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Down Syndrome

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At 10 weeks

At 10 weeks

A paper in The New England Journal of Medicine, Cell-free DNA Analysis for Noninvasive Examination of Trisomy, reports on the effectiveness of a new proprietary method to screen for Trisomy 21, which is the cause of 90% of cases where individuals exhibit Down Syndrome. This issue is well known at this point. There are many methods to screen and diagnose Down Syndrome prenatally, but they all suffer from drawbacks, from invasiveness to false positives. Currently the vogue is for methods which analyze maternal plasma. That is, all that’s needed is a blood draw from the mother. This is one such method.

auc Their data set was large, N > 15,000, and not particularly old, with a mean maternal age of 31. Here’s a key point: “Among the 11,994 women with low-risk pregnancies on the basis of a maternal age under 35 years, cfDNA testing identified 19 of 19 women with trisomy 21, with 6 false positive results.” This is actually a good result, as older methods have a much higher false positive rate. But many people will not be reassured when they see that the true positive and false positive ratio is so high. Base rate neglect is always going to crop up. For many couples who get positive results confirmatory evidence is essential. That is why it is crucial that the mean gestational period of detection has to be pushed back beyond the beginning of the second trimester if these tests are to cause the minimum amount of discomfort for the couples. The later the abortion, the more psychologically and physically stressful the process.

But, I put a question mark in the title of this post because there is often an assumption that widespread screening will result in a massive decline in the number of individuals with Down Syndrome, to the point of extinction. Actually, I’m not sure about that. It seems that widespread adoption increases the pool of people who are getting tested, and fewer of these in the United States terminate pregnancies through abortion that the early adopters. As mean maternal age creeps up the number of people with Down Syndrome in the United States may not decrease nearly as much as we expect.

• Category: Science • Tags: Down Syndrome 
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Fetus at ~12 weeks

I am going to get back to the eugenics debate at some point, but it is hard to motivate myself. This is due to a combination of complacency and sanguinity. Many of those who use eugenics as a “scare word” or are “very concerned about it” don’t really seem to get past generalities when it comes to the present situation (i.e., there is detailed exploration of past atrocities, and some exploration of rather unrealistic scenarios, such as occurred with the “Chinese eugenic” story, but little concrete engagement with realities such as the high abortion rates for positive tests for Down syndrome). In more crass and intellectually vapid discussions liberals and conservatives tend to use eugenics as a term of selectively useful instrumental rhetoric, a bludgeoning instrument only in the mindless screaming discourse.

Meanwhile, we have advances like the whole genome sequencing of second trimester fetuses. This is still basic science, but in genomics basic science is translated really fast to the consumer market. I’m ~90 percent sure my daughter will have a 10 x whole genome sequence by the end of 2014 (I might even get her parents in on the game for a trio). So, submitted for your interest are two papers on first trimester noninvasive screens for Down syndrome due to aneuploidies (and other syndromes). Non-Invasive First Trimester Blood Test Reliably Detects Down’s Syndrome and Other Genetic Fetal Abnormalities:

An Ultrasound in Obstetrics & Gynecology study by Kypros Nicolaides, MD, of the Harris Birthright Research Centre for Fetal Medicine at King’s College London in England, and his colleagues is the first to prospectively demonstrate the feasibility of routine screening for trisomies 21, 18, and 13 by cfDNA testing. Testing done in 1005 pregnancies at 10 weeks had a lower false positive rate and higher sensitivity for fetal trisomy than the combined test done at 12 weeks. Both cfDNA and combined testing detected all trisomies, but the estimated false-positive rates were 0.1% and 3.4%, respectively.

A second Ultrasound in Obstetrics & Gynecology study by the group, which included pregnancies undergoing screening at three UK hospitals between March 2006 and May 2012, found that effective first-trimester screening for Down’s syndrome could be achieved by cfDNA testing contingent on the results of the combined test done at 11 to 13 weeks. The strategy detected 98% of cases, and invasive testing was needed for confirmation in less than 0.5% of cases.

We did CVS. We’d rather not have to in the future. The key is to move positive tests into the first trimester. No matter the reality that most couples who receive a positive result in early second trimester choose to terminate, when it comes to killing a fetus every week counts. You can see what I mean when you look at how abortions are performed as a function of fetal development. Not only that, if you read the source papers you see that the typical woman who receives these sorts of screens is 35-40 years of age, and in that case with the fertility clock ticking every week is of the essence.


  1. Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies.Ultrasound in Obstetrics & Gynecology, 2013; DOI:10.1002/uog.12504
  2. First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood cell-free DNA testing. Ultrasound in Obstetrics & Gynecology, 2013; DOI:10.1002/uog.12511
• Category: Science • Tags: Abortion, Down Syndrome, Eugenics, Health 
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I often criticize Lefty readers for their lack of reality-basis. Specifically, they often want to align reality with their own normative preferences, even though normative preferences aren’t necessarily contingent upon reality (e.g., sex differences). My post on Down Syndrome has elicited similar responses, but from people one might term social conservatives. So, for example, Ursula and Matthew Hennessey have taken to denouncing me on Twitter, albeit for statements that they no doubt find extremely objectionable. Not too surprising. But I found this post, A gift named Magdalena, particularly instructive:

But we aren’t victims. In fact, we’re the opposite. We are supremely lucky. Magdalena isn’t sick. Down syndrome is not a disease; it’s merely a collection of traits, all of which occur, though not all at once, in so-called “normal” people.

But how could Down syndrome be a gift? Surely that’s taking it too far. How could a lifetime of likely dependency be a gift? How could impaired cognitive development be a gift? How could gastroesophageal reflux disease and its expensive, twice daily medicine be a gift? How could two full years of potty training with no end in sight be a gift?

The truth is that there is no objective bright line between trait and disease. In fact, nature does not know trait or disease, it only knows phenotypes. Being white skinned in a pre-modern world is a disease at the equator, and being black skinned in Scandinavia would also have been a disease. In theory you could argue that Down Syndrome is not a disease either. The Hennessey’s are correct that the collection of traits of DS individuals can be found elsewhere. So imagine that a chemical exposure or some such thing functionally transformed a child with a normal karyotype into one with Down Syndrome. How would most people feel about this? Would parents view it as a gift?

Unlike some people who support abortion rights I don’t think that being pro-life is a malevolent anti-woman position. I think it is a sincerely held normative stance which has a basis in some straightforward logic. If you are pro-life, and you think abortion is the killing of a person, you don’t need to outline to me how valuable a human life is. That is something we begin with a priori. As it is, the reaction of some social conservatives to the reality of the abortion of individuals with congenital defects seems to me to resemble the caricature of Leibniz’s solution to theodicy. Instead of plainly stating why it is wrong, they seem to want to abolish the reasons which people give for having an abortion as reasons at all. The reasons may be valid even if the action is not right.

In any case, the Hennessey’s response is not that unusual in the specifics. Many people have had to take care of family members who are ill or infirm. They often state that these experiences build their character, and there is no doubt that their actions are the right, proper, and moral thing to do. But that does not entail that illness and infirmity are not things to be avoided if that possibility was available!

More broadly my point is that as a society we don’t have a good way to talk about human difference. We accept moral equality, but then implicitly go beyond that to destroy the distinctions between us, horizontal (e.g., male vs. female) and vertical (e.g., intelligent vs. not intelligent). The paradox is that in our choices we continue to acknowledge the power of difference, likely because our cognitive intuitions are keen toward detecting and sifting across differences.

• Category: Science • Tags: Down Syndrome, Health 
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An interesting comment:

“If you add copies of a gene the result is not always good because of dosage effects (Down Syndrome is an extreme case of this on the smallest chromosome).” [From my post, -Razib]

As a father of a child with Down syndrome, I would take exception to this comment. First DS, is not “bad” – my daughter is an amazing and wonderful person, and her DS is part of that wonderful person. She is one of the most amazingly positive things that has ever happened in my life. So I have a hard time reconciling that with your “extremely bad” synopsis.

Second, DS is not an at all extreme case – it is rather run of the mill. It is so minor of a variant that it is survivable and very common place (1 in 733 births). People with DS lead full, productive and meaningful lives. That is not extreme, it is mild. Extreme would be being born inside out or having no chance of surviving 72 hours.
Please don’t add to the misconceptions around Down syndrome. Most of us parents, siblings, and self-advocates find this to be both untrue and unhelpful.

I feel to some extent that the commenter is engaging in a few rhetorical tricks (e.g., contrasting Down Syndrome with diseases which result in mortality within a few days of birth). But his point is well taken. I think it is useful because it smokes out some presuppositions about the nature of the world and the values we hold. The sketchy statistic is that 90% of couples who receive a positive result for Down Syndrome opt to kill their fetus (the shift toward older mothers though means that the number of children growing up with Down Syndrome is not declining nearly as much as you’d think). But in the media you see many more pieces such as George F. Will’s: Jon Will’s gift (for the record, Will is an agnostic). There seems here a disjunction between how people act, and what people say. Or, perhaps more accurately what people don’t say.

One tack would be address Brad, the commenter, head on. I might point out that Down Syndrome can be bad, even if his daughter is a joyful and happy person who brings nothing but good into his life. But I don’t want to argue on the details of one specific case here. I suspect most readers will accept that I don’t think that just because I believe Down Syndrome is a disease I mean to imply that the lives of people with the disease are totally bereft of happiness, or that they are without value. That’s a caricature which only leads to fruitless and symbolic discussion, which plays out mostly for public consumption, and is not getting to the heart of the issue.

And the heart of the issue is that I believe that humans flourish best when they are beautiful, intelligent, and healthy. Some people deny that beauty and intelligence are anything but social constructs. But I bet a survey of progressive and enlightened women who might accept such propositions at face value, but who are in need of sperm donors, would indicate that no matter what people say for their peers to align with social norms they believe that beauty and intelligence are heritable, and their preference would reveal that they value these traits (individuals looking for sperm donors tend to value intelligence, height, and athleticism in the potential biological fathers). As far as health, as Brad’s comment suggests that’s a somewhat subjective proposition. Many of us have allergies. Are we diseased? I’m a very happy person who brings great joy to some people, but I do have this common autoimmune disease. Additionally, I’d also be happy to get rid of it. To address Brad more specifically: his daughter’s Down Syndrome is not a necessary condition for her being a wonderful and amazing person. I wish she did not have Down Syndrome.

All of this naturally opens us up to the “slippery slope” rebuttal. I think that’s a useless argument and I’m going to ban you if you bring it up. I don’t want to create a clone race. Being tolerant of a reasonable range of genetic and phenotypic diversity does not mean that one should be equanimous to the birth of people with karytotype abnormalities. I’m sure at some point someone will use the term “karyotype diversity” in more than a technical sense. It’s keeping with the spirit of the age, but it’s a farce. Diversity is not strength when that diversity is diversity of disease. Heart disease, congenital defects, disfigurements, obesity, and mental retardation are not strengths. They are all tragedies of various degrees.

The point of this post was to forthrightly admit and assert what I think are values which most of the human race holds implicitly. These values to some extent have been silenced because of the unfortunate fact that the Nazi regime took these intuitions and warped them to perverse and inhumane purposes. But I do not think that the world we have today is the “best of all worlds”, I think we can do better, as individuals, and as a society. It is doubtful we can abolish disease, but we can make a dent it in. It is doubtful that we can all be as svelte and fit as we wish, but we can aim toward such a goal. Unfortunately we do not cultivate our minds to the extent we would like, but we can agree that it is a goal worth pursuing and elevating.

In sum, humans differ, and that difference is not always a strength. The tall, handsome, and intelligent, have traits which most people feel to be superior. There is inequality. We can not abolish inequality, but we can increase the basal level of human quality of life. This may seem like an abstract digression, but it is not. In the near future we will have a much better sense of our mutations, and those of our potential offspring. Our values will guide our actions. Let’s have a frank and honest discussion about them.

Image credit: Tolgrenn

• Category: Science • Tags: Bioethics, Down Syndrome 
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Evolution’s winner. Real headline.

In the mid-2000s two British biologists of some public note attempted to revive or resuscitate the good name of eugenics, Richard Dawkins and Armand Leroi. My own suspicion is that this emerges in part from a implicit cultural history in the British Isles in regards to eugenics: in those nations,* unlike in the USA or Germany, eugenics was generally conceived of in the positive rather than negative sense. By this, I mean that a disproportionate amount of thought was given to the procreation of the favored, rather than coercive restriction of the unfit. This is exemplified by R. A. Fisher, the co-founder of both evolutionary genetics and statistics, who worried about the high mortality rate of the British elite during World War I. Fisher himself went on to have eight children, a situation which occasionally left him in financial distress, as would be predicted from standard Malthusian assumptions (see R.A. Fisher: The Life of a Scientist).

But despite the best efforts of Dawkins & Leroi, eugenics is still a swear word. For example, a few months ago Chris Mooney was accused of being a eugenicist because of the nature of his arguments in The Republican Brain. Of course there’s a difference between the word, and the reality. Idiocracy had an implicitly eugenical moral. And there are dating sites like Good Genes:

Our mission is to help Ivy Leaguers and similarly well-educated graduates and faculty find others with matching credentials. We introduce people who enjoy sharing thoughts, opinions and quality time.

Apparently good genes do not entail web design skills which post-date 1997. In any case, “good genes” has been obviated by the emergence of social networks, where people can sort and segregate to their hearts’ delight. And of course there is a copious social science on the strong racial and ethnic preferences of people dating. In particular, this preference seems to be much stronger in females, as one would predict from behavioral ecology (i.e., women are looking for “good genes” because they have a smaller number of potential reproductive opportunities).

Finally, there’s the famous statistic that 90 percent of couples who receive a positive test for Down Syndrome choose to terminate the pregnancy. That is, they request the doctors kill the fetus. This datum is at the heart of a recent Ross Douthat column, Eugenics, Past and Future. I appreciate Ross’ take though I disagree on the details and normative implications. He at least attempts not to be trite or trivialize the matter. Many conservative critics of eugenics are more interested in using the term as a cudgel against liberals, while liberals abhor eugenics the term, but dismiss the eugenical implications of individual freedoms which they defend (the abortion & crime argument being an exception). Douthat is clearly against eugenics, but he draws up real statistics and cutting edge science which attests to its reality in our time.

In particular he is putting the focus on non-invasive forms of prenatal testing. I do think that he overestimates the power of individual prediction broadly in the near term (and possibly the long term). Though there are many traits, like height, which are highly heritable, they’re so genomically diffuse that you have to screen from a wide range of embryos before you pick the “right” one. And that assumes you can adduce a good correlation between genotype and phenotype. But, there will be some immediate yield when it comes to large effect genetic abnormalities.

We can have theoretical discussions about genetics and ethics, but the real phenomenon which aggravates me about people who act Very Serious is that this is a domain which manifests not through discussion, but action. If you read the articles about “test tube babies” from the 1970s you notice how frightened everyone was, and contrast it with the banality of in vitro fertilization now. The past is not always prologue to the present, but if we have such high abortion rates of fetuses with Down Syndrome via amniocentesis and CVS, it is totally reasonable to assume that the rates will increase even higher with widespread and nearly obligate screening.

I’m not a pro-choice absolutist. In fact, I don’t even believe in rights, as such. I’m generally predisposed toward stronger restrictions on post-1st trimester abortions on the grounds which pro-life people would recognize. But, I also think we do need to open the possibility toward restrictions on 1st trimester abortions in some circumstances if feasible, because I do not believe children are a parental consumption good. In other words, becoming a parent is not an increment of individual utility in toto. The child is going to be a member of a community, to which they will have responsibilities, and from whom they will derive benefits.**

We did choose to go through CVS testing when my daughter was in utero. And I plan to have some form of non-invasive screening performed for our next child. That’s a personal choice. When I explain my rationale to people often I get standard-issue ignorant repugnance. My main annoyance is that it’s an unthinking reflex in a world already saturated with artifice. We need to have a serious conversation about the limits of individual self-actualization when it comes to the potential lives of other human beings who are integral elements of society. But, in the interests of candid realism I am very uninterested in the stories of people like George F. Will (who is, by the way, an agnostic) about the value of their Down Syndrome son. George F. Will is a man of means. I’d like to see how a struggling lower middle class family manages. There are many more of them. This is a frankly base consideration, but such are the things which constitute a life lived in the real world.

* Britain is home to three nations, England, Scotland, and Wales.

** My concern about sex-selective abortion is as much a consideration of a well balance society as it is about sex-bias.

• Category: Science • Tags: Bioethics, Down Syndrome, Personal Genomics, Testing 
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I’ve mentioned this before, but I thought I’d pass on the latest report on MaterniT21, the prenatal noninvasive Down Syndrome test. Currently it has a $235 copay for women with insurance. As of now only a few percent of the ~5 million pregnancies in the USA are subject to amnio or c.v.s. This procedure may result in the screened proportion going from ~1 percent to ~50 or more percent (though the firm that is providing this can only process ~100,000 tests per year as of now). I stumbled upon this after doing a follow up on my post, Would you have your fetus genetically tested? Interestingly the proportions who would get tested doesn’t differ that much between demographics.

And the outcomes can sometimes surprise. A story in the Columbus Dispatch relates the story of a couple who kept their daughter, who tested positive for Down Syndrome. They had originally decided that if the tests came back positive the would terminate. In contrast, the nurses relate that one strongly anti-abortion couple at the beginning of the process seems to have terminated. Right now 1 in 700 pregnancies result in Down Syndrome.

• Category: Science • Tags: Bioethics, Down Syndrome 
Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"