetic test. However, as the genetic counseling profession has grown alongside the expansion of genetic testing, it has become increasingly intertwined with and dependent upon the financial success of commercial genetic testing laboratories. The relationship risks undervaluing genetic counseling and the breadth of the services genetic counselors provide.

The genetic testing industry has seen rapid growth over the past two decades, with many new companies and billions of dollars invested into start-up genetic testing labs. Despite the enthusiasm of venture capitalists and other investors, commercial genetic testing labs are largely unprofitable, and the losses are significant and sustained. This is shown in Tables 1 and 2 below which are derived from analyzing publicly available, quarterly and annual financial reports (10-Q and10-K Filings) of publicly traded companies whose primary business is clinical genetic/genomic testing.

As shown in the tables, it is common for publicly traded, genetic testing labs to report annual losses of >$100 million. In 2021, only one lab, Fulgent, made a profit (Table 1). However, Fulgent’s 2021 – 2022 quarterly reports (Table 2) indicate that profits aren’t attributable to genetic testing, but rather to COVID test sales, which accounted for ~88% of their 2021 revenue. Myriad has seen a consistent decline in revenue since the US Supreme Court’s ruling in 2013, which forbid human gene patenting and therefore caused Myriad to lose their lucrative BRCA testing monopoly. Although the losses have not been as severe as their competitors, Myriad has not been profitable since 2019, and they have reported greater losses in the first two quarters of 2022 than their annual loss in 2021.

Profit and loss data is difficult to obtain from private genetic testing companies such as Color Genomics, as well as from genetic testing labs owned by much larger, diversified companies, as is the case with Ambry being owned by Konica Minolta. Similarly, profit and loss data on genetic testing is unavailable from integrated health systems, academic medical centers, or publicly traded labs –like Quest, LabCorp, and BioReference— who only have a small portion of their overall testing business in genetics. In regards to academic labs and labs in integrated health systems, our experience, as well as discussions we have had with colleagues strongly suggest that genetic testing is performed at a financial loss, and that it is the overall profit of these full-service labs that allow them to support genetic testing.

Why aren’t genetic testing companies profitable?

Publicly traded genetic testing labs are unprofitable for a variety of reasons. The top reasons are poor reimbursement from insurance plans and patients; intense competition; and excessive expenses for sales, marketing, and executive compensation. In addition, the inclusion of genetic counseling, which companies have highly valued as part of their testing service, adds an expense that is not seen in the other analytic sections of a full-service clinical lab.

Insurance reimbursement

The service of genetic testing is a costly one to deliver and is much more expensive than a lab’s cost to perform other tests. For example, the fully loaded cost of performing a typical test in a highly automated, hospital-based core laboratory is in the range of $10-$20 per test. This includes common tests like complete blood counts, electrolytes, basic coagulation tests, thyroid screening tests, and liver function tests.  For an insurance plan this type of common testing is >65% of their expenses. The cost to labs of genetic testing is much higher, often 10-100-fold higher. Genetic testing usually represents < 20% of an insurance plan’s spending on lab tests.

Why is genetic testing so costly to labs? The main reason is that it is difficult scale genetic testing in a manner analogous to common, high-volume laboratory tests. Compared to common tests, genetic testing is more labor-intensive, more time consuming, involves higher-wage staff, and involves technology that has a higher cost per test. Genetic testing is time consuming because it requires complex tasks not seen with common tests, such as variant analysis, curation, review, and updating. And for many companies, it also includes providing the genetic counseling service, which is often bundled into the service of providing the test. Overall, genetic testing is a personalized, complex technical service which has resisted, for now, the type of full automation that has benefited other parts of the clinical lab.

The high cost for performing genetic testing necessitates high costs to patients and their insurance companies. Historically, insurance companies are mediocre at regulating high-volume, low-cost lab tests because it is too cumbersome and expensive to manage. However, insurance companies have many effective tools for regulating high-cost procedures, including genetic tests. The result is that high-volume, low-cost laboratory tests have a relatively open door to reasonable insurance payments, and insurers invest only a little energy toward closing that door. In the case of genetic testing, the door is closed or only partially open.

Besides negotiating fees with certain labs, the main method that insurance plans use to control genetic test reimbursement is detailed medical necessity policies tied to preauthorization systems. Insurance companies either develop the policies and pre-auth systems or purchase them from third-party benefits managers. Overall, the method involves using software that aids decision making in combination with genetic counselors, nurses, and physicians who adjudicate cases at various decision levels. This approach is then married to an insurance plan’s usual and customary procedures for handling grievances from patients and labs that have been denied payment. For insurance plans, this type of complex system, which is both software and labor intensive, would have a poor return on investment if applied to low-cost, high volume lab tests. But for genetic testing, this type of system has an excellent return on investment, and so insurers are highly motivated to regulate genetic testing. In addition, these insurance systems tend to be overly tuned to block fraud, waste and abuse, and often delayed in keeping up with scientific evidence. Therefore, insurance systems may block some medically necessary genetic testing.

Patients bear high out-of-pocket costs for genetic testing. This is because they are financially liable when their insurers do not cover the test, and, even when insurers provide coverage, there still can be high deductibles or co-pays. In the laboratory industry, it is very expensive to recover the money that the patient owes, and poor financial recoveries from patients is common. This failure to recover the patient portion of the bill adversely affects the bottom line of genetic testing labs.

Response to poor reimbursement from insurers and patients

Many labs performing genetic testing have responded to preauthorization requirements by investing in resources – which sometimes can create an entire division or department – that provide support with prior-authorizations, as well as appeals and support when test coverage is denied. This can help grow the testing business because it removes a barrier that blocks some providers from ordering testing. However, the removal of the barrier comes at a high cost to the genetic testing lab.

To help patients directly, some labs have promised patients low out-of-pocket costs either through reducing the patient’s responsibility under their insurance plan, or by promoting self-pay options that avoids involving the insurance plan. Thus, some labs promise patient out-of-pocket maximums, typically advertised as about $100 when insurance does not cover testing.

For self-pay options that do not involve insurance, the price for genetic testing for patients is often much lower than the list price available to care providers, and it is highly likely that price does not cover the costs of the tests. The current going rate at most labs for self-pay testing for multigene panels is around $250, which is usually much less than what labs try to collect from payers, including Medicare and Medicaid for the same test.

Sales and Marketing

A review of publicly available, 10-K submissions, show that it is not unusual for genetic testing companies to have marketing and sales budgets around 40-50% or more of revenue, which is much higher than typically seen in established, full service clinical laboratories. This most likely relates to the goal of growing revenue and capturing market share, despite the high cost of achieving this in a competitive, and poorly reimbursed business. Those NSGC parties, sponsored luncheon and dinner events, “free” CEU opportunities, and even the complementary genetic counseling, all come at a cost for the marketing and sales budgets of these companies.

Executive compensation

Another contributor to financial losses in publicly traded genetic testing labs is the high pay of executive leadership, including chief executives. Review of executive compensation data shows that executive pay is often inversely correlated with net profits – the longer that a company lasts, regardless of how deep the losses grow, executives tend to be well rewarded. For example, Natera reported compensation for the company’s chief executives totaling $8 million while company losses totaled $128 million in 2018. Contrast this to 2021, when Natera’s C-Suite compensation was > $53 million despite company losses that were > $471 million.

Although these companies are not generating operating profits, their investors aren’t necessarily hurting as a result. Stock prices for boutique, genetic testing labs don’t often sync with the lab’s financial health, and based on reported trading of company insiders, some investors are gaining significant wealth despite the losses of these labs. For example, Invitae hit all time stock highs in December 2020 despite enormous losses reported in every quarter that year. The net loss for Invitae in 2020 was >$600 million, while that same year Invitae insiders cashed out more > $46 million in stock. Another example is that the current CEO of Natera cashed in nearly $76 million in stock over the past four years, while cumulative losses for Natera totaled >$ 1 billion over that same period.

What is at stake for genetic counseling?

A 2018 publication in the Journal of Genetic Counseling analyzed the financial challenges of commercial genetic testing labs and what that could mean for genetic counselors. The authors speculated that genetic testing companies may not find a path to profitability, and their ability to support genetic counseling services may subsequently decrease.

Since this initial analysis, the losses of these companies have continued to grow, and investors have become less enthusiastic. This has put pressure on many companies to change and adjust their business strategy in order to survive. For some, this means cost cutting measures to decrease their cash burn with hopes to increase the odds of profitability. And as predicted, difficult decisions are taking place with many genetic testing companies resulting in layoffs of staff, including genetic counselors. Last month, Invitae announced layoffs of over 1,000 staff, including most of their clinical genetic counselors. SEMA4 and Ambry Genetics have also had layoffs in recent months. Given the overall picture of the financial health of all these labs, and increasing challenges in raising funds, it is likely there will be more layoffs to come for genetic counselors and others who work at these companies.

What does the current financial state of genetic testing laboratories mean for the delivery of genetic services and for the genetic counseling profession? A substantial portion of genetic counseling is now delivered through genetic testing laboratories who have packaged genetic testing with the offer of genetic counseling to draw in clients. If we see fewer companies maintaining genetic counselors on their staff, where will genetic counseling support come from for these patients? In addition to the labs themselves, many of the growing genetic counseling telehealth companies are closely tied to the testing laboratories, with much of their funding and contracts coming through commercial laboratories rather than direct patient referrals or contracts with clinics. It seems possible that these arrangements could also be negatively affected with current financial pressures and cuts to “extra” costs. Genetic counseling is not an “extra” bonus service, but rather a critical part of the genetic services process. Relying on genetic testing companies’ funding to ensure access to this service does not appear to be a sustainable model.

For genetic counseling services to be sustained, independent of the financial health of corporate testing laboratories, it is essential that genetic counseling be recognized and reimbursed as an independent service, with inherent value that is separate from genetic testing. Recognition by the Centers for Medicare and Medicaid Services is a necessary step towards sustainable and independent genetic counseling services, regardless of service delivery modality. I hope you all will join in continued advocacy to see the Access to Genetic Counselor Services Act H.R. 2144 / S. 1450 enacted into law.

Michael L. Astion is a clinical pathologist who is Medical Director, Department of Laboratories at Seattle Children’s Hospital and Clinical Professor of Laboratory Medicine at the University of Washington. For almost two decades he worked at the University of Washington, Department of Laboratory Medicine where he was a Professor and Director of Reference Laboratory Services. His career is divided between clinical service, teaching, clinical service, and research and development. He is the editor-in-chief of Patient Safety Focus, which appears quarterly within AACCs Clinical Laboratory News. He is one of the founders of PLUGS (Patient-centered Laboratory Utilization Guidance Services), a national collaboration whose mission is to improve test ordering, retrieval, interpretation and reimbursement. Dr. Astion is a frequent speaker at professional meetings, where he lectures on issues related to laboratory test utilization; test interpretation; laboratory economics and outreach; and medical errors.

Jessie Conta is a licensed genetic counselor in the Department of Laboratories at Seattle Children’s Hospital. She received her Master of Science degree in genetic counseling from Brandeis University. As the Manager of the Laboratory Stewardship Program at Seattle Children’s, she leads genetic test stewardship interventions, including insurance alignment related to genetic testing. Jessie is also a co-founder and Director of Genetic Counseling Services for PLUGS (Patient-centered Laboratory Utilization Guidance Services), a national collaboration whose mission is to improve test ordering, retrieval, interpretation and reimbursement.

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GUEST POST: The NSGC Annual Conference needs a high-grade mask mandate

by a collective of GCs concerned about COVID-19 risk at the 2022 AC

We urge the NSGC Board of Directors to change the mask recommendation for the 2022 Annual Conference (AC) to a requirement for attendees to wear high grade masks (N95, KN95, surgical). 

We encourage our fellow genetic counselors to join us in advocating for high-grade masks at the AC by signing this petition and sharing it with their colleagues. 

Below we share examples from recent conferences to demonstrate that without a masking requirement, the AC is likely to be a superspreader event and that masking requirements are indeed feasible at conferences of this type and size. We also lay out why this policy change is imperative given NSGC’s stated J.E.D.I. commitments and our profession’s responsibility to our attendees (including vendors, exhibitors, facility workers, and the press), patients, colleagues, families, the local community of Nashville, and society broadly. 

Likelihood of high level of COVID-19 transmission at events like the AC

Unfortunately, even in 2022, conferences without masks continue to be superspreader events. The Society for Academic Emergency Medicine Conference had an estimated 18-67% of its ~3000 attendees contract COVID-19 at their May 2022 conference. This conference required vaccination but not masks. A July 2022 meeting of IT developers had at least 50% of attendees test positive for COVID-19 after the conference. That meeting required both vaccination and pre-conference testing, but not masking (same as the policies proposed for the 2022 AC). This example shows that transmission rates can still be high even with the policies proposed for the AC. 

In contrast, the 2022 Academic Surgical Congress required high-grade masks (N95, KN95, surgical) and far fewer attendees contracted COVID-19. In a recent paper Silver et al. (2022) report that 1.8% of in-person attendees at this conference tested positive for COVID-19 after the meeting, a rate that is both markedly lower than the unmasked conferences mentioned above and similar to the rate among remote attendees (1.5%). It is notable that this paper came out after the Board made decisions about AC policies, which further prompts the need for re-assessment of those policies. 

NSGC staff have shared that they hope that attendees will heed the recommendation to wear masks. However, rates of masking at conferences with a recommendation as opposed to a requirement suggest that many will not, as does an informal poll in which 30% of respondents who plan to attend the AC in person said they would not wear a mask under the currently proposed policies. 

Feasibility of mask mandates

It is notable that many recent in-person medical conferences have required masks and had a high rate of masking compliance. This suggests that a mask mandate is indeed feasible and also that masking rates are higher with a mandate than a recommendation. In addition to the Academic Surgical Congress discussed above,the Heart Rhythm Society and American Academy of Neurology 2022 meetings are notable examples. Both required masking. Genetic counselors who attended these meetings report that compliance was very high and that security guards and conference staff provided cordial reminders to mask when they were already interacting with attendees, such as at entry points. This suggests that a high rate of masking can be achieved when a mask mandate is coupled with a minimal level of additional work from existing conference staff. Further, the Heart Rhythm Society registration page informed potential attendees in advance of requirements, including mandatory masking, and asked that individuals who could not meet those requirements attend remotely. Within the genetic counseling profession, the Southern California Genetic Counselors’ 2022 conference is an example of another recent meeting that required masking and had very high compliance. If these societies were able to implement a mask mandate and achieve a high level of compliance, then so can NSGC. 

Lastly, many upcoming conferences are requiring masks, most notably this includes the American Public Health Association Annual Meeting

J.E.D.I.

NSGC has made significant strides in recent years in recognizing the need for greater equity and inclusion within the society. However, opting for a mask recommendation over a mask mandate is counter to the society’s stated J.E.D.I. goals. Specifically, by not including this feasible and highly effective mitigation strategy, NSGC has rendered in-person attendance at the AC out of reach to attendees who are at high risk for COVID-19 complications, or who live with someone who is. This policy choice disproportionately harms disabled individuals. In-person attendance at the AC offers many more choices for educational talks and provides access to additional networking opportunities, pre-conference symposia, and sponsored sessions. In the same informal poll referenced above, 11.5% stated they would change from remote to in-person attendance if masks were required. 

Our collective responsibility

As both a professional society and a collective of healthcare providers and individuals, we have a responsibility to minimize the risk of transmission at our Annual Conference. So much so that one group of experts titled their article on this topic “The irony — and ignominy — of medical conferences as superspreader events.” To abide by our duties as healthcare providers and our responsibilities to our patients, we must do whatever we can to save lives and prevent long COVID-related disability by minimizing the number of attendees who bring COVID-19 home to their families, communities, clinics, and workplaces. Not taking that step would be against the values of care and respect for our patients’ welfare that are the foundation of our Code of Ethics. 

Clearer communication of rationale for policy choices and risks to attendees

Lastly, we urge the Board to provide clearer communication on COVID-19 policies for the AC, even if they do not adopt a mask mandate. Communication from NSGC to date does not provide a rationale for the chosen policies or clarity on the process for selecting those policies, nor does it communicate where the current policies may cause significant risk to attendees. The risk of attending should not be left to attendees to discern. As a profession that facilitates and is committed to informed choice, we owe it to each other to help provide accurate and up-to-date information on the risks of conference attendance, especially given that such information is not readily provided from sources most attendees would encounter. 

Signees

Colleen Caleshu

Brenden Phung

Sohnee Ahmed

Kaleigh Patton

Emma Snyder

Gina Sanchez

Breanne Prindeville

Sarina Kopinsky

Samantha Freeze

Charlene Preys

Emily Toering

Sally Rodriguez

Naomi Wagner

Meg Hager

Michelle Takemoto

Suzy Cahn

Ariel Breeze

Vickie Bacon

Julia Stone

Liz Mizerik

Natasha Berman

Catriona Hippman

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NSGC Board: With Roe Overturned, and Over a Decade Without Medicare Recognition, It’s Time For Change 

A Guest Post by Misha Rashkin et al

The Supreme Court’s recent decision to overturn Roe v. Wade is an historic event, and in many ways genetic counselors are in the eye of the storm. The National Society of Genetic Counselors (NSGC) has historically remained silent on the issue of reproductive rights, citing Medicare recognition as a bipartisan issue that supersedes patients’ reproductive freedom. Though the threat of losing Roe has been clear since Brett Kavanaugh joined the Supreme Court, and all but inevitable after Justice Coney Barrett took the oath, NSGC leadership has continued to focus solely on Medicare reimbursement. After more than a decade of following this strategy, NSGC is nowhere near getting our bill passed, and now patients are losing fundamental rights. It’s time for change.

What is Next for Genetic Counselors?

  • Going forward, there will be laws proposed in many states that could regulate what genetic counselors can document or say to their patients. 
  • To enact change, NSGC leadership will need to get involved in many legislative, legal, and electoral efforts. 
  • Electoral efforts will need to focus on local elected officials like District Attorneys offices, ballot measures, and state constitutional amendments

Bottom line: It is not acceptable for NSGCs political operation to remain silent on reproductive choice. We must act on issues that impact our professional lives and the wellbeing of our patients. To remain silent is to capitulate.

What about our bill to be recognized by Medicare? 

  • Based on public records, NSGCs efforts to have Congress recognize genetic counselors as Medicare providers has been ongoing since 2007, longer than many counselors’ careers. 
  • Our bill has been introduced three times as HR 7083 in 2018, HR 3235 in 2019, and HR 2144 in 2021, and has yet to be considered by a single committee in Congress. 
  • While progress has been minimal, costs have ballooned 450% over 10 years, from $80,000 per year to $360,000 per year! 

Bottom line: Sacrificing our commitment to patient autonomy and agency is a grave ethical error for an industry that prioritizes these values. Sticking with the status quo is a failure of the leadership’s ethical and fiduciary responsibility. Board members are required to accept their fiduciary responsibility for NSGC the same as they would for their own personal finances.

What Can NSGC Do To Repair the Damage?

  • The NSGC Board should put out a Request For Proposals (RFP) requesting bids from new lobbying firms every few years, beginning now. This is standard practice for nonprofit organizations. Smith Bucklin has not been held accountable for their lack of progress. 
  • RFPs should include lobbyists who have worked to get mid-level providers recognition.
  • This process should be transparent and prioritize bids from political operatives who have:
    • Experience working with our targeted committees (Energy & Commerce, and Ways & Means in the US House) to move our legislation forward.
    • Experience working on reproductive freedom at the state and federal level. 

Bottom Line: The Board should create a process where an RFP is put out at some regular cadence, such as every three years. It’s time to hold our Director of Government Relations and lobbyists accountable. If you agree, please sign this petition to register your support for accountability, transparency and change. 

[alphabetical order]

Barbara Biesecker, PhD, MS, CGC

1989-1990 NSGC President

Jordan Brown MA, MS, CGC

2022 Chair, NSGC Public Policy Committee

Member, NSGC Reproductive Freedom, Access, and Justice Task Force

Founding Member, Genuine Collective

Elizabeth Fieg, MS, CGC

2020-2022, Public Policy Committee Member

Michelle Fox, MS, CGC

2020-2021, NSGC Director at Large

2008 Chair, Jane Engelberg Memorial Fellowship 

Shreshtha Garg, MS, CGC
2020-2021 Chair, Equity and Inclusion Implementation Committee

Carrie Haverty, MS, CGC

2022 Chair, NSGC Membership Committee

Brianne Kirkpatrick, MS, CGC

204-2017, NSGC Public Policy Committee Member

Shelby Koenig, MS, CGC

Member, NSGC Reproductive Freedom, Access, and Justice Task Force

Megan Mckenna, MS, CGC

NSGC Member since 2020

Kristen Miller, MGC, CGC

2022 Senior Co-Chair, NSGC Prenatal SIG

Ana Morales, MS, CGC

2016-2020, ABGC Board of Directors (President, 2019)

2022, NSGC Expert Media Panel

2022, NSGC Practice Guidelines Committee Member 

Shivani Nazareth, MS, CGC

2020-2021, NSGC Director at Large

2021-2022, NSGC Reproductive Freedom, Access and Justice Task Force Member

2013-2016, Public Policy Committee Member

Kate Partynski Emery, MS, CGC

NSGC Member Since 2015

Aarti Ramdaney, MS, CGC

2019-2021, NSGC Prenatal SIG Co-Chair

Misha Rashkin, MS, CGC

2018 Chair, NSGC Public Policy Committee

Hillary Rieger, MA, MS, CGC

NSGC JEDI Task Force, 2021-22 

Sally A. Rodríguez, ScM, CGC

2021-2023, NSGC Membership Committee Member

2021-2023, NSGC Justice, Equity, Diversity, & Inclusion (J.E.D.I.) Committee Member

Katie Sagaser, MS, LCGC

2020-2022 NSGC Public Policy Committee Member

2019-2020 NSGC Prenatal SIG Co-Chair

Founding Member, GENUINE Collective

Kendra Schaa, ScM, CGC

2020-2021, Chair, NSGC Access & Service Delivery Committee

2017-2020, Member, NSGC Access & Service Delivery Committee

Heather Shappell, MS, CGC

2020-2021, NSGC Director at Large

Ashley Svenson, MS, CGC

2021-2022, NSGC Reproductive Freedom, Access, and Justice Task Force Member

Elizabeth Varga, MS, CGC

2018-2019 NSGC Director at Large

2016-2017 Co-chair, Pediatric Subcommittee, Cancer SIG

2014 Chair, Nominating Committee, American Board of Genetic Counseling

Chelsea Wagner, MS, CGC

2022-Present, Prenatal SIG Co-Chair

2022-Present, NSGC Abstract Review Committee

2019-2021, NSGC Marketing and Communications Working Group

2017-2020, NSGC Membership Committee

Kate L Wilson, MS CGC

2014 Chair, NSGC Access and Service Delivery Committee

2018 Chair, NSGC Education Committee

2012 Chair, NSGC Prenatal SIG

2017 Chair, NSGC Laboratory/Industry SIG

Beth Wood Denne, MS, CGC

2019 NSGC Cares Task Force

2011 Chair, Annual Education Conference

2013-2016, ABGC Board of Directors (President, 2016)

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The Power Of Symbols: The Pedigree As A Tool of Conformity and Oppression

Pedigrees are paragons of infographics — “graphic visual representations of information, data, or knowledge intended to present information quickly and clearly.” Yup, that’s pretty much what a pedigree is. Just think of how much clinical and genetic information you can glean from scanning a pedigree for even just a few moments. Eliciting a pedigree during a counseling session is also a great way to establish rapport and trust with a patient, get a grasp on family dynamics, and gain insight into patients’ understanding of disease etiology (“I’m not very close with my father. He left when I was pretty young. I think he had leukemia but he worked in a shipyard and was exposed to all kinds of chemicals.”). The family story is often more interesting than the family history. Then there’s that appealingly simple geometry of squares/circles/diamonds/lines and the satisfying symmetry of the paternal lineage on the left and the maternal lineage on the right. Nice, neat, clinically objective, non-judgmental, and harmless, right?

Well, maybe not always so harmless and objective. Symbols can be imbued with power by the information they communicate and that power can be used to control, harm, and manipulate people and reinforce social power structures.

As I’ve written about before in this space before, pedigree nomenclature and structure reflect what Judaeo-Christian Westernized cultural values consider to be an “ideal family.” Standard pedigree structure works best for a single mating between a man and a woman, along with their respective offspring and antecedent and descendant generations. Maybe you can squeeze in a second mating for one or two individuals in the family, but after that, things get pretty messy and difficult to read.

Over the last century or so, cousin marriages have been discouraged in most Westernized countries and in some cases are illegal. Although pedigrees can incorporate an occasional consanguineous mating without becoming too unwieldy, the picture gets complicated if there are multiple inbreeding loops like those found in the many societies where cousin marriage is the norm. And as far as sex and gender go, you have two choices — square or circle, man or woman — that are dictated by an assessment of your genitalia (this will change with the latest iteration of pedigree nomenclature; see below).

The implicit cultural messages here are that you should have one life-long unrelated mate and that you are either a man or a woman, no allowances made for people who identify otherwise.

The oppressive potential of pedigrees is illustrated in the pedigrees collected by the Eugenics Record Office, which operated out of Cold Spring Harbor on New York’s Long Island in the first few decades of the 20th century. Look at the trait key used to classify people in a pedigree and it evokes a smile, an eye roll, tears,  a grimace, a forehead slap, or all of the above. Sexually immoral. Criminalistic. Wanderer. Neurotic (for those of you who like language trivia, the pointing finger symbol that is used to indicate a proband is called a manicule or, more informally, a bishop’s finger).

Pedigree Symbols Used By The Eugenics Record Office

But these labels and symbols are not just harmless historical curiosities that were the products of a few warped minds. This was the era of mandatory sterilization laws in the US and elsewhere. If one of those symbols represented you, the state had the legal right to perform surgery on you against your will to prevent you from having any(more) children. Three generations of imbeciles are enough already, and that ruling was by a liberal Supreme Court that included Louis Brandeis in the majority opinion.

In contrast to how “dysgenic” families were portrayed, pedigrees could manipulate the viewer in the other direction by omitting information of eugenically desirable families. The Darwin Family pedigree below was, for all intents and purposes, the logo of The Eugenics Education Society, headquartered in London and whose president at the time was Leonard Darwin, one of Charles Darwin’s sons. Note that virtually all of the males in the family are “Brilliant” or had “Scientific Ability” but none of the women apparently possessed these traits. More subtly, many of the dysgenic traits described in eugenically undesirable families were omitted from the Darwin pedigree – opium addiction, deafness, intellectual disabilities (Darwin’s much beloved last child, Charles Waring Darwin, likely had Down syndrome), seizures, and alcoholism. Indeed, Darwin himself was so concerned about his family history that he wrote a letter to his father asking for his advice before starting a family (Darwin’s father wrote a similar letter to his father too).

A stark illustration of the power of symbols came up in discussions about updating pedigree nomenclature among the NSGC Pedigree Standardization Task Force, of which I am a member. One of our recommendations is a gender-first nomenclature, that is, a person’s self-identified gender should dictate the symbol’s shape, not their sex assigned at birth. We also considered symbols to use for people who do not identify as either male or female. In reviewing the literature and eliciting suggestions from the genetics and other communities, some suggested using an inverted triangle for someone whose gender identity is nonbinary. However, we rejected that suggestion in favor of a diamond shape because inverted triangle badges were used in Nazi concentration camps to distinguish among the various types of prisoners, such as political prisoners, criminals, prisoner of war, “gentiles who assisted Jews,” Roma, mentally ill, or Jews (the Magen David is essentially, two triangles). The triangle that defined you could mean the difference between life and death.

                            Inverted triangles used to distinguish among the types of prisoners in Nazi concentration camps.                 (https://en.wikipedia.org/wiki/Nazi_concentration_camp_badge

The potential harm of pedigree symbols looms large today now that states have taken to passing laws that criminalize abortion. Suppose that you are practicing in a state like Louisiana after a strict anti-abortion law is passed and you are taking a family history from a someone who had a pregnancy in which anencephaly was diagnosed and she managed to obtain a pregnancy termination through an underground network. If you document that pregnancy with the annotation VTOP (voluntary termination of pregnancy) below, you could potentially open her up to legal prosecution.

                                                                  Evidence of a crime in some states

 A similar outcome could arise in a states like Texas or Alabama that have banned gender-affirming treatment for children, legislation that, as far as I can tell, is often motivated by cynical politics and hate-driven willful ignorance. If you practice in these states and are consulting with a parent who has a child who identifies as female but was assigned male at birth and has undergone gender-affirming treatment such as puberty blockers, you would – under the new guidelines – depict this in the pedigree with a diamond, the annotation AMAB (Assigned Male at Birth), and perhaps further annotations about what treatment was provided. If that pedigree fell into the wrong hands, the parents and the treating physician could be charged with child abuse. And, by law, you may be required to report it to the state, just as health professionals are usually required to report any type of child abuse.

                                                                         Pedigree indicating child abuse in some states

A genetic counselor could be put in the position of either falsifying the medical record or omitting clinically critical information. Talk about a rock and a hard place.

In the idyllic past, we mostly worried about insurance companies getting their hands on pedigrees. Now we have to worry about the prosecutorial system accessing them. Absolutely nothing good will come of that. It’s possible that the judicial system may block or limit some of these laws, but I am not too hopeful at the moment.

Nothing in science and medicine is value-neutral. Everything we utilize and do in our clinical practice can be used for good and for bad and we often have no control over how it is used and abused. Nor should we lose sight of the fact that one day future genetic counselors will look at our pedigrees and other practices and pass critical judgment on us. We should strive for ethical humility amidst our righteousness.


As an added bonus for that small circle of practitioners who love pedigrees as much as I do – fellow PedHeads – you might be interested in this article I wrote long ago in a genetic galaxy far away about the history of the pedigree in genetics.

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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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The Questions We Should Really Be Asking After Reading the NY Times Article About Prenatal cfDNA Screening For Microdeletions

As the genetic counseling world knows all too well, the New York Times recently published a story about prenatal cfDNA screening for chromosomal microdeletion syndromes. The gist of the article is that screening for microdeletions has a high number of false positives that produce significant patient anxiety and, in a very small number of cases, patients have elected to terminate a pregnancy before confirmatory diagnostic testing. The Times piece generated 1100+ comments on its site, including many from genetic counselors and physicians, not to mention vitriolic sturm und drang on various social media.

Clearly the article touched a collective genetic counselor nerve — a lot of the reaction has been more reflexive than reflective. Which is kind of surprising, considering that cfDNA for microdeletions is a so-so screen for a handful of rare conditions that genetic counselors have not widely agreed should be included on these tests.

Most of the criticism centered on the article not always making a clear and consistent technical distinction between a screaming test, er, uh, I mean, a screening test (which cfNDA is) and a diagnostic test (which cfDNA is not). This confusion has been an ongoing problem since the early to mid-1980s when AFP screening for neural tube defects — and maternal anxiety over testing — was first working its way into clinical practice (I remember one of my patients back then referring to AFP as “alpha-fucking protein”). Forty years later, and the anxiety and misunderstanding has not improved much.

Some of those criticisms are fair, particularly when the article describes cfDNA results as being “wrong” or “inaccurate.” To the specialist, the term false positive has a very specific definition,* and hence the source of the reaction to the article. But from a semantics standpoint, doesn’t the word false in false positive imply wrong? You can also think of calling a result “wrong” as an example of the tried and true counseling strategy of reframing, i.e. “Well, Jane, your test result actually says that there is more than an 80-90% chance your baby does not have a microdeletion.”

In my opinion the article otherwise does a decent job of highlighting the statistical complexities of cfDNA. The accompanying Figures are helpful in explaining what is essentially the positive predictive value of the tests. In fact, I think the graphics are better than the explanations and graphics on many of the testing laboratories’ websites. Many of these websites are even guiltier of muddling the differences between screening and diagnostic tests, and labs really should know better. It’s no wonder that patients might be confused and anxious when they read that a test is “highly accurate,” “an alternative to amniocentesis or CVS,” and can be assured of a “healthy baby” when results are normal. To be fair, some of the websites also address the distinctions between screening tests and diagnostic tests, but only if you click down into the rabbit warren of information.

I think most of the criticism by genetic counselors glosses over more important and fundamental questions that should be the focus of critiques of prenatal testing and our reaction to the Times piece (here I am defining prenatal testing as including screening and diagnosis). These critical questions include:

• Should we test for any condition prenatally? This is an ethically and for some a religiously complex question but it underlies all of the subsequent questions.

• If there is broad agreement that prenatal testing should be available, then what is its purpose? Realistically, with a few exceptions, is there any purpose beyond selective termination? While termination is an important option and benefit of the test for some, it’s not a course of action that all parents will choose. Some parents might decide to have prenatal testing for “preparation” but as I have argued elsewhere there is minimal data saying one way or another whether prenatal knowledge of a condition helps babies or their families, medically, emotionally, or developmentally (thought at least one study is beginning to address this shortcoming). If patients are going to be put through the emotional ringer of prenatal testing, we should be able to provide solid data on whether prenatal knowledge of a condition provides benefits in addition to the option of termination.

• What criteria should be used in determining which conditions should be subject to prenatal testing? Even if every genetic condition could be detected prenatally (and we might actually get close to that point one day), it wouldn’t make sense to test for many of them. Clinically rational and ethically acceptable criteria need to be developed to guide the selection of conditions to consider for prenatal testing.

• Who decides which conditions are screen-worthy? As Ilana Löwy and others have noted, commercial labs often spearhead this choice but decisions are reinforced and supported by the medical and genetics communities that order the testing. If no one ordered a test, labs wouldn’t offer it. As Liza Minelli, Joel Grey, and Scarface remind us, money makes the world go around. Are we screening for some conditions primarily because we can screen for them and labs offer it? What about input from patients, the public, multiple medical specialties, ethicists, social scientists, people with disabilities, and others?

• Is widespread screening for rare conditions the best use of laboratory and genetic counseling resources? Follow up of screen positive results consumes a significant amount of genetic counselor time and energy, to say nothing of patients’ anxiety and health care costs. Should these resources be focused on more pressing conditions?

• Many jobs in the genetics sector — labs and clinical providers — are dependent on the existence of genetic testing. Labs make their living off of testing but so do many genetic counselors working in clinics. While genetic counselors are not trying to push testing on patients, many genetic counseling jobs depend on the availability of genetic testing, either helping patients decide whether to have a test or explaining results to them once the testing has been completed. For better and worse, the genetic counseling profession has intimately identified itself with genetic testing. Clinics would employ far fewer prenatal, cancer, cardiogenetics, and other specialty genetic counseling jobs if there were not so many genetic tests. Think about how many clinical positions would evaporate if prenatal testing — or, really, almost any genetic testing — disappeared tomorrow. Some jobs would remain, for sure. But the demand for genetic counseling would likely drop off significantly if fewer tests were available. How much does this conflict of interest influence genetic counselors’ attitudes toward, and willingness to adopt, genetic tests, and how much does it subtly and subconsciously influence some of the strong reaction to the Times article?

• First and foremost, a patient’s decision to undergo — or not — prenatal testing should be preceded by a soul-searching exploration with partners and care providers about what parents want out of their children and addressing parental fears of disability, along with ethical and spiritual reflection. The decision requires more emotional expertise than numerical expertise. Should we be offering tests to all pregnant women that require them to master abstruse statistical knowledge in order to decide about whether to pursue testing? Even in a (unrealistic) world where all pregnant patients meet with a genetic counselor prior to testing and everything was explained in excruciating detail, many patients will misinterpret, forget, and misunderstand most of the technical information about false positives, false negatives, and distinctions between diagnostic tests and screening tests. What is the best way for patients to make medically and emotionally informed decisions? Laboratory website are less than ideal sources of information. Websites are essentially marketing tools, and marketing is antithetical to nondirectiveness. Chatbots alone don’t cut it for this purpose, although they could have an ancillary role.

• What message does it send to people with disabilities, their families, and their advocates if we continually add, seemingly willy-nilly, more and more genetic conditions to the prenatal testing list, especially, as I noted above, if they obtain no tangible benefit from testing? More testing readily begets further routinization of testing. And when you start testing lots of pregnancies for lots of conditions, you start creeping further into eugenic territory.

There are no easy solutions to any of these questions. Some may very well prove to be unanswerable and some parties will remain dissatisfied if we do manage to come up with some answers. It will involve vigorous and at times contentious debates among multiple viewpoints, and lots of people convinced that they are so damned right and why the hell can’t everybody else see that? But that doesn’t mean we shouldn’t be taking on the challenge. We may wind up with less than perfect answers, but they will be better than what we are doing now. The practice of genetic counseling demands it and patients deserve no less.

__________________________________________________________________

*- Another source of confusion here is the distinction between the false positive rate and a false positive result. The false positive rate is the number of pregnancies that do not have a condition but test positive. Thus, a lab can accurately claim that cfDNA for microdeletions has a false positive rate below 1%. You can see why a patient with a positive result might misinterpret that to mean there is over a 99% chance that her baby does indeed have a microdeletion. On the other hand, a false positive result is one specific patient’s test result which incorrectly indicates that a condition is present. Thus a patient who has a positive microdeletion result has an 80-90% chance that her baby does not have a microdeletion. Lord have mercy! You can see why pregnant patients might be confused. Then try to sort through all that while experiencing the joys of hyperemesis, or if you are a non-English speaking immigrant from a village in Central America working through an interpreter, or if you are also trying to figure out at about the same time the meaning of your rubella result, your HIV status, your nuchal thickness scan, and the results of your carrier testing.

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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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The American Plan: The Incarceration and Forced Treatment of “Good Time Girls”

 this poster features an apparently average and conservatively dressed woman who might also pose a threat. Featured in the poster is the warning to all servicemen that 'She May Look Clean–But pick-ups, 'good-time girls' and prostitutes spread syphilis and gonorrhea. Publisher information at bottom of poster.

 

Every girl under supervision, we know where she works, who her friends are, and how she puts in her time….While the girls are in the hospital, we grade her mentally, and make a detailed social investigation… Her mental grading helps us in determining what she can do… We are locking up just as many feeble-minded girls as we can.  – Katharine Ostrander, Michigan State Board of Health, Director of Social Services (1919)

I recently became aware of a little known chapter in 20th century American history known as The American Plan, a chapter so creepy it could have been written by Margaret Atwood. While it is not directly connected to genetic counseling, the usual focus of this blog, as you will see it does intersect with eugenics. I feel it is shocking enough that it should be brought to the attention of the blog’s Good Readers; I suspect that many will be as stunned and surprised as I was. Most of what I have to say is drawn from Scott W. Stern’s 2018 book The Trials of Nina McCall – Sex, Surveillance, and the Decades-Long Plan To Imprison “Promiscuous” Women. Please note that in the posting I am using the  historical vocabulary of that time period to capture the zeitgeist of America in the first part of the 20th century.

The US entry into the First World War resulted in the drafting of nearly 3 million men into the military. Draftees were administered, among other things, an IQ test and a physical exam for social diseases, as sexually transmitted infections (STIs) were euphemistically labeled at the time (even the US Surgeon General was not allowed to say “syphilis” on a radio broadcast). The results were alarming – a substantial number of draftees had a very low IQ and a high incidence of social diseases. We looked like a nation whose men were sex-crazed morons (“moron” was a supposedly objective scientific category based on low IQ score). Perhaps many readers are thinking “Well, yeah, men haven’t changed much in the last 100 years”.

The Enemy in Your Pants – Mother Jones

Military and political leaders were concerned that the US fighting force would be defeated by its own diseases. To combat social disease the US government enacted The American Plan, based on similar plans from European countries. Some readers may be familiar with the cheesy posters warning soldiers in both World Wars of the dangers of venereal diseases but these smile-inducing graphics belie a dark side to some of the strategies employed by The American Plan. In an attempt to “protect” the troops from syphilis and the like, a range of laws and policies on the federal, state, and local levels were enacted that gave authorities and even some civilian entities almost blanket permission to arrest, isolate, examine, treat, and reform anyone suspected of spreading social diseases. Although the initial focus was intended to be communities near military camps, it soon spread to many towns and cities throughout the country, regardless of their proximity to military facilities. Every state and hundreds of cities and towns passed nearly identical versions of American Plan laws.

Multicolor poster with white lettering, depicting a woman standing outside a bar or dance hall. The woman has blond hair and wears a short-sleeved steel blue dress, pink bracelet, and blue ring. She has a dark red purse tucked between her arm and body, freeing up her hands to hold matches and light the cigarette dangling from her mouth. Her attractive features are hardened by her eyebrows coming together, as in anger, and a slight snarl on her lips. Initial title words at top of poster, remainder overlap woman's midsection. Artist's name in lower right corner. VDgraphic-25 appears in lower left corner.

Essentially, any woman suspected – not convicted – of being a prostitute, engaging in “promiscuous behavior,” premarital sex, or other “suspicious behavior” could be forced to undergo an invasive pelvic exam, almost always by a male physician. If the physician decided that the the person had evidence of a a social disease, they could be confined to an institution – a jail, a hospital, a “reformatory,” depending on local conditions. Whatever building or camp was used, the women were incarcerated, plain and simple. Once incarcertated they were forced to undergo largely ineffective, painful, and toxic treatments with a mercury- or arsenic-based regimen. This even though diagnosis was rarely definitive unless the person had flagrant disease; indeed, some women were diagnosed as being “slightly infected,” whatever that means. For good measure, many were also given IQ tests, and if they scored low enough they could be forced to undergo sterilization under some state eugenic laws. There was also a profit motive to incarcerating women; the Federal Government provided money to the states, and states passed the funds on to local authorities, with the amount depending on how many women were detained. 

 

Beware of Chance Acquaintances, American Society for Social Hygiene VD  Poster | David Pollack Vintage Posters

The policy was not limited to brothels and known prostitutes, who in fact usually had a low incidence of social diseases. Women of any age were forced into the program, including young teens and even pre-teens. It is astounding what could be labeled as a “suspicious behavior.” One woman was detained because a vengeful former boss reported her as sexually suspect after she quit her job. Another was detained after she volunteered as a witness to a car theft. Another was detained because she was on a date with a man who was drinking alcohol. Think about this. A woman might be flirting with a couple of guys in a dance hall or soda shop or go out for a drink on her own, or just be walking down the street in Anytown, USA in a “suspicious” manner and she could be forced to undergo a painful pelvic exam by a physician, confined to a treatment center for an indefinite period based on faulty testing and disease criteria, and then made to endure painful, debilitating and largely ineffective treatment until such time that the authorities had decided that she was cured and socially reformed. These incarcerations helped shape the modern American women’s carceral system, which currently has nearly a quarter million women within its walls.

Retro WW II Loose Women Loaded With VD Venereal Disease 45 Auto World War  Poster | eBay

It was felt that if women were reformed they would not return to their former loose life styles. Reform usually meant making them clean, cook, sew, and perform other activities – mostly to maintain the institutions where they were being incarcerated – that were thought be be appropriate for proper women. Authorities had the power to hold the women for days, weeks, or months until such time as it was decided that they were deemed medically and socially fit to re-enter society. Even after release, women could be required to check in with institutional directors for permission if they wanted to move, get a job, or even to get married. Some directors asked employers to monitor released inmates’ behavior and report suspected relapses.

The American Plan continued to be actively enforced for ~30 years until the end of WWII and the advent of antibiotic treatment, though there are reports of abuses until the 1960s (in 1965, the then 18 year old writer and radical feminist Andrea Dworkin was forced to undergo a painful pelvic exam under New York’s American Plan law when she was arrested at an anti-war demonstration). Not to worry anybody, but these laws are still on the books in most states and cities. 

Black women, Native American women, immigrant, and Latinx women were disproportionately singled out. Non-white women were said to have the racial characteristics of excessive promiscuity and – according to the Surgeon General of the United States! – to be anatomically susceptible to spreading social diseases. The laws were written as largely gender-neutral but men were only rarely singled out, and then usually just treated rather than detained for a prolonged period. The laws glossed over how men can transmit social diseases to other men; homosexuality was not something to acknowledge or discuss and, besides, it was already illegal in most states.

Because many records have been destroyed, the exact number of women subjected to this practice is not known, but at minimum it involved tens of thousands of women. Despite all this enforcement, the architects and enforcers of The American Plan were never able to demonstrate that it was effective in lowering the incidence of social diseases.

There is no fun in V.D.&quot; Anti-venereal disease poster, c. 1945.:  PropagandaPosters

The American Plan was not some dark government secret known only to an elite few insiders. It was widely reported and supported in newspapers and politicians of all bents, including Presidents, condoned it. Supporters – men and women alike – could be found across the political spectrum but there was particularly strong support among Progressives and liberals – the American Civil Liberties Union, the American Bar Association, Eleanor Roosevelt, Earl Warren (who would go on to become a liberal Chief Justice of the US Supreme Court), the League of Women Voters, to name a few. Some of these supporters criticized some specifics of the American Plan but they were not opposed to The American Plan itself. At the other end of the spectrum, Eliot Ness, he of The Untouchables, was actively involved in carrying out the plan at one point, as was J. Edgar Hoover and the FBI. They all pretty much thought they were doing good for society and helping women. Many of the key players in developing and carrying out The American Plan also subscribed to eugenic beliefs and were members of eugenics societies. A source of consistent and significant financial support for many of the activities, beyond governments, was John D. Rockefeller, Jr., and the Rockefeller Foundation (the Rockefellers also helped fund the Eugenics Record Office). Even when law suits were brought by women who had been incarcerated, the decisions sometimes supported a woman’s claims in a few cases but the legal validity of The American Plan itself was never questioned by the courts. 

Racist, sexist, rude, crude and dishonest: the golden age of Madison Avenue  .. 'because innocence is sexier than you think' | London Evening Standard |  Evening Standard

 

The primary non-governmental agency driving The American Plan was the American Social Hygiene Association (ASHA). Formed in 1913 with Rockefeller funding, the ASHA essentially crafted the details of The American Plan, provided expert advice to the government, employed undercover agents in cities to hunt out suspicious locations and field workers who would work with local police in coordinating arrests, and crafted model legislation that was adopted almost verbatim by most states. The organization also pushed for enforcement of American Plan laws beyond primarily protecting soldiers to protecting the general public. ASHA has since changed its name and is now called the American Sexual Health Association, and its activities and goals are quite different and perhaps more noble than those of its predecessor. However, its website makes no acknowledgement of this shameful history and has only this to say about its past:

“ASHA was founded as the American Social Hygiene Association in 1914 by a group of public health reformers committed to attacking an undesirable social condition–venereal disease, or VD–that they believed could be improved through medical and educational means. The shame and reluctance to talk about sexuality was now weakened enough so that the public was at least generally aware of the dangers posed by VD. This was the first social marketing effort to mix physical and moral fitness for prevention of VD.”

I am in no position to speak for the ASHA but if I were a member I would want my organization to be more honest, open, and reflective about its past.

Propaganda and the law of unintended consequences &lt; Yale School of Medicine

I am reluctant to draw lessons from history and I am hesitant about judging the past through the lens of the present. With such widespread and enthusiastic support for The American Plan, if we were alive then many of us might have been swept up by the social currents of the times and supported it in some fashion, just like many of us would probably have embraced some aspects of eugenics. We are not morally superior to our ancestors and we are all products of our times. That being said, this was a gross injustice carried out in the name of “doing good.” It needs to be more widely known and subjected to scholarly investigation and a national dialogue, at the very least.

When you are so convinced that you are doing good it can blind you to your actions’ downsides. As I’ve written about before, genetic counselors are particularly susceptible to “do-goodism.” What looks progressive to one generation can look awfully repressive to another generation. When we seek to do good, we should do so with humility, an eye to history, and a keen awareness that when we try to do good we can wind up doing a lot of bad.



For an interview with author Scott Stern about The American Plan on YouTube https://www.youtube.com/watch?v=_p0LjJ8tTh0

For a podcast about this topic, see the History This Week Podcast: https://play.acast.com/s/d9768fa0-a79a-4ead-9102-f965e8a470bc/82177119-c36c-4a67-b906-94ae38000416



Unrelated to the above posting, I recently had a thirst for a dose of spirituality, a thirst perhaps driven by the existential wear and tear of the last few years. I am not a religious person – I am pretty much a we-are-all-star-stuff kind of person – but I do derive a deep satisfaction from contemplating the magic of life and the incomprehensible complexity of the universe. Which got me to thinking of the Indigenous Canadian singer Buffy Sainte-Marie’s 1969 song “God Is Alive, Magic is Afoot.” The lyrics are taken from a section of the poet Leonard Cohen’s novel Beautiful Losers. As far as I know, Leonard Cohen never recorded it as a song. Incidentally, Buffy Sainte-Marie’s music was unofficially blacklisted in the US for a period because of her anti-war activities and her involvement with the Native American political movement. Honestly, the song doesn’t make much cognitive sense to me, but it does make intuitive sense. In particular, the closing lines always give a jolt to my sense of wonder:

And mind itself is magic coursing through the flesh
And flesh itself is magic dancing on a clock
And time itself, the magic length of God

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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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