Is Down Syndrome Disappearing? Well, Not Exactly But….

Iceland has given the world the Eddas, Sigur Rós, Björk, and some magnificent geology.  A more ambiguous achievement, though, is suggested by a recent CBS News story that claimed that Down syndrome is disappearing from Iceland as a result of prenatal testing. The claim has been bouncing around the Internet for a few years. The earliest reference I could find was a November, 2015 letter sent to the Office of The United Nations High Commissioner for Human Rights authored by Downpride, an international advocacy group for people with Down syndrome. The letter is an “[a]ppeal to the United Nations to stop discriminatory use of prenatal genetic screening aimed at eradication of people with Down syndrome and other groups.” It was, in my view, an understandable and justifiable reaction to largely non-critical widespread adoption of Noninvasive Prenatal Testing (NIPT) from a community that has good reason to be concerned. Needless to say, it generated a lot of heated reaction. Just Google “Iceland Down syndrome” and you will see what I mean.

Delving into the story was like getting lost in a hall of mirrors; many sites simply referenced each other. But the claim that Down syndrome is disappearing from Iceland and that 100% of pregnancies with Down syndrome in Iceland are terminated turns out to be not quite so straight-forward. While Iceland represents a microcosm of the larger concerns of people with disabilities, their families, and their supporters, it is not necessarily an accurate reflection of the macrocosm of the larger population dynamics of Down syndrome in other countries, particularly the United States.

The ultimate source of the data, according to the Downpride letter, was testimony presented to The Althing, the Icelandic parliament that is the world’s longest existing legislative body. I tried unsuccessfully to find that testimony. I then searched PubMed but found only limited help. So I decided to do my own back-of-the-napkin calculations. I obtained the birth distribution by maternal age in Iceland for 2016, and grouped the ages by quinquennia. The expected frequency of Down syndrome was based on data from 1976, prior to the advent of widespread prenatal diagnosis.

Age Group # of Births Exp. Frequency of Down S. Exp. # of births with Down S.
15-19 72 1/1667 0
20-24 592 1/1587 0.37
25-29 1305 1/1087 1.2
30-34 1218 1/763 1.6
35-39 672 1/248 2.7
40-44 165 1/79 2
45+ 10 1/24 0.4
Total 4034  1/488 8.27

 

Thus, in Iceland in 2016, there were 4034 births. In the absence of prenatal diagnosis and selective termination, 8 or 9 babies with Down syndrome would be born, for a frequency of ~1/450-500 births. I then made the following assumptions, acknowledging that each has some potential error:

  • Based on a 2016 publication, about 80% of pregnant Icelandic women will choose to undergo prenatal screening
  • According to Dr. Hulda Hjartardóttir, chief of obstetrics at Iceland’s National University Hospital, among Icelandic woman who have a positive screen, about 25% decline diagnostic testing and continue the pregnancy. Thus, roughly 1/3 of Icelandic pregnant women either do not undergo screening to begin with or decide to continue the pregnancy and not proceed to diagnostic testing if a screening test is positive. The impact of these percentages on Down syndrome frequency depends on the age distribution of those who declined screening or diagnostic testing, but for argument’s sake, I assumed an equal distribution across maternal ages.
  • 100% of women whose pregnancies are diagnosed with Down syndrome will choose to terminate. I could not verify this claim, but I decided to go with the most extreme scenario. This has not been the experience in many countries, where termination rates have been high but not typically 100%.
  • The CBS News story mentions the Combined Screen, so I assumed this was the standard screening test in Iceland when the claims were made in The Althing. I therefore set the detection rate for Down syndrome to 90%, that is, of all women undergoing screening, about 10% of pregnancies with Down syndrome will be screen normal and would not proceed to termination (some studies suggest that the Combined Screen may have a sensitivity somewhat less than 90% but because about 21% of pregnancies in Iceland occur in women 35 and older, a higher sensitivity – and false positive – rate is expected).

Based on these assumptions and the above table, of the potential 8-9 babies born with Down syndrome, about 2-3 would actually be born because their mothers did not undergo either prenatal screening or diagnostic testing, and another baby with Down syndrome would be born because the Combined Screen would be expected to miss about one case. In other words, the total number of newborns with Down syndrome in Iceland would be expected to drop from 8-9 every year to about 3, maybe 4, per year. These numbers could increase or decrease with many factors, such as changes in fertility rates, maternal age distribution, the sensitivity of screening tests, social trends that influence the choice of abortion, and random fluctuations that occur with any demographic trend especially with the small number of births in Iceland (about that many babies were born last year in the hospital where I work in Seattle). If readers know of empirical data from Iceland to support or refute my estimates, please share it.

Of course, for advocates, every loss of a pregnancy with Down syndrome is serious, no matter how small the number. But these estimates put the concerns in some perspective. Among other things, it is fair to say that most, but not 100%, of pregnancies with Down syndrome are terminated in Iceland, and the birth prevalence of Down syndrome in Iceland is falling considerably but not likely, in my view, to disappear entirely.

I think a more realistic picture of the impact of prenatal screening on Down syndrome, in the US at least, is provided by Brian Skotko and his colleagues Frank Buckley, Jennifer Dever, and Gert de Graaf in a recent publication in the American Journal of Medical Genetics. Over the last few years, they have consistently provided some of the most reliable estimates of the demographics of Down syndrome and the effects of prenatal screening.

According to the de Graaf et al. paper, a detailed look at changes over time in the demographics of Down syndrome in 9 states, the number of people living with Down syndrome has steadily increased since 1950. The two major factors driving that growth have been longer survival due to better medical care along with the unrelenting trend of the last 35-40 years of delayed childbearing. This growth, however, has been partially offset by a loss of births with Down syndrome due to prenatal screening. The loss varies with geographic region, but overall, the prevalence of Down syndrome is roughly 70% of what it would be if prenatal screening were not available. Interestingly, the most growth in the Down syndrome population occurred among Hispanics and Native Americans. So, unlike the near elimination of Tay-Sachs disease in many Ashkenazi Jewish communities, the prevalence of Down syndrome is dropping, but not close to disappearing, at least in the US.

Other factors may affect the Down syndrome birth frequency, such as changes in maternal age distribution, availability of abortion, and access to health insurance. For example, in the highly unlikely event that every woman 35 and older refrained from pregnancy, the birth frequency of Down syndrome in the US and many Western European countries would be reduced by more than 50%. On the other hand, if abortion were to become illegal (not highly unlikely), then presumably the birth frequency of Down syndrome would increase. Limiting access to good medical care (unfortunately also not highly unlikely in the US) could lower the overall prevalence of Down syndrome because of reduced survival.

Current trends suggest that, for the immediate future, prenatal screening will continue to reduce the birth prevalence of Down syndrome. It is becoming increasingly easier for women to undergo prenatal screening and more difficult to just say no. This is due to aggressive marketing by commercial labs of “newer, better, bigger, cheaper” screening tests like NIPT; the dearth of time and resources devoted to unbiased education about Down syndrome and the pros and cons of screening tests; inequitable social distribution of medical resources and social support; and the rarity of long, difficult discussions between pregnant women/couples and their providers about whether they should even enter the prenatal screening cascade to begin with. It also does not help matters that the current US President lacks any moral decency and takes pleasure in mocking people with disabilities.

Although I am a strong supporter of women’s reproductive rights and well-informed, gut-wrenching decisions to terminate a pregnancy, it is becoming increasingly difficult to provide ethical justification for further expansion of prenatal screening, or expanded carrier screening for that matter. This is something that society needs to address but particularly genetic counselors because we are in the thick of it.

As I have previously argued, almost no research has been conducted that has tried to demonstrate whether prenatal screening can improve the medical, social, and emotional lives of people with disabilities and their families. Some women undergo prenatal screening because they think it will prepare them for raising a child with Down syndrome, but we really can’t tell them if screening does help or if it is worth their emotional and psychological investment. Carrying out such research is critical. If we can demonstrate broader benefit of prenatal screening, then we can open up a dialogue with the disability community rather than continue the shouting matches, and offer greater and more equitable justification for NIPT and other screening technologies.

Or we can continue shouting at or dismissing one another.

 

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Human Germline Editing: our crazy, scary, wonderful future is coming, but not quite yet

Publication this week of a paper by reproductive biologist Shoukrat Mitalipov and others put the subject of editing little baby humans front and center – above the fold news in the NY Times. Universally, the Mitalipov study was recognized as a milestone, and so it appears to be – a milestone on our journey to…wherever it is we are headed.

 

What did they do, and why is it important? Mitalipov improved greatly on previous efforts at germline editing, targeting embryos created using donor eggs and sperm carrying a pathogenic variant in the MYBPC3 gene associated with hypertrophic cardiomyopathy. Modification was successful over 70% percentage of the time, no off-target effects were detected, and only one of the 58 embryos was found to be a mosaic of altered and unaltered cells. While significant safety and efficacy concerns remain to be addressed, this work goes a long way toward validating the idea that, sooner rather than later, clinical use of this technology will be a realistic possibility.

 

The experiment raised hopes, but also some questions. CRISPR is often described as a DNA version of a search-and-replace function in a word processing program, but CRISPR itself only does search-and-remove. The ‘replace’ part leverages the cell’s own machinery for fixing breaks in DNA, and its innate penchant for tidying up any loose ends. Quick to the breach, cells can often be coaxed into using a template for the repair if one is provided along with enzymatic scissors and a guide RNA, allowing us to insert a custom DNA sequence. This bespoke DNA can be anything, but in this case it was meant to be a benign version of the MYBPC3 gene. In a surprising development, the cells preferentially ignored the synthetic template and used the unaffected version on the sister chromosome as a guide instead.

 

This had the desired effect of introducing a functioning wildtype gene, but if it is not overcome as a technical issue, will limit the range of what can be achieved via gene editing. This model doesn’t work at all with recessive disease, where there are two copies of the pathogenic variant. Additionally, it would not allow for the introduction of DNA sequences other than what is carried by a parental allele – a capability which is, I would argue, the truly unique feature of gene editing.

 

Articles about CRISPR may (and usually do) talk about its potential to prevent Mendelian diseases like Huntington’s or sickle cell, but we are already capable of preventing transmission of these diseases using IVF with PGD to identify embryos that are unaffected. Yes, as has been pointed out, this is not foolproof. A round of IVF may produce no unaffected embryos. In rare circumstances, one parent may be homozygous for an autosomal dominant disease. These are non-trivial events when they occur but they are rare and limited circumstances. For the rest, replacing one expensive and complicated technology with another is incremental progress at best, and not the reason why this story was A-1 on the NY Times website. Media interest, let no one be confused, was about the potential of CRISPR to produce what they referred to (inevitably) as designer babies.

 

Screen Shot 2017-08-04 at 9.27.15 PM

Antonio Regalado of the MIT Tech Review decodes media coverage of human genome editing

 

Can the technology produce designer babies? This would be an easier question to answer if designer babies were actually a thing that you could define, but they’re not. Generally, what people mean by ‘designer baby’ is one created through any use of reproductive technology to ensure specific traits, as opposed to using identical technology to avoid diseases. The problem with this is that drawing the distinction is a bit of Impressionistic painting – clear from a distance, but blurring together when you get close. A number of articles this week suggested that designer babies can’t happen because traits are not something that can be manipulated by tweaking a gene or two (here and here). This is comforting but may not hold up. It’s fair to say that you can’t tweak general intelligence – but what about, for example, executive function? And while we’re on it, would that be increasing intelligence (bad) or avoiding ADHD and other mental health problems (good)?

 

But this is leading me into rabbit holes, where we debate what is or might be or could be possible, when just now I want only to say that the potential of gene editing to add an entirely new dimension to what we can currently offer is bound tightly to its ability to introduce DNA sequences that are different from what either parent can contribute. When we are able do that, we can expand the concept of what it means to ‘choose’ a child’s genotype. We can add rare variants that confer some protection or competitive edge. We can even contemplate adding synthetic variants designed in a lab and not borrowed from natural experiments. When move past embryo selection to embryo improvement, we will have our little Gucci baby whose possible existence causes so much consternation.

 

So does this week’s blockbuster paper put us closer to that day? Yes, because the technology has moved forward a giant step. Not that technology ever moves backwards, but the speed with which it has improved is staggering, and while momentum is not going to carry it over the remaining hurdles like a hot wheels car going loop the loop, it does make it easier to assume that all technological barriers will eventually fall. But at the same time, the template surprise reminds us that every step forward reveals another twist in the road.

 

Are we almost there?  Who knows. If 2016 taught me anything, it was to stay out of the prediction game.

 

So what would a wise republic do? Coincidentally, a workgroup under the auspices of the American Society of Human Genetics published a paper yesterday in the AJHG laying out recommendations for public policy on human germline editing. The position statement was approved by ASHG, NSGC and 9 other organizations from six continents (full disclosure: I am one of the co-authors). The take home point is that modification of the human genome (egg, sperm or embryo) would be premature at this time but may be justified in the future, providing that there is a compelling medical rationale, an evidence base to support its use, ethical justification and a transparent public process to solicit and incorporate stakeholder input. In the interim, the organizations encourage governments to permit and to fund work like Mitalipov’s that investigates the potential of human germline engineering.

 

Having been a part of this group, I can attest that we thought long and hard about this aspect of the statement, and that we made it despite our concerns that this technology holds risks for both individuals and society, including the potential to increase existing inequities in health and quality of life. We may try and regulate use and norms such that we get the upside and not the downside, but we must acknowledge that to a large extent the two are inextricable.

 

Speaking only for myself, I can say that I see the allure of a form of intervention that might prevent rather than merely treat sickness and suffering, even as I sympathize with those who worry about the impact of the technology on future generations. If the choice were mine, it would be a difficult choice. But in the end, what I recognize is that we are not given a choice between going backwards and going forwards. The truth is that gene engineering is going to happen.  No one government or individual is going to stop it — the world is too big and the stakes are too large. The questions that sit in front of us are not yes or no, but where, how and under what circumstances. I believe that a thoughtful society should engage with the technology, providing capital and oversight, resources and regulation. To turn our back is to sacrifice whatever leverage we could bring to bear as we establish norms for use, and to cede our leadership role in the scientific community at the dawn of an era, the start of a journey to…wherever.

 

 

 

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Sour Grapes: A Tragicomic Dystopia Set In The Consumer Genomics Counseling Space

So-called recreational genetic testing that provides information about non-clinical traits is often dismissed as harmless. Maybe that’s so. But there is a worrisome potential to any test when technology, artificial intelligence, marketing, and medicine become increasingly intertwined with our personal lives. The mini-play below is a tragedy lurking around the edges of a comedy.

Parental Warning: Some readers may find parts of this posting to be offensive. On the other hand, one of the roles of dark humor is to shock us into ethical recognition.

Setting:  The living room of a married couple who are planning to start a family and desire genetic counseling after learning the results of their ReProfile test, a (fictitious) direct-to-consumer genomics test panel aimed at providing genetic information to prospective parents prior to conceiving a baby.

Dramatis Personae:

Jeanoma [J], a Virtual Personal Genetic Counseling Assistant

Husband [H]

Wife [W]

W: Jeanoma, On! Please pull up our ReProfile results. We received them last night and now we want to discuss them with you.

J: This conversation may be recorded for quality assurance and marketing purposes. Hello, Wife and Husband. I have your ReProfile Basic® test results right here. What are your questions and how can I best address them for you? And are you interested in the ReProfile Expanded test®? It covers more traits than the ReProfile Basic®test. I can upgrade you now, if you’d like, at our Preferred Customer discount price.

H: Jeanoma, no upgrade for now, thank you. We are planning on having children soon so we took that saliva test to have as much genetic information as possible. We want to make the most informed pregnancy plans, have healthy children, and manage our hereditary risks in a rational way that reflects our beliefs and values.

W: Jeanoma, wine is a very important part of our lives. We are dedicated red wine drinkers, as were our families. Of course, I know better than to drink it when I become pregnant. But we have wine with dinner almost every night. We belong to wine clubs. We regularly visit wineries for tastings. We have taken continuing education classes on oenology. Sommeliers sometimes ask us for recommendations. We met at a tasting for 2012 Willamette Valley Pinot Noirs. As I am sure you know, pinot noirs are particularly sensitive to soil characteristics. We think that the unique terroir of the Willamette Valley AVA produces a wine that sometimes put Burgundies to shame. So you can imagine our shock when we learned from our ReProfile test that we might be at risk of having a child who will like only white wine…….champagne for celebrations, sure, okay, we get that, but…..chardonnay, so oaked, or so… bland (Represses a tear). As we understand it, multiple genes determine wine preferences. The two of us have mostly Red Wine genes, but we each have some recessive White Wine genes and our children have a 38% chance of inheriting enough White Wine genes that they would be white wine drinkers. That risk is so high!

H: Nods in agreement, reaches for his wife’s hand. She pulls it away and turns her head to look out the window.

J: These genes code for a molecule called oenorin, a taste receptor that influences your wine preference. Different versions of these genes, called alleles, correspond to red and white wine preferences.These different alleles are named rouge and blanc. We stock an exclusive selection of  small batch release Oregon Pinot Noirs that I can have on your doorstep tomorrow, if you’d like.

H: Jeanoma, so that means that our taste preferences are determined by our genes…..Let me think about that pinot order for a bit.

J: Let me be clear – genes don’t determine our fate. There is a lot of variability in our palate profiles related to our upbringing and environment that influence the ways that our genes are expressed. It must be hard on the two of you to adapt to this new information. What are your feelings about these test results?

W: Jeanoma, we know that we could cope with any issues and problems our kids might have. I am sure that we will love them no matter what. We are not bad people. We know plenty of white wine drinkers who seem content. But why not use the latest technology to help avoid those problems?

J: It looks like this is a very important issue for your reproductive plans. Tell me more about your wine experiences with your families when you were growing up. I can also order the Family Ancestry Test® to further explore your genetic heritage. If you agree to donate your DNA to our Product Development Research Lab you receive a 10% discount.

W: Jeanoma, I felt just terrible for my older sister. We all love her to death. But she didn’t have the Red Wine genes. She was left out of family conversations at supper, stayed home during family outings to wineries. My other siblings teased her mercilessly. She would storm away from the dinner table in tears, her glass of cab untouched or secretly fed to our dogs Rosso and Barolo. She spent many nights locked in her bedroom where I know she was surreptitiously sipping an overly sweet Riesling. My parents wound up yelling at us, and eventually at one other. My mother always blamed the White Wine genes on my father’s family. She would drop the sarcasm bomb – “What does your family know about wine? They’re from North Dakota.” It tore my family apart and my parents eventually divorced. I promised myself that my own family would never be like that. That was why we took that genetic test – to help avoid a broken family. Now, I wish I never had that stupid test. It only upset me and made me anxious. And thanks but no Family Ancestry Test® for now.

H:  Jeanoma, I was an only child, so I never had a sib that I could share my wine experiences with. I wanted something different when I had my own children. I wanted to have four kids who would bond over their pleasure in red wine.

W: Four kids? You never said anything to me about wanting four kids.

H (Shrugs his shoulders): I thought you knew that I’ve always wanted a big family.

J: It sounds like you two need to have some important conversations. Have you thought about seeing a marriage counselor? I can set up an appointment if you would like. Or I can order the three best-selling marriage improvement books from our bookstore and download them on to your e-readers.

H and W (in unison): Jeanoma, uh, that kind of counseling is not for us. We can handle our own problems ourselves.

W:  Jeanoma, right now we don’t feel like reading about our problems either. We want to talk about them.

H: Jeanoma, what do you think we should do?

J: I can’t tell you what to do. Only you two know what’s best for you. But there are a couple of options that might help you. Some of these are very sensitive and you may initially think they are not for you. But you should give each one serious consideration. Challenges sometimes force us to question and change our beliefs.

Some couples in your position just do nothin, choose to roll the reproductive dice, and see what turns up. I can order a set of casino quality deluxe dice for you and have them delivered in two hours to your roof deck with our Drone Delivery System®. Other couples decide to use a genetically screened sperm or egg donor. I can arrange a contract with a donor from Eugene/Eugenia®, our proprietary donor list, if you’d like.

H: Jeanoma, you mean use another man’s sperm to get my wife pregnant or have another woman’s egg in my wife’s womb? No way! And rolling the dice is not an option. We had this testing so we would not have to leave child-making to Lady Luck.

J: Yes, it is difficult to consider, but I urge you to keep an open mind. Another option is preimplantation genetic diagnosis, or PGD.

W:  Jeanoma, is that some kind of test tube baby or something? One of my friends did that.

J: PGD is a special type of test tube baby. You would undergo in vitro fertilization outside of the womb, using your own egg and sperm. The fertilized eggs would be tested for their wine preference profiles. Only Red Wine Profile fetuses would be implanted into your uterus. I can set up an appointment with our Accessorize Your Baby fertility clinic for later this week so you can learn more about this option.

H: Jeanoma, that sounds like it would be expensive. Is it covered by insurance?

J: It is expensive. Some insurers cover all or part of it. Other people choose to have prenatal diagnosis, like amniocentesis or chorionic villus sampling, and then make a decision about whether to continue a pregnancy based on its genetic profile. Other people would not terminate the pregnancy but use that time before birth to adapt to the idea of having a differently wine-enabled child. This way when the baby is born, the parents are well prepared. But I have to advise you that these tests carry a small risk of miscarriage. Would you like to purchase miscarriage insurance? It is much cheaper if you buy it before you become pregnant.

W: Jeanoma, I might consider prenatal diagnosis. I don’t believe in terminating a pregnancy, but I might like to have the emotional preparation. That could be helpful for us, even if there is risk of losing the pregnancy from the testing. Knowledge is power. I would know not to drink red wine before breast-feeding because a White Wine Child might reject my breast milk. I could read about it on the Internet and join online support groups for parents who are attempting to raise White Wine Children or Trans-Wine Children who like both red and white wines. If it’s a girl, we could name her Rosè!

H: Jeanoma, what about this CRISPR thing I’ve read so much about on the Internet?

J: CRISPR is a technology that can alter the DNA sequences of the embryo before it is implanted, to correct any gene mutations. Think of it as a genetic nip and tuck. However, I have to warn you that this is a controversial new approach. Would you like to sign up for Jeanoma Inc.’s CRISPR Helix Adjustment Program®?

W: Jeanoma, I think it could help us solve our problem if it works. And it avoids a lot of the uncomfortable ethical issues of prenatal diagnosis. I am sure we can figure out how to pay for it, no matter what the cost. This is a priority for us. Maybe you can get that appointment set up for us.

J: I can do that. But let me first bring up something else. The ReProfile Basic results of Wife indicate that Wife is at a higher risk of developing breast cancer. What are your thoughts about that, Wife? Would you like me set up an appointment for a mastectomy? Would you like to purchase breast insurance?

W: Jeanoma, oh, that doesn’t worry me. I exercise a lot, I have a very healthy diet, I will be very good about my mammograms, and I only have one or two relatives with breast cancer and they were both smokers, so I think I am not at such a high risk. Besides, all the breast cancer is in my father’s family.  He certainly can’t give me any breast cancer genes. And I look just like my mother and there’s no cancer in her family.

J: Okay, can I do anything else for you today?

H: Jeanoma, yes, please do order that case of Oregon Pinots.

W: Jeanoma, Off!

J: Goodbye Wife. Goodbye Husband.


Thanks to Emily Singh for help with graphics

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Genetic Counseling ≠ Genetic Testing

I know that I am old and curmudgeonly. I acknowledge that my musical tastes and my concept of genetic counseling are hopelessly stuck in the 20th century. I sense in a frighteningly helpless way that my generation of genetic counselors is becoming increasingly irrelevant to the profession. It is like watching the air slowly leak out of my inflatable raft in the middle of a swift flowing river and realizing I don’t have a lifejacket. If you press me on it and buy me a few drinks, I will let slip out an admission that DNA analysis technologies like ion semiconductor sequencing and pyrosequencing are incomprehensible magic to me. I feel like I have become a visitor in my home country and I can barely speak the native tongue anymore.

So this paradox might sound like a useless warning flare fired from a sinking vessel before it goes under, a futile attempt to alert my younger upstream genetic counseling colleagues who are new to navigating these tricky waters: I love genetic testing; I hate genetic testing.

Genetic counselors and genetic testing have grown hand in hand since the early 1970s. At least in the US, one would not have flourished without the other. Amniocentesis, CVS, carrier screening, maternal serum screening, ultrasound, DNA sequencing, microarrays, and other genetic testing advances have all been ushered into medical practice by the genetic counseling profession. The tests generated a need for our unique skill sets along with the security of employment and the financial wherewithal to support our positions. Without genetic testing, we wouldn’t be where we are today. So what’s to complain about, even for a complainer like me?

Well, I have two related complaints. My first complaint is the ever-expanding list of genetic tests that we feel obliged to offer our patients in prenatal, oncology, and other settings. Don’t get me wrong – I think genetic testing can be incredibly valuable from both a medical and a psychological perspective. But I wind up spending way too much valuable counseling time highlighting the differences between Panel A and Panel B and the relative merits of this lab versus that lab. And, oh, by the way, many of the genes included on these panels are largely irrelevant to your particular clinical concerns. I hear similar plaints from some of my colleagues in prenatal – this carrier test for 75 conditions or that one for 200 conditions, or this prenatal screen versus that prenatal screen.

It is often not clear to me why some of these tests are part of clinical practice to begin with. Probably a variety of forces are behind it – the push from labs to offer more tests and to compete with other labs; the common trait of genetic counselors to be early adopters of new technologies; trying to show that we are at the cutting edge of genetics; our obsession with offering ALL options to ALL comers; demands from patients and referring physicians; worry that if we don’t offer the shiniest, newest products our patient population will go shopping at the next medical center down the road, or Heaven forbid, shop online; and a nagging fear of being sued or at the very least of providing sub-standard care. As I have written about previously, sometimes genetic tests became standard of care before they were thoroughly vetted, evaluated, and debated.

Which leads me to my second complaint. There is a tendency, sometimes overtly and sometimes silently, to conflate genetic testing and genetic counseling. Yeah, sure, genetic testing is an important part of what many of us do, but my job title says counselor, not tester. For some genetic counselors, testing is not even part of their job. We educate, provide clinical expertise to other care providers, and participate in research. There are other services we provide to our patients, not the least of which should be an intense psychological, personal, and occasionally angst-filled exploration of why patients might even want testing to begin with, never mind which test they want. We are there to support and work with them when no testing was done, when testing is irrelevant, or when testing was done in the past and we are helping them adapt to their new medical and emotional status. Let’s look at what your worries and fears are, and why you are in my office to begin with. What has it meant for your life that you or your child or your sister have this condition? What resources do you need? How have your loved ones been supportive or not of you? What are your health care and life goals? Or bigger picture questions such as what are the medical, economic, and social impacts of genetic disease?

At times I think that genetic counseling for psychiatric conditions is the last pure form of genetic counseling – reliable genetic testing is not available for most psychiatric conditions, so you are “forced” to rely on your counseling and clinical skills. Okay, so perhaps I exaggerate a bit, but you catch my drift. I remember my long time colleague Vickie Venne once saying to me that cancer genetic counseling became a lot less interesting to her once BRCA testing became available. While not denying the many benefits of BRCA testing and how it has helped save lives, there is a measure of wisdom in Vickie’s statement.

As a profession, we should extol and support our role in ordering and interpreting genetic testing. But we, or at least I, don’t want testing to be our defining activity. Yes, as one of our skill sets, we are pretty damn good at it. But let’s not forget that it is a counseling session, not an Informed Consent session or a sales pitch. We should boast more about our abilities to help patients make sense of genetic disease for their lives in a psychologically meaningful way, and testing is only one means of achieving this goal. Genetic counselors are not Genetic Testers; Genetic Counseling is not Genetic Testing.

 

 

 

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Euphemisms, Chucklers, Pet Peeves, And Wincers: Thoughts On Our Professional Vocabulary

Words are the clothes thoughts wear.

– Samuel Beckett

I struggle with words. I struggle when I counsel patients to find just the right words to explain genetic complexity while also trying to engage them in a counseling relationship. I sometimes catch myself silently groaning at the stream of what sounds like the absolutely wrong choice of words pouring out of my mouth. I wind up feeling like the voice of the parents in those Charlie Brown cartoon specials; just Wah-Wah-Wah, nonsense utterances that have no meaning or relevance to the central characters. I struggle to understand the psychological meaning of the words patients use to express their thoughts, fears, anxieties, understandings, and misunderstandings. I agonize over these blog postings, repeatedly re-working them until they have the right tone and tenor but still I always feel slightly dissatisfied with some detail of the never-quite-finished product. A close friend says that for him the wrong word is like a flat note in a musical composition. One jarring note and it takes a while for your ear to re-adjust.

So yes, I confess that I am overly obsessed with words. It is yet one more of those Devil-and-Angel aspects of my personality. Good and bad must co-exist else neither exists at all. That obsession is the impetus for this blog posting – exploring the deeper meanings, ramifications, and implications of the vocabulary of genetics, medicine, and reproduction.

I start with words that make me wince. I have previously written about products of conception, habitual aborter, and mutant. Let me add incompetent cervix and birth defect to that list. Even though these words are not used with dark intent, they say a lot about underlying unconscious attitudes and biases. Incompetent cervix is clearly a term created by men for women. Would a man who has difficulty attaining or maintaining an erection ever be said to have an incompetent penis? Birth defect is no better, though in all honesty I catch myself using it from time to time. Just another malfunctioning piece of machinery, a mistake, a reject, an inferior product of conception. And don’t get me started on crack babies. These are all judgmental and harmful words, weaponized to induce blame, shame, and guilt.

In some contexts, benign words can be manipulative, such as high risk. Every patient has a unique and flexible definition of high. But when professionals say high risk it can create a disproportional sense of worry and anxiety. For example, it is often said women 35 and older are at high risk of having a baby with Down syndrome. You can try to soften that by saying higher but the patient mostly hears the high part of that word. In fact, though, the chance that a 38-year-old woman will not have a baby with an aneuploidy is 99%. Those are pretty good odds in my book. But the presumably unconscious and unstated attitude of health care providers is that aneuploidy is an unacceptable outcome – a risk, not a probability – when they show a woman a graph or table displaying age related odds without an objective reference point to put the numbers in context. That is a lot scarier than reframing it as barely 1%, as well as sounding like an unstated scolding – “Well, if you hadn’t waited so long to have a baby, you wouldn’t have this problem.”

Some words are euphemisms. Family balancing – using reproductive technologies to choose the sex of a baby for non-medical reasons – comes to mind. It is fine and normal to want a baby of a particular gender. There are also different cultural imperatives and norms, and complicated psychological reasons why a particular gender is strongly desired.Calling it balancing glosses over the darker implications of reinforcing, and profiting from, sexism. And it implies that a family of all girls, all boys, or varying gender mixes might be out of balance.

Family balancing is a cousin to gender swaying. At first I honestly thought it referred to someone like David Bowie who seemed to fluidly float along the gender spectrum. As I have come to learn, gender swaying describes the practice of trying to increase the odds of having a baby of a particular gender by using folk methods and pseudoscientific techniques, like ovulation timing, cervical PH, and, my personal favorite, positive and negative ions in the air that can be affected by artificial lighting (just why would artificial lighting be found, uh, “down there”?). Somehow it seems more ethically innocuous than family balancing, maybe because the success rate is usually not statistically significantly greater than 50%. But family balancing and gender swaying are on the same moral spectrum. Another euphemistic term is fetal reduction, which neutrally smooths over the rougher ethical edges when a medical procedure transforms a quadruplet pregnancy into a twin pregnancy.

In genetic counseling, we try to reciprocally engage our patients to make the experience more counseling than lecturing. But there is still an underlying power dynamic that can sneak between the cracks and that can remind the patient who is in charge. An example is when we say that we take a family history. Although it is not how we intend to use the word, taking implies that I have the power to assume ownership of story that belongs to the patient, a story that is deeply personal. And by taking it, I now own this intimate knowledge and transform it into something that I reframe into a medical context that gives me power by “interpreting” it for the patient. The message can be “I know what you think about your family history, but let me tell you what it really means.” Perhaps too this power differential  underlies some of the unease many genetic counselors have about Direct To Consumer genetic testing – it diminishes our gatekeeper role of controlling access to genetic testing.

Along those lines, think of the power relationship implied by medical consultation notes that state that the patient denies a family history of genetic disease or drug use or certain symptoms. Denies? Like they are suspected of lying or a criminal activity, and I am the Grand Inquisitor trying to drag the truth out of them? Were these patients ever expecting the Spanish Inquisition?

Not all of my vocabulary pondering is dark. Some reflect my personal pet peeves on usage. I am not a Language Fascist who tries to enforce arbitrary grammatical rules because, dammit, that’s the right way. On the contrary, I love language for its variety, constant evolution, playfulness, and wonderfully creative adaptability. But a few words rub me the wrong way. Pre-existing condition is an ear-sore for me. How can something be pre- to existing? Either something exists or it doesn’t. They are existing conditions. Of course, this mild upset is nothing compared to the outrage I feel at the pig-headed, uninformed, downright nasty views about pre-existing conditions expressed by the President of the United States and his lackey Director of the Office of Management and Budget, they who are too shameful to be named. Now there’s a pair of bad hombres you’d love to rope with Wonder Woman’s Lasso of Truth. Another “earitation” is when someone writes “The patient was told to return in 3 weeks time.” In that sentence, the word time belongs in the Department of Redundancy Department; the same information is communicated if the word is omitted. For my internal ear, it is a jarring note.

Another, perhaps more justifiable, pet peeve is when an author or speaker says something along the lines of “there was a 500% reduction in disease occurrence following this intervention” or “a five fold reduction in occurrence.” Sorry, just flat out impossible. Nothing can be reduced by more than 100% or 1 fold. After that, it ceases to exist (unless of course it were pre-existing) or it becomes an imaginary number*. If the number of cases of a disease decreases from 500 patients to 100 patients, that is an 80% reduction. Or there are one fifth of the number of cases that occurred prior to the intervention. And I don’t believe I am being a kvetcher here. Accuracy in statistical analysis and interpretation is at the very core of the scientific process and discourse, so it is critical to use the right words to describe research results.

There are some words that make me smile when I hear them, such as Captain Underpants’ arch-nemesis Professor Pippy Pee-Pee Poopypants or HMS Boaty McBoatface (okay, they have nothing to do with genetic counseling but even if your inner mind is not permanently mired like mine in the 8 year old boy phase, these names make you chuckle). Similarly, I smile when I hear surgeons describe large breasts as generous. How nice that someone has generous breasts! It almost sounds like a description of a wet nurse. A long time favorite is Instant Baby Formula, which I first encountered 45 years ago when I was a stock clerk at a Brooklyn grocery store. Just add water, and Voila! You have a baby. What could be simpler? None of the icky bother of 9 months of pregnancy or the agonies of labor.

I would love to hear from the Good Readers of The DNA Exchange about their thoughts on the vocabulary of genetics and medicine. What in our professional lexicon makes you irritated, raises your moral hackles, induces euphemistic groans, or you just enjoy? Given the widespread employment of genetic  counselors in laboratories, is there some new Lab Vocab starting to emerge?

As Raymond Carver once wrote in a NY Times piece, “That’s all we have, finally, the words, and they better be the right ones.” So let us make sure we think carefully about them, choose and use them wisely, never weaponize them, and remember to enjoy them.


  • – Yes, I know that this is not technically an imaginary number. I am just employing poetic license.

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Why Me?

“We tell ourselves stories in order to live.” – Joan Didion

Even after decades of clinical experience I am still struck by the sometimes random and sometimes cruel nature of the occurrence of genetic and congenital conditions. You meet a family with 3 successive children with a profoundly serious recessive condition and the next carrier couple that you see have 6 unaffected children. A grandmother watches her husband, son, and grandchildren die from Li-Fraumeni cancers, and then you encounter a TP53 mutation in a young woman with breast cancer and a family history devoid of other cancers. A gene panel reveals that a woman has dodged a BRCA1 mutation in a pedigree overflowing with breast cancer – but she has a pathogenic APC mutation and not a single relative with colon cancer or polyposis. An adopted woman learns she is pregnant the same day she is contacted for the first time by her biological family and told that her biological father just died of Huntington disease.

We consult the Codex of OMIM or the Oracle of Bayes, and then tell scientific stories of skewed mendelian ratios or stochastic processes (Literal translation: Shit happens), stories as much for ourselves as for our patients. My favorite (non)explanatory story is “a multifactorial combination of genetic and environmental factors.” Come on, please. What human trait is not the result of a combination of genetic and environmental factors? We can wind up committing the original sin of genetic counseling – responding only with cold, meaningless facts to patients’ cris de coeur for comfort, validation and acknowledgment of their emotional states, their quest for a psychologically meaningful understanding and acceptance of their situation, and the need to make sense of their suddenly upturned lives. We should be forgiven though. Genetic counselors are only human and who among us is without sin? None of us were immaculately conceived.**

Patients will fill this void with their own stories. It was that stress in my life. They used to spray insecticide all the time in my neighborhood and now every house on my block has someone with cancer. Then there are the somewhat morally judgmental plaints – I am a vegan, I exercise daily, and put no poisons in my body; my sister eats only fast food, smokes, drinks, and has a new boyfriend every weekend, but I am the one who gets cancer and it’s just not fair. Or it must have been the manufacturing plant down the road with that awful chemical smell (How come no one ever lays the blame on pleasing aromas like cinnamon buns in the oven, freshly roasted coffee, or the sensual curry infused scent of an Indian kitchen?).

If Joseph Campbell was right, mythopoesis is as innate as erythropoiesis. Our minds can’t help but tell stories like our marrow can’t help but make blood. So let me offer my own mythological explanation of the epidemiology and distribution of genetic and congenital disorders – Pedigrus Rex, the god and ruler of pedigrees. Pedigrus is definitely  in the classic Greco-Roman tradition of a powerful god ready to unleash his power at a mere whim or perception of insult, without the slightest thought to consequences. As much Zeus as Trickster.

Pedigrus rex

Sometimes he is benevolent. Let’s see, I will render that woman pregnant after she has given up, exhausted from years of unsuccessful fertility treatments. Sometimes he is terribly unkind (Pedigrus Wrecks?). Hmmm, I think I will give a tetralogy of Fallot to that baby with severe ichthyosis. Hey, why not introduce yet another common mutation in another gene to the Ashkenazim? Sometimes he is astonishingly trivial in his malevolence, like making my pedigree software malfunction after having entered a hugely complex family history. Usually, though, he is emotionally indifferent, just going about his business of indiscriminately sowing the seeds of sadness, joy, shock, and love into the soil of human reproduction. We may try to appease him with sacrifices in our temples or try to understand his motives by consulting seers and prophets in our clinics. Mostly, though, he is beyond comprehension and placation.

This is not to lessen the importance of providing medical and scientific explanations. Many patients want technical information and often that is why they come to us. The beam of knowledge sheds some light for them but does not fully illuminate. They will integrate the scientific story into their own narrative – but on their own terms. It is only part of what they are seeking. Our duty to patients is not discharged once we have given them a recurrence risk or a name to their child’s condition. We need to help them create a psychologically meaningful narrative, a life story, that helps them cope and adapt to their situations, to grow and move on.

The Greek tragedies teach us that we have the ability transform sadness into love, shock into acceptance, fragility into strength, denial into hope. Suffering (pathos) turns into recognition (anagnorisis) and reversal (peripeteia). Humanity trumps divinity by telling stories that work emotional miracles. We can all be greater than gods.

“Mythology, in other words, is psychology misread as biography, history, and cosmology.”
― Joseph Campbell, The Hero With a Thousand Faces

Thanks to Emily Singh for help with the graphics.


** Let me digress here and correct a common “mythconception” about the term Immaculate Conception. Most people use the term to describe a conception that occurred without the benefit of sexual intercourse. This is quite incorrect; this is confusing Immaculate Conception with Divine Conception. Immaculate Conception refers to Mary, the mother of Jesus, and not to the conception of Jesus. In Roman Catholic doctrine, Mary, who was the product of conjugal relations between her parents Joachim and Anne after years of infertility, was the only human ever conceived without Original Sin on her soul, i.e., she was immaculately conceived. Jesus, on the other hand, was the product of Divine Conception by the Holy Spirit. He could not have been conceived in the usual style because that would have tainted him with Original Sin, a trait he would have inherited from Mary’ s husband Joseph. Mary learned of her pregnancy at The Annunciation, traditionally 9 months before Christmas on March 25th, when the Angel Gabriel announced to her that “the Holy Spirit would come upon thee” resulting in the miracle of divine conception in Mary’s virginal womb that was unblemished by sin or sex, and without Joseph’s, er, assistance (Joseph had his own visit from an angel who sort of explained the situation to him. So you  might understand why Joseph was deserving of sainthood.).

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FDA and 23andMe change their Facebook status to ‘in a relationship’

In 2007, 23andMe launched their personal genome scan, a SNP-based test that offered consumers an estimate (some might say a guess) as to how certain elements of their genotype might contribute to their likelihood of having an array of traits and diseases. It was a great success, if success was to be measured in ink and column inches rather than actual dollars. Anne Wojcicki’s company quickly came to represent the embodiment of direct-to-consumer genetic testing, an icon of what was more a movement than an industry.

 

For that reason, six years later, when the FDA surprised 23andMe with a cease and desist order for their genome scan, it could reasonably be taken as a rejection of not only one company but the entire DTC ethos. At the time, many canny observers pointed out that the FDA’s drastic move seemed to have more to do with 23andMe’s attitude than it did with any specific risk posed by testing. As Duke University genetic professor and trenchant observer Misha Angrist was quoted as saying at the time, the FDA missive read “like the letter of a jilted lover…‘We went on fourteen dates! We exchanged all these e-mails! We held hands in the park! Now you’re telling me, “Fuck you,” and kicking me to the curb.’ ”

 

In response, a chastened 23andMe kept a toe in the DTC puddle by offering testing for ancestry and non-medical traits like sleep patterns and eye color while negotiating a slow courtship of the regulatory body. Eventually they got flowers back from the FDA – or rather a single flower, permission to offer just one carrier test, for the aptly named Bloom syndrome. But this blossom, like many others, was freighted with greater significance, and now that they were friends again the FDA decided that other DTC carrier tests would no longer require individual premarket approval, allowing 23andMe to add back a layer of medical testing to their business model.

 

The FDA drew a line between giving out information on carrier status (okay) and giving out information that was diagnostic (not okay). This created the odd situation where 23andMe could tell a customer if he or she had, for example, one CF-causing variant but was forbidden to inform them if they had two, since that was a presumptive diagnosis. Let’s leave aside how confusing this all gets, since sometimes people can have two disease-causing variants and remain healthy, and sometimes carriers can have medical complications. I’m not even going to mention that. See how I didn’t mention that? The bottom line was that 23andMe could inform you of a risk for something that might happen, but only if it was a mere possibility and not if it was certain or highly likely.

 

Two years later, the FDA has come out with another announcement – this time I assume that 23andMe is less surprised than the rest of us – that will expand the universe of what is available through DTC testing. The company will now be allowed to provide testing for susceptibility to 10 diseases and conditions with significant health implications, including late-onset Alzheimers disease, Parkinson’s. celiac, Gaucher’s disease type 1, hemochromatosis, and others. Again, this isn’t just a bouquet of flowers being handed out to a patient suitor. It signifies a change in thinking at the FDA about the value of DTC genetic testing, which they noted in their press release “may help to make decisions about lifestyle choices or to inform discussions with a health care professional.”

 

No but really this is getting embarrassing get a room you two.

 

The FDA announcement indicated that these 10 diseases were merely a beginning. In the future, 23andMe and other trusted practitioners will be able to introduce tests with less regulatory scrutiny. The FDA’s commitment to a streamlined and less burdensome process demonstrates a new interest in making DTC genetic testing widely available.

 

The important thing, emphasized Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, was that consumers did not come away believing that genetics was destiny. “…it is important that people understand that genetic risk is just one piece of the bigger puzzle, it does not mean they will or won’t ultimately develop a disease.” For this reason, the FDA has doubled down on it’s practice of differentiating between susceptibility and diagnosis.

 

Conceptually, this makes sense. Practically, in some cases, it creates a situation where DTC customers can access the sort of probabilistic information that we are generally loathe to give out in a clinical setting – like their chance of getting late-onset Alzheimer’s disease – but are blocked from getting exactly the sort of definitive, actionable information we value the most.

 

Possibly, this might serve to differentiate the realm of DTC testing from the kingdom of clinical medicine. Genetic counselors, often DTC skeptics, might feel more comfortable adopting a live and let live approach if areas central to GC practice like susceptibility for cancer and heart disease were reserved for the clinic. Still, when it comes to ApoE, it is a bit of a paradox that the solution to information deemed too hot to handle by counselors is to give it out with no counseling at all. The impact, I am inclined to believe, will be to speed the integration of probabilistic testing into genetic practice. In the meantime, it will almost certainly herald a period of rapid expansion of health and wellness testing in the DTC space.

 

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