Tag Archives: prenatal diagnosis

Guest Post: NIPS: Microdeletions, Macro Questions

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics. 

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At the recent National Society of Genetic Counselors Annual Education Conference in New Orleans, a presentation raised some important questions about noninvasive prenatal screening (NIPS). According to the speaker, a woman with a vanishing twin pregnancy underwent NIPS with an expanded microdeletion panel and the results showed findings “suggestive” of a chromosomal microdeletion syndrome.

The patient underwent amniocentesis with a SNP microarray and the results were normal. In a follow-up call with the NIPS lab, the genetic counselor learned that multiple copy number variants were observed (not originally reported) in the original sample. The lab suggested that these variants could be associated with a malignancy or fibroid tumor (and were of course unlikely to be associated with a microdeletion syndrome in the fetus).

As a result of this genetic counselor’s follow-up phone call and due diligence, the patient underwent an extensive work up for possible cancer, but no explanation was found. NIPS was repeated and this follow-up study was normal.

My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? NIPS is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?

In October 2013 Sequenom expanded their NIPS test to include screening for microdeletion syndromes and Natera followed suit in Spring 2014. Some new companies entering the NIPS market are also advertising screening for microdeletion syndromes.

The addition of microdeletions is a brilliant business strategy for expanding the testing market to include all pregnant women. Even though microdeletions are rare, their incidence—unlike that of Down syndrome –is not linked to maternal age. Women who are currently not offered NIPS because they are not included in the high-risk categories proposed by the American College of Obstetricians and Gynecologists (ACOG) guidelines could now be given a reason to undergo NIPS—even though the predictive ability of the NIPS for rare conditions is less than impressive.

Women who elect the test because of an interest in Down syndrome or because they are eager to learn fetal gender may unknowingly be screened for rare microdeletion syndromes which they know little to nothing about. To add to the complexity, a maternal microdeletion condition may be an incidental finding. In a poster presented at the NSGC meeting this year, Sequenom presented a series of 22q11 deletions detected with their MaterniT21 PLUS test. Included in this report were two mothers who were themselves incidentally diagnosed with 22q11 deletion syndrome. Based on the consent form on the Sequenom website it seems unlikely that these women had any idea such a result may occur.

Where is the evidence to support this expanded screening?

These tests are being performed despite there being no published clinical validation studies. There have been some case reports and proof of concept studies; however given that this testing has been commercially available for over a year now, there is shockingly little published about cell free DNA screening for microdeletions. An abstract from a poster presentation at the ACOG annual meeting in April 2014 evaluated 6 samples (or is it 7? – it is not clear from the abstract) from pregnancies known to be affected with microdeletions and 8 simulated samples. They conclude, “This is the most comprehensive, accurate validation of noninvasive microdeletion detection hitherto… This approach will enable accurate, noninvasive, prenatal population screening for these severe disorders.”

Proof of concept is one thing; proof of clinical validity is another. If we value evidence-based medicine, a sample of six (or seven) affected pregnancies is a long way from being a basis for population screening. Whether population-wide screening for extremely rare disorders is worth paying for is, of course, a question in itself.

But in the unregulated environment of laboratory-developed tests, we adopt first and report out results later. Accompanying this process is a lack of transparency – labs performing NIPS with microdeletions have not made performance statistics publicly available and thus patients and providers have no way of determining the accuracy of microdeletion NIPS. In a webinar hosted by Sequenom , the presenters were asked about the positive predictive value (PPV) of Sequenom’s screen for microdeletions. One speaker replied, “We have calculated them. However, what we would like is essentially to wait a little bit to give you more clinically relevant results. Because so much depends on the fetal fraction of the sample and so on and so forth, so we feel that the more appropriate number to release is after we have done 50,000 samples, how many have we found, how many have we reported back, how many were confirmed, how many were in line with the clinical picture.”

Shouldn’t the accuracy of the test be publicly known before it is run clinically on 50,000 women?

Labs have given us only a glimpse of their performance statistics. I was previously provided information from Natera regarding estimated PPVs for the microdeletions on their panel, but I cannot locate this information anywhere in the public forum. The table I was provided stated a 1/19 PPV (5.3%) for 22q11 with a Fetal Fraction >6% and dropping much lower (to 1/45) with decreased fetal fraction (interesting thread here of multiple women with a 1/19 chance of 22q11 on their NIPS result).

In a letter to the editor, former CMO of Sequenom Allan Bombard and colleagues reported that they had evaluated 264 samples from pregnancies with known microdeletion and microduplications or “enriched genomic mixtures” and report a 100% sensitivity and 99.3% specificity. Applying these statistics to 22q11.2 deletion syndrome (the most common microdeletion syndrome on the panel with an incidence of 1 in 4,000) indicates a PPV of about 0.036 or 3.6% . The overall PPV would be expected to be lower given the very low incidence of the other microdeletions on the panel. At the NSGC meeting this year, Sequenom presented some preliminary data from a series of 120,726 samples screened from October 2013 – July 2014 with test performance that exceeds those estimates. Although they did not have complete follow-up data for positive and negative results, a press release from the company following the NSGC meeting reports “high positive predictive values (estimated combined PPV ranged from 62% to 94%)”.

The limited information available suggests PPVs for microdeletion syndromes fall within a broad range of <3% – >90%. Published peer-reviewed studies are needed to help clarify the PPV associated with this testing so that healthcare providers and patients can make informed decisions about utilizing and interpreting this testing.

About a year and a half ago I published a piece on the DNA Exchange that discussed the importance of PPV in interpreting NIPS results. This was written for an audience of genetic counselors, but the posting is being increasingly used as a venue for patients to share their stories and seek information about their test results. Many patients report considerable anxiety – “the waiting is killing us…we have been devastated for the better part of 3 weeks now” – and some express regret for undergoing this testing at all, “I too wish I would of just done the typical old fashion test so nothing was in the back of my mind and hours of my life would be given back…” Recently, a woman remarked that she did not consent to additional testing for microdeletions and indicates her frustration with not being able to find information about the PPV for this test, “Not only are they essentially experimenting on us…they are not transparent about the potential problems with validity or low PPV.”

As genetic counselors, we are implicated in these companies’ approach. We should be demanding better evidence before leading our patients towards testing that could create this kind of distress. We need to be asking good questions, and we should demand good answers. If we cannot figure out how reliable a screening test is from a thorough review of the literature, I think we really need to ask ourselves if we should be offering it in a clinical setting.

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A Mixed Verdict

A recent $50 million dollar jury verdict in a “wrongful birth” lawsuit in the Seattle area* has caught the attention of genetic counselors, hospitals, patient advocates, and legal experts. The ruling in this case may have both positive and negative implications for the genetic counseling profession. Let me be clear up front – I am not passing judgement on the verdict, the medical providers, the parents, the quality of care, or the laboratory. This case is very complicated and no doubt many details were not publicly reported. Although I know some of the parties involved, I was not directly connected to the case and I have no insider knowledge. Indeed, I did not know about the case until it hit the news.

In 2007 a woman underwent chorionic villus sampling (CVS) because her husband was a known carrier of a very subtle 2;9 translocation. The institution where the procedure had been performed had no genetic counselor working on the day the CVS was performed, contrary to departmental guidelines for complex cases. Somehow the details of the translocation were not clearly communicated to the cytogenetics laboratory. The fetus had an unbalanced translocation that was erroneously reported out as a normal karyotype. The couple continued the pregnancy to term and the misdiagnosis was detected after the child was born. In 2010 the couple sued the hospital, the laboratory, and the physician who performed the CVS. The physician and the plaintiffs entered into a “High/Low” agreement  in which the defendant agrees to pay a minimum recovery in return for the plaintiff’s agreement to accept a maximum amount regardless of the outcome of the trial. The medical center and the laboratory  were held equally responsible for the $50 million payout, with half the money going to a Guardian ad Litem for the child to pay for his medical care and other expenses and half going to the parents.

The core argument of the plaintiff’s lawyer was that the error would likely have been prevented if a genetic counselor had overseen the patient’s prenatal testing to assure that the critical information about the translocation was clearly communicated to the laboratory. The medical center had reduced the genetic counseling staff despite pleas from the maternal fetal medicine specialists and in the face of growing patient volumes and increasing net revenue. Lawyers for the plaintiff further claimed that the medical center and laboratory did not follow Error Prevention and Quality Management Policies and that the misdiagnosis was the result of a systemic failure. These arguments were important to the extraordinarily large size of the award; the missed diagnosis was attributed to “true negligence” rather than a one-time human error.

The outcome of this case can be beneficial in several ways for the genetic counseling profession. The jury acknowledged the critical role that genetic counselors serve in the delivery of medical care. For genetic counselors trying to justify their positions and salaries can now also argue that their institution’s legal vulnerability can be dramatically reduced by having an adequately staffed genetic counseling service. After all, genetic counselors’ salaries are a pittance in the overall hospital budget and pale in the face of multi-million dollar legal damages. Genetic counselors served as expert witnesses for both the plaintiffs and the defendants, further enhancing the profession’s status.

On the other hand, the verdict did little to improve the rocky and complicated relationship between genetic counselors and people with disabilities, their families, and their advocates. From the perspective of many in this group, prenatal diagnosis and selective termination are bright shining examples of society’s intolerance of people with disabilities. Because genetic counselors are integral to the delivery of prenatal diagnosis services, we are criticized for being part of a larger social and systemic bias.

Genetic counselors counter that they do not direct patient’s decisions, only support them. Genetic counselors are all too familiar with the gut-wrenching, emotionally draining process that patients go through when they decide to terminate or continue a pregnancy in which the fetus has a chromosomal imbalance. And in many situations, genetic counselors serve as advocates for people with disabilities and their families. But this defense does not hold water with those who argue that the very existence of prenatal screening is an insult to people with disabilities who, after all, do not see much in direct benefit from NIPS, amniocentesis, CVS, etc. What positive message can someone with disabilities find when half of the fifty million dollar award was for pain and suffering of the parents, and the very justification of the life of someone with disabilities is called into question when he or she is labeled “a wrongful birth?”

For now, we live in a society where women have the hard-earned right to terminate a pregnancy for whatever reason they choose (although the ability to act on that right can be severely hampered by socio-economic status and governmental policies). Genetic counselors line up behind the defense that they nondirectively help women to act on this reproductive freedom. Disability advocates are often avid supporters of reproductive rights too but do not feel that prenatal testing is necessary to the expression of reproductive freedom and point out that society’s negative view of disabilities and unwillingness to allocate appropriate resources further worsens the effects of disabilities. The two sides seem to be at an impasse and the fact that genetic counselors might applaud this court’s decision may only further contribute to this impasse.

We cannot ignore the voice of our critics.  I am not sure what the solution is. Prenatal diagnosis is unlikely to go away unless abortion becomes illegal again. If genetic counselors suddenly decided to pull out of prenatal diagnosis services, I suspect that informed patient decision-making would deteriorate and people with disabilities would lose one of their few potential advocates in the prenatal system.

As a profession and as individuals we need to reach out to our critics and find some common ground, such as the recently developed Open Lines forum where disability scholars, genetic counselors, parents, and people with disabilities can openly and safely discuss their perspectives. Surely the two sides are not as dysfunctional as the US Congress. It will be painful and difficult, but great achievements often require great suffering.

* – King County (Washington) Superior Court Case # 10-2-43289-2, Judgment Record # 13-9-35173-6 & 13-9-33521-8

Note: Some of the information in this posting is based on an article written by the plaintiffs’ lawyer (Gardner T, “Significant verdict in wrongful birth suit” Trial News, January 2014, pp. 9-11).

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Guest Post: Adrienne Asch – Reflections from a Genetic Counselor

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetic counseling.

We recently said good-bye to Adrienne Asch, a thoughtful and powerful voice in bioethics, disability, and reproductive rights. Adrienne passed away at her home in New York on November 19, 2013, surrounded by the love of many friends and family.

Adrienne touched my life deeply in the brief time I knew her and I am grateful to have had a connection with her. Her perspective has significantly shaped the way I view the genetic counseling profession and my role within it.

Adrienne was an accomplished scholar and an incredible person. Several beautiful tributes speak of character and her accomplishments, and these only give us a glimpse of her impressive body of work. See the The New York Times, as well as blogs related to philosophy, feminism, and bioethics for more about Adrienne.

Many genetic counselors are aware of Adrienne’s focus on the intersection of disability rights with reproductive technologies.   She was supportive of abortion rights, but questioned the implications of prenatal diagnosis and selection for disability rights, for individual parent expectations, and for humanity. She asked the question, if individuals with disabilities are not welcomed into family life, how can we expect inclusion in schools, in the work place, in society?

In her scholarly work, Adrienne spoke frequently about the parent-child relationship, and I had often wondered about her personal experiences as a child in this relationship. I came across the transcript of a fantastic interview with Adrienne conducted by Anna Kirkland at the University of Michigan, in 2006. I was delighted to find these insights into Adrienne’s own family life and it is heartening to realize that Adrienne’s views on this topic were in part shaped by her own childhood experiences of being supported to be true to herself:

“My parents taught me to think for myself and to be comfortable with who I was, even if people around me weren’t entirely comfortable with who I was either as a leftwing type or somebody who loved classical music, or someone who was Jewish, or someone who was blind. So they just taught me to be myself.” 

At one point the interviewer asking Adrienne if she had ever had the opportunity to address genetic counseling students. Adrienne has been an outspoken critic of prenatal diagnosis and this has made her quite a controversial figure among genetic counselors.

Anna: I’d be interested to know, have you ever had the opportunity to address a group of genetic counseling students or…or… 

Adrienne:  Yes. I have. 

Anna: Yeah. How did that go? 

Adrienne:  Not well. 

Anna: [laughs] What [laughs]…what did you say to them? 

Adrienne:  The same kind of thing I’m saying to you. But it challenges…I mean, maybe that I haven’t said it gently and kindly enough and I’m trying to do that. I have sympathy for how difficult it is to do this work. But I have no sympathy for people telling me that parents aren’t interested in this information or it’s not appropriate to give them the kinds of information that I’m describing. I think in fact that’s what genuine information is.

Recently, I had a chance to work closely with Adrienne when she helped to conceptualize a symposium for the National Society of Genetic Counselors Annual Education Conference, Reaching for Common Ground: Prenatal Genetic Counseling and Disability Equality. Although  Adrienne’s health prevented her from traveling to Los Angeles for the meeting, she was determined to hear all of the presentations live and to participate in the conversation. We achieved this through the technological miracles of cell phones, speakers and microphones for the entire 6 hour conference and this allowed her to both listen and contribute to the conversation.

In early October, she recorded a video for this conference and the National Society of Genetic Counselors has kindly allowed me to share it here. I encourage you all to take the time to listen to Adrienne’s final address to genetic counselors. I think she finds the balance she was striving for in being sympathetic to the difficulties inherent in the work of genetic counseling and remaining strong in her challenge to our profession to be more than genetic educators.

In genetic counseling, you have an enormously important role to play in helping prospective parents’ to think about the meaning for themselves of the genetic impairments or prenatally diagnosable impairments that they might discover in a fetus or an embryo.   And the role that you have to play is not genetics education alone.  It is genuine counseling.  It is counseling with a genetic component.  But it is dialogic counseling.  It is not merely reciting facts about laws and services and family support for people with Down syndrome.  It’s not reciting how wonderful it is and how loving the children are…It’s not reciting how terrible it is and how bad group homes might be.  It’s asking parents to think about the goals they have for their family life and how a child with characteristics that they can know in advanced will affect the achievement of those goals… The other reason you have a big job is that you are not given much time in which to do it. And all of the institutional forces work against that kind of conversation.  But I am urging that genetic counselors take their respective places as counselors to really help prospective parents think through what they want for their family life.  How a particular characteristic or impairment will affect that…

…Just as life is made up of many experiences that are shareable, you don’t need to have particular characteristics in common to share a life and to share experiences.  And you as a genetic counselor have an opportunity to communicate that to prospective parents. And ask prospective parents to think about what they want in their family’s lives.  And whether a child with a particular characteristic you can name in advanced will make the achievement of those goals any harder or any less possible. 

That’s a job of real counseling.  It’s not a job of imposing your values.  It can be as nondirective as you like but it is a job of asking questions maybe questions parents don’t want to be asked but that’s often true of any counseling.  No therapist worth his or her salt merely smiles and nods and says, “Ahah!”, and says, “I see what you mean”.  Therapy and counseling are about asking people to reflect and think twice or three times about the views and the values they are bringing to their lives.  You don’t have three years or 3 months or sometimes even 3 weeks to do that with the people in front of you.  But in the 45 minutes to an hour that you have, or if you’re lucky, more than that, you have a chance to communicate the joys of parenthood, the problems of parenthood, and the ways in which a child with any set of characteristics may or may not fulfill the goals that a parent has.”

Part of our fundamental core professional values as genetic counselors is to be non-directive in our counseling – not to decide the morally ‘right’ path for pour patients. We strive to support individuals to choose the path that they decide is right for them. Our responsibility as genetic counselors is to do our best to make certain that the decisions people make are as informed as possible.

What Adrienne helped to crystallize for me is that part of ensuring informed decisions requires inquiry into of the prospective parent’s expectations, hopes and dreams. It may also call for us to challenge misconceptions about how life with a disability is imagined and this may need to begin first with examining our own misconceptions and biases.

Adrienne certainly dismantled my preconceptions about life and limitations for someone who has been blind since shortly after birth. Although too short, her life was undeniably rich and full and her contributions were many. I imagine there are many DNA Exchange readers who have some interesting reflections about Adrienne of their own. I hope you will share them here.

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Guest Post: NIPS And The Threat To Informed Decision Making

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetic counseling.

A few months ago, I reached out to the DNA Exchange readership and called for more truth in advertising by the Noninvasive Prenatal Screening companies regarding the accuracy of test results. I recently returned from the National Society of Genetic Counselors meeting where I had the opportunity to survey the marketing and patient materials from labs offering NIPS and to learn about the experiences of my fellow genetic counselors with these new tests.

Not surprisingly, in this dynamic and rapidly evolving field, all of the companies have updated their materials. Some brochures proudly acknowledge how quickly this testing is being integrated into clinical use. It feels like we are being patted on the back for adopting this new test quickly and without question.

I remain very concerned about the misleading claims in the marketing materials aimed at providers and in the patient directed brochures. It is easy to see how the language of the brochures could lead healthcare providers and patients to conclude that these tests are diagnostic or near-diagnostic. These quotes from the materials illustrate my point:

“Definite, informative results.”

“Positive or negative results.  Never maybe.”

“No confusion.  Just simple, clear results.”

To my knowledge, there are no new large studies to dispel my concerns about the positive predictive value of NIPS. Depending on the prior probability, a significant portion of positive results may be false positives– especially with rarer conditions such as Trisomy 18 and Trisomy 13. And because these technologies have been rapidly integrated into clinical practice based on limited research, we do not have robust outcome data to see how false positive and false negative data are playing out in clinical practice.

Since most NIPS testing is done outside of a clinical research protocol, the labs that choose to put resources into follow-up are at the mercy of the providers to share that outcomes information.  Even in the best scenarios, voluntarily reported outcome data are not likely to tell the whole story. I spoke with a testing company representative regarding a poster presented at ACMG last year which based its false positive and false negative results on ad hoc feedback. When I inquired about the meaning of ad hoc feedback, it was explained to me that the company didn’t have the resources to track outcomes so were relying on providers to let them know if the testing results were incorrect. Of course, if a patient terminates her pregnancy based on a false positive test result, nobody will know that the NIPS result was incorrect.

Don’t think a patient would terminate based on NIPS alone? We all hope that women who receive adequate counseling about the limitations of the testing would confirm results with a diagnostic test, but this is not always the case. At a presentation during the recent NSGC Annual Education Conference, one lab referenced preliminary data showing some patients are terminating pregnancies without first getting diagnostic testing, and in the absence of ultrasound findings. While this tracking has some limitations, this lab should be applauded for investing resources in tracking outcomes data and for sharing these data with genetic counselors. Hopefully we will see it published soon and other labs will follow suit.

This situation of patients making reproductive decisions based only on NIPS results may be particularly problematic in communities that don’t have ready access to genetic counseling and/or maternal fetal medicine services.

Imagine this scenario:  a 35-year-old woman living in small town, USA who has limited access to abortion services beyond the first trimester, receives a positive result for Trisomy 13. Based on positive predictive values calculations, there is an 8% chance that her “positive” result is a true positive. But, the patient – and her doctor – may think the probability is much higher, maybe even close to 100%, based on the reporting practices of the labs, which may say “Aneuploidy detected” or “Positive” for Trisomy 13. This does not support informed reproductive decisions.

This patient has 3 options:

  1.  Wait for an appointment at a high risk referral center, at some distance from her home to undergo diagnostic testing. This may limit her reproductive options by delaying time to diagnosis (the later a pregnancy termination occurs, the more expensive it is, and pregnancy termination outside of the first trimester is often not available in many smaller communities).
  2. Seek out pregnancy termination options in her local community based on the NIPS results alone – knowing that she is up against a gestational age ticking clock.
  3. Decline further testing and continue the pregnancy.

If the patient feels that she would not want to continue a pregnancy given a Trisomy 13 diagnosis, and she understands the limitations of the testing, I would imagine that she likely would feel it was worth the wait and the travel for diagnostic testing. However, given the emphasis on the accuracy of NIPS based on the lab reports, and the misconception by OB providers that this testing is “nearly diagnostic”, it is easy to imagine a scenario where she may elect to have a termination based on NIPS alone.

Based on an aggregate of data from the NIPS companies from the first quarter of 2013, one health economist estimates that NIPS is utilized by 40% of the high-risk population in the US, and this number is growing rapidly. So while the patients you see in your genetic counseling practice may be very informed about the limitations of the testing given your expert counsel, this statistic suggests that most NIPS is probably taking place outside of our offices.

We must continue the conversation about how NIPS is marketed and used in prenatal care. While the advantages to a more sensitive screening test are obvious (e.g. fewer women needing to undergo diagnostic testing), we must recognize the largely undisclosed limitations and dangers. Without adequate counseling, patients are being harmed by the misleading claims about the accuracy

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Albatross

Ah! well a-day! what evil looks
Had I from old and young!
Instead of the cross, the Albatross

About my neck was hung.

And till my ghastly tale is told,

This heart within me burns

He went like one that hath been stunned,
And is of sense forlorn:
A sadder and a wiser man,

He rose the morrow morn.

– Excerpts from The Rime of The Ancient Mariner, by Samuel Taylor Coleridge

Eugenics. I can hear the thud as the collective eyes of genetic counselors roll heavily at the mention of the E-word.  That finger has been wagged in our faces ad infinitum. Alright already, we have learned our lesson from this shameful past. That was like more than half a century ago. Do we have to still keep apologizing for something we never did? Enough with the hand-wringing and perseveration. We’ve smoked this one down to the filter.

Well, no, apparently we are not done. As historian of medical genetics Nathaniel Comfort has pointed out in a recent thoughtful Genotopia blog (with an equally thoughtful commentary by Alex Stern, the biographer of our profession), eugenics discussions are back with us. We need to keep having the discussion because apparently we are not sadder and wiser people this morn. Some even think – with great hubris, in my view – that with our supposedly greater wisdom and technological advances, maybe some version of eugenics is not such a bad idea after all.

I am not going to repeat Nathaniel’s and Alex’s arguments here; visit the Genotopia blog and read the originals. What I want to do is to offer a  framework for thinking about the issues raised by these historians and introduce the concept of genetic discrimination into the mix.

Genetic discrimination, in my definition, is discrimination based on a person’s presumed or actual genotype and it’s presumed or actual phenotypic expression. The word discrimination comes from  the Late Latin discriminationem, meaning “to make distinctions” and can have both negative and positive connotations. Racial and gender discrimination that results in suffering and inequity is bad. But a discriminating person is one who shows great taste for fine things. Not to try to dance too many angels and devils on the head of this pin, but perhaps when discrimination has a negative effect, it could be called dyscrimination.

Eugenics, then, can be viewed as a form of negative genetic discrimination, the goal of which is to improve the genetic health (whatever that means) of future generations.

Prenatal diagnosis, the usual aim of eugenic critiques, is not eugenic because it does not try to alter allele frequencies of future generations. Down syndrome is almost never an inherited disorder, and people with Down syndrome rarely reproduce. Prenatal diagnosis is not an attempt at “the self direction of human evolution,” as the 1921 Second International Eugenics Congress defined eugenics.  But from the standpoint of some, prenatal diagnosis is a form of negative genetic discrimination – fetuses are discriminated against because of their genome and the common but inaccurate perception of the Down syndrome phenotype as a backward child with a heart defect but a pleasant personality. Although the insensitive term mongolism is rare these days, the common image of “the Mongol child” has not evolved as much as it should have.

Pre- or early pregnancy screening of parents for mutation carrier status for various genetic conditions, on the other hand, might rightfully come under eugenic criticism since its explicit goal is to improve the genetic health of future generations and to wipe out genetic diseases by preventing the conception of homozygous recessive offspring. Never mind the nonsense spewed forth on some websites; carrier screening usually has very little to do with improving the health and quality of life of babies who are born with genetic conditions. Carrier screening can result in reduced suffering if fewer children are born with life threatening or medically serious disorders but it rarely improves the health of babies who are born with those conditions. Whether this is a “good” or a “bad” form of eugenics, and how commercial laboratories advertise their product, are questions open to healthy debate.

Newborn screening, as it is currently practiced, is not eugenic because its intent is to improve the health of a child by treating the presumed phenotype based on the genotype. Newborn screening could thus be viewed as a positive form of discrimination, albeit one with flaws that we are not comfortable acknowledging . But newborn screening can also be viewed as negative genetic discrimination, depending on the condition being screened for. Some people who are deaf have raised serious concerns about screening newborns for hearing loss.

Genetic screening for adult onset disorders like Lynch syndrome or familial hypercholesterolemia may be positive genetic discrimination. The goal of this screening is to treat the phenotype based on the genotype with the hope of reducing the incidence of serious, life-threatening diseases or to mitigate their effects. Dietary changes, treatment with statins, high risk cancer screening, and surgery are strategies that are offered to people at increased hereditary risk of developing these diseases. Of course, if there were to be widespread preimplantation or prenatal diagnosis for these conditions, then we should rightly raise eugenic questions.

Why make these distinctions? Because the word eugenics has become an angry accusation that ends discussions. The social effects of genetic medicine and genetic counseling should always be open to vigorous scrutiny but the criticism needs to be accurate and sensitive to nuance. Maybe some of what we genetic counselors do is eugenic, and maybe under certain situations, this may not be as terrible as it sounds. And maybe some of what we do is dyscriminatory but not eugenic; we need to understand why it is dyscriminatory so we can do something about it. And maybe lots of what we do is very helpful for many people and not particularly eugenic. To cram all of medical genetics into a eugenic framework prevents any progress from ever being made. The two sides start to resemble Democrats and Republikans in a dysfunctional Congress, never able to engage in meaningful debate. Let’s get this albatross off our necks.

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Guest Post: NIPS Is Not Diagnostic – Convincing Our Patients And Convincing Ourselves

By Katie Stoll, MS

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics.

A couple of years ago we were just beginning to learn about a new prenatal testing technology termed Noninvasive Prenatal Diagnosis. It was soon relabeled as Noninvasive Prenatal Testing, and now the American College of Medical Genetics and Genomics recommends this be taken one step further by terming it Noninvasive Prenatal Screening (NIPS) to highlight the limitations of this new technology.

As currently reported by labs, NIPS presents new challenges for genetic counselors. Of particular importance is figuring out how to convey to patients and healthcare providers why relying on sensitivity and specificity alone may lead to misinterpreted results. In the absence of positive and negative predictive values there may be a tendency to assume that the high sensitivity and specificity reported with NIPS means that these tests are more powerful – more diagnostic – than they actually are.  

It is imperative that we understand both what the terms mean and how they relate to a person’s likelihood of having a condition.   Sensitivity measures the true positive rate – the proportion of actual positives which are correctly identified as such (e.g., the percentage of fetuses with Down syndrome (DS) who have a positive test result). Specificity measures the true negative rate – the proportion of actual negatives which are correctly identified as such (e.g., the percentage of fetuses who do not have Down syndrome who have a negative NIPS result for DS).

A test can have both a high sensitivity and specificity without being a good predictor of whether the condition is actually present. The likelihood that a positive test is a true positive result also depends on the incidence of the condition.

Sensitivity Graph

Genetic counselors are used to thinking about aneuploidy screening in terms of PPV, as this is generally the format for reporting maternal analyte screening such as Integrated , Quad screens, etc. Analyte screening takes into account the prior probability based on maternal age and provides a PPV as the end result. For instance, an analyte screen result may be reported as Positive with a 1 in 50 chance of Down syndrome. The PPV with analyte screening lets us know how many patients with a “positive” test will actually have a pregnancy affected with the condition and reporting results this way makes it clear that this is a screening test.

Can we apply the same interpretation to NIPS results?  Some labs provide a “risk score” which appears similar to what we see with analyte screening, but I am told by the labs that the vast majority will be reported as either >99% chance or <.01% chance.  Some labs do not report a risk score, instead giving essentially a positive or negative result. But does this mean that greater than 99% of women who receive a >99% or a positive result are actually carrying a fetus with Down syndrome or other chromosome condition?

Given that women 35 year and older are a population targeted for NIPS let me work out the expected NIPS results given the approximate sensitivities and specificities reported for a hypothetical population of 100,000 thirty-five-year old women (while I cannot tell you the specific number of women age 35 who give birth per year, CDC data suggests that for the past several years about 400,000 – 500,000 women in the age 35-39 have given birth each year in the United States – so 100,00 births annually by 35-year-old mothers is probably in the ball park of the national trend.

The performance data vary significantly from lab to lab – for the purpose of this illustration, I am using sensitivity and specificity in the range of what has been reported.  The data below are based on the chance of Trisomy 21, 18 and 13 at the time of amniocentesis for a woman 35 at time of EDD1.

Down Syndrome

Trisomy 18

Trisomy 13

Incidence

1/250

1 / 2000

1 / 5000

Affected Fetuses

400

50

20

Sensitivity

99.5%

98.0%

90.0%

Specificity

99.9%

99.6%

99.8%

Total test positives

498

449

218

True test positives

398

49

18

False positives

100

400

200

Positive Predictive Value

80%

11%

8%

If we add all of the positive results together in a population of 100,000 thirty-five-year old women we see that 1165 (1.2%) have positive test results for Trisomy 21, Trisomy 18 or Trisomy 13.  Note, though, that only 465 of these results will be true positives. This indicates that the majority of the time (greater than 60% using these statistics), a positive result on NIPS for a 35-year-old woman will be a false positive – and this doesn’t even include calculations for sex chromosome aneuploidy which some NIPS labs also screen for.

Notably, the negative predictive value for NIPS is very high indicating that a negative test result is a true negative >99% of the time. But how do we reconcile that for many women, the chance of a false positive with NIPS may be higher than the chance of a true positive result when that seems to be contradicted by way the labs are reporting the results? 

In trying to explain the chance of a false positive result to patients with a “positive” test report in hand, I have found that I am met with disbelief. I can understand why – if a test says there is a>99% chance of Down syndrome and the lab says the test has >99% sensitivity and >99% specificity, how could this test be wrong?

While genetic counselors understand the limitations, the reporting practices of the labs place us in a position in which we have to work hard to convince our patients that NIPS is only a screening test.

Currently four labs offer NIPS in the U.S. and all have different strengths and weaknesses in their reporting practices. All could be improved by making the limitations of this technology more obvious.  In some cases the language used in the reports gives the appearance that NIPS is diagnostic. For example, one company’s report suggests that the healthcare provider should advise for “additional diagnostic testing”.  The labs vary in whether the need for genetic counseling following a positive result is recommended.  Additionally there is variability in the transparency of how the performance data are derived.

Given that the performance statistics vary significantly, we need to be sure to take these details into account when considering PPV. I  encourage genetic counselors and other healthcare providers to critically look at how the performance data are derived.  The sample sizes on which these numbers are based are often quite small and the confidence intervals can be broad.  I was surprised to see in the fine print of one report that the performance data “excludes cases with evidence of fetal and/or placental mosaicism.” Given that mosaicism is a known cause of false positive results and because mosaicism cannot be definitively determined through NIPS, it doesn’t seem accurate that these cases should be excluded from calculations of test performance.

The pitfalls of interpreting NIPS results is a challenge we need to address because NIPS is increasingly taking place without the involvement of genetic counselors in pretest or post-test counseling. There is real concern that patients are making pregnancy decisions based on screening tests with the misunderstanding that NIPS is diagnostic. 

I write this as call to the NIPS labs to change their reporting practices to better emphasize the screening nature of this technology. Providing some positive predictive value estimates would be tremendously helpful as we try to make sense of NIPS results for our patients. While it may be difficult to provide individualized risk assessment, a general table of how prior probability impacts individual test performance would be beneficial for interpretation. Furthermore, eliminating language from the reports that suggests these tests are diagnostic and giving more transparency to ways in which performance data are calculated would also be welcome changes.

As genetic counselors, we strive to ensure informed decision-making for the clients we see. Key to informed decision-making is an understanding of the limitations of this evolving technology. As fellow patient advocates, I hope the genetic counseling community will join me in requesting increased accountability and responsible reporting on the part of the labs regarding NIPS.

I would like to acknowledge Evan Stoll, retired GAO data analyst for his contributions to this piece.

Please Note: Authors who contribute to The DNA Exchange cannot offer medical advice. Many commenters have raised interesting and thoughtful questions about NIPS. If you have undergone NIPS and have questions, you should meet with a certified genetic counselor. To locate a genetic counselor, go to the  Find A Genetic Counselor section of  the website of  The National Society of Genetic Counselors.

  1. Hook EB. Prevalence, risks and recurrence. In: Brock DJH, Rodeck CH, Ferguson-Smith MA, editors. Prenatal Diagnosis and Screening. Edinburgh: Churchill Livingston, 1992.

 

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Considering The Future of Genetic Counseling, Act II

When it comes to the future, there are three kinds of people: those who let it happen, those who make it happen, and those who wonder what happened.
John M. Richardson, Jr.

Those who predict the future are doomed to be wrong; just ask anyone at the race track or on Wall Street. But fear of failure should not hold us back; we have much to learn from error. So, to continue with the theme of the future of genetic counseling (see my previous posting), I will venture a few more guesses about the issues we should be considering when planning for tomorrow.

1. ) Safe and Legal Abortion Is Not Guaranteed For The Future : Abortion and abortion providers are under legal, social, and physical attack. It is not out of the question that Roe v. Wade may one day be overturned. Although it makes us uncomfortable to hear it, prenatal diagnosis is largely predicated on the availability of abortion.  It does not make economic sense to offer aneuploidy screening primarily to prepare parents for the birth of a

child with disabilities. If abortion becomes unavailable, insurers may be less likely to cover prenatal diagnosis, which could result in a dramatic drop in prenatal diagnosis job opportunities. And economic issues aside, is it morally justifiable to undertake the small risk of losing the pregnancy from amniocentesis or CVS simply because of parental anxiety or the desire for emotional preparation? You say that prenatal diagnosis can be important to long term developmental/medical outcome and familial adaptation. I say, aside from rare exceptions, the data is just not there to support your contention (and remember that the plural of “anecdote” is not “data”). So go out and do the studies and prove me wrong.

2) We Can’t Afford to Ignore Cost Effectiveness: Genetic counseling will likely come under increasing economic scrutiny. While I want to believe that our value to health care goes beyond dollar-savings, we nonetheless have to fiscally justify our employment and work loads. And, at times, we may be facing contradictory economic pressures. We will want to show that we lower healthcare costs by reducing the number of unnecessary genetic tests, ensuring appropriate medical screening based on genetic assessment, or whatever other means to demonstrate that we help produce a healthier population in a cost-effective manner.

On the other hand, we will be receiving subtle and not so subtle pressures from our employers to increase the number of revenue-raising activities. Back in the early 2000s, many centers, including my own, experienced a sharp drop in the number of patients who underwent amniocentesis, I suspect the result of  a social trend in changes in attitudes toward abortion and disability. At one point, my boss said only half-kiddingly “Bob, you are counseling yourself right out of a job.” Genetic counselors need to take the lead in conducting studies that show our cost-effectiveness while simultaneously demonstrating that we do not hurt our institutions’ bottom lines.

3) The Human Genome Project May Not Deliver On Its Promises: Genomic medicine is the medical technology du jour. All sorts of claims have been made about how genetics will revolutionize health care and cure everything from diabetes to the heartbreak of psoriasis. We have promised the moon. But what if the “genetic revolution” never comes? Or what if genomic medicine simply falls by the wayside as some new medical technology becomes sexier and more promising than genetics? Will funding for genetic research and clinical positions dry up? We need to stay alert to changes in other areas of medical care and adapt genetics to the changing practice of medicine.

4) The United States Will Not Be The Center Of The Genetics Universe: Until relatively recently, genetic counseling and genetic counselors have been concentrated in the US.  Although I haven’t tabulated the numbers, I am pretty sure there are more genetic counselors in the US than in the rest of the world combined. While many valuable contributions have come from Canada, the UK, both sides of the Tasman Sea, the Netherlands and other countries, the US has been the leader in the field (I will accept any criticisms of national chauvinism leveled by my international colleagues). But over the last 10-15 years, genetic counseling has spread to many other countries. New genetic counseling models will emerge as genetic counselors work in different cultural and geographic settings, especially  in non-English speaking countries. More international meetings, communication, and cooperative transnational research will be critical to the future of genetic counseling. The US model is one way of providing genetic counseling; it is not THE way, or necessarily the best way.

5) Office Visits and Flipbooks Are Soooo 20th Century: As Allie Janson Hazell and others keep reminding me, the Internet and e-technologies offer opportunities to reach more patients in a variety of ways. And as Vicki Venne recently pointed out, Millenial Generation students and patients are not going to stand for old fogey communication and teaching techniques. Some of us are just beginning to utilize the telephone to communicate test results.

I mean, come on, Sugar, it’s time to take a walk on the Wild Side.

We must open our minds and embrace, adapt to, and integrate new communication technologies to better serve our patients. Brick-and-mortar counseling has a critical place, but it may not always be the best way to ply our trade. And on-line genetic testing is not necessarily the spawn of Satan. We can’t – and maybe shouldn’t – control access to all genetic testing, but we can work to make sure genetic testing is used effectively and appropriately by patients and health care providers.

I hope I have provoked some of you into disagreement, thought, and action. Where am I off the mark? Which of my predictions are bound to be wrong? What are your predictions? How can we best prepare ourselves for the future?

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