Questioning the breastfeeding-IQ-FADS2 connection, again

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Razib noted, in his post on the IQ-breastfeeding-FADS2 story, that it reminded him of research on MAOA. There’s a reason: it’s by the same group. In fact, the IQ study is the third in a “trifecta” of gene-environment interactions postulated by Avshalom Caspi and colleagues. Curious about whether their statistical methods were similar in all these studies, I went back to them.

1. In 2002, the authors reported an interaction between variation in MAOA and childhood maltreatment on the probability of developing “antisocial problems”. The relevant graph is on the right. It’s important to keep in mind, from a statistical standpoint, what an interaction is: in a regression of variable Y on variable X, if the slope of the line significantly differs depending on another variable Z, one concludes for an interaction between Z and X. In this, the slopes do appear to be different, and the authors find this is indeed statistically supported. They don’t include parental “antisocial behavior” as a covariate in their regression, either because they don’t have that data or didn’t think to include it.

2. In 2003, the authors then genotyped another locus in the cohort studied above, this time the serotonin transporter. They reported a significant interaction between polymorphism in this gene and stressful life events on risk of depression. Again the relevant graphs are on the right. Across several measures of depression, there does appear to be an interaction. Again, no inclusion of parental phenotype in the regression.

3. Now let’s consider the IQ-FADS2 story. Again, they use the same cohort (as well as a replication cohort). This time, instead of genotyping known functional variants in a gene thought to be involved in the phenotype, they genotype a couple tagging SNPs in a gene picked through some spectacular logical leaps (1. there is a link between breastfeeding and IQ. 2. That link is modulted through fatty acid metabolism. 3. Of all the genes involved in fatty acid metabolism, the one of interest is FADS2). This has to change your priors on whether anything they find is real. Again, check the graph on the right: this time, they don’t have the nice dose-response curve that they had in the others, so they go for a bar chart. And it does indeed look a little noiser. The replication, though, is something that wasn’t present in the other studies.

The fact that they have a measure of maternal IQ but don’t directly include it in the published multiple regression suggests that they tried it, but didn’t like the results. They didn’t include parental phenotype in any of their previous studies, but there, at least, there was some functional evidence linking the polymorphism and the phenotype. Here, there’s nothing. Considering the fact mentioned in a previous post that other researchers find absolutely no evidence for link between IQ and breastfeeding (the entire basis for this study), this has to be classified as highly questionable. And regardless of the veracity of any gene-environment interactions here, the huge effects of breastfeeding on IQ shown by the authors are clearly artefacts of the heritability of IQ, and it’s unfortunate that they are being propogated.

Half Sigma is apoplectic about this; I’m not so much– this is a case of researchers having a hammer (their cohort and a desire to find gene-environment interactions), and seeing every problem as a nail, not some ode to breast-feeding.

Anyways, on a completely unrelated note, here’s small nugget from their Supplementary Table 2, where they break down IQ by social class. I suppose I’d seen figures like this before (ie. in The Bell Curve), but it still gave me a start:

Low class: 93.5 (11.6)
Middle class: 100.5 (13.7)
High class: 111.4 (12.8)

In parentheses are standard deviations.

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  1. As a practising neonatologist I really feel the need to weigh in on this (in a somewhat disjointed post- limited time. 
    There are currently formula wars going on- predominantly between Meade Johnson Nutritionals and Ross (,a subsidiary of Abbot), makers respectively of the Enfamil and the Simulac brands of infant formulas. Enfamil contains a substantially higher dose of DHA and ARA than does Simulac. Consequently the Meade Johnson people are making claims about the IQ and retinal effects of enfamil and the simulac people are refuting the claims. I had the pleasure(?) a few months ago of attending a Meade Johnson sponsored wine/ dinner event where the featured speaker was the lead investigator for the meade sponsored study. He claimed that the high PUFA content actually increased IQ. Out of around 30-40 neonatologists present, I was the only one to arise from my Merlot induced stupor to ask the question – something about the 600 lb gorrilla in the room being maternal/ parental IQ. The response was stunningly aggressive for a laid back group such as it was. Of course they had controlled for maternal IQ, details were not presented and the vitriol was such that there was no further point in extending the discussion ( I have enough of a malcontent reputaion in local neonatology circles). 
    Bottom line: 
    Given available data and subjecting it to analysis more rigorous than most lead authors would want, I personally cannot conclude either way regarding the putative associations between Br milk PUFA’s and IQ.  
    Either way, this obscurantist pc-luddite claim re neer-magical powers of br milk is patently absurd. Br milk is simply a aqueous mixture with major and minor componenets. Some of these have phyisiologic roles and some are simply along for the ride. Nutritional science ( is there such an entity ?? ) is bit by bit making progress in understanding the biochemical/ physiologic role of various components of this aqueous mixture. And there is no reason to conclude that an artficial product- Formula – cannot EVER equal or exceed the nuatral product. 
    As far as imuumologic claims re br milk 
    the literature is replete with unmitigated garbage interspersed with some good stuff. 
    The one major immunologic component to br milk is the presence of secretory IgA in br milk, which via the enteromammary circulation provides amodicum of protection against pathogens that are present in the mothers gut. and so the secretory IgA confir a transient passive immunity against enteral pathogens the infant is most likely to be exposed to in the near future. 
    As far as the WBC in br milk are concernedliterature abounds with the kind of garbage I had the dubious distinction of once attaching my name too. My only defense is that i knew not even the ABC of clinical or other research at the time and was just doing what i was told to do by my ( idiot? ) boss. Here is what we did- we took some br milk from mothers, spun it down and isolated br milk luekocytes, radiolabelled them and fed them to lab rats. sacrifed the rats and found radioactivity in the liver and spleen. Now there could have been a whole slew of explanations for how the radiolabel made its way into the spleen etc, and as i rapidly matured, i vented on this with my boss. I thought that was the end of the matter but lo and behold an year later this shit was published in a reputable journal. with my boss ( now at the NICHD) and my co minion ( now CEO of a childrens hospital) as senior and first authors ( i was somewhere there too)making the outrageous claim that this study demonstrated that br milk leukocytes were absorbed into the circulation via the still immature gut and contributed in some way to the immunity of the fetus.  
    My own read is that benefits of br feeding literature , perhaps more than others is full of such utter shit research that making any valid conclusions without a critical read on original source material is haxardous. 
    sorry for a long sometimes off topic response but this uncritically examined punditry really gets my goat. Especially when in my practice i have to deal constantly with new moms full up to their ears with all manner of new age shit about the magical properties of br milk.

  2. Given available data and subjecting it to analysis more rigorous than most lead authors would want, I personally cannot conclude either way regarding the putative associations between Br milk PUFA’s and IQ. 
    so there is data on this, ie. formulas with different concentrations of fatty acids? if you had a cohort of all formula-fed children but with varying concentrations, you could run the regression of IQ on concentration of some relevant compound, if you assume no relationship between parental IQ and the formula chosen (maybe a dubious assumption, given that some are more expensive than others).

  3. I think there is data 
    1. I dont think they have controlled for maternal IQ, protestations by lead investigators, to the contrary 
    2. This is drug company data with immense marketing potentials and pitfalls and they will not share raw data with anyone (except maybe the FDA)

  4. And there is no reason to conclude that an artficial product- Formula – cannot EVER equal or exceed the nuatral product. The question isn’t whether formula can theoretically at some point in the future be as good as breast milk, the question is whether formula is as good as breast milk right now
    In the absense of strong evidence that they are the same, the reasonable presumption is that formula is a poor copy of breast milk – and that, barring medical need, should be eschewed in favor of breast milk.

  5. Shouldn’t a good study get both parents’ IQ, population mean (to account for regression towards the mean) and maybe birth weight/premature birth if there is a relationship between either of those and breastfeeding? 
    I ran that FADS2 (aggregated groups, not CC, CG, and GG using population means of 100, and a regression of .5, and the fathers would need to be about 92 in the nonbreastfeeding group and 111 in the breastfeeding group for there to be no effect of breastfeeding on IQ when regression is accounted for.

  6. 1: Pediatrics. 2003 Jan;111(1):e39-44. 
    Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy 
    and lactation augments children’s IQ at 4 years of age. 
    Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. 
    Institute for Nutrition Research, University of Oslo, Oslo, Norway. Peter Möller, 
    avd Orkla, ASA, Oslo, Norway. 
    OBJECTIVES: Docosahexaenoic acid (DHA; 22:6 n-3) and arachidonic acid (AA; 20:4 
    n-6) are important for development of the central nervous system in mammals. 
    There is a growth spurt in the human brain during the last trimester of pregnancy 
    and the first postnatal months, with a large increase in the cerebral content of  
    AA and DHA. The fetus and the newborn infant depend on maternal supply of DHA and 
    AA. Our hypothesis was that maternal intake of DHA during pregnancy and lactation 
    is marginal and that high intake of this fatty acid would benefit the child. We 
    examined the effect of supplementing pregnant and lactating women with 
    very-long-chain n-3 polyunsaturated fatty acids (PUFAs; cod liver oil) on mental  
    development of the children, compared with maternal supplementation with 
    long-chain n-6 PUFAs (corn oil). METHODS: The study was randomized and 
    double-blinded. Pregnant women were recruited in week 18 of pregnancy to take 10  
    mL of cod liver oil or corn oil until 3 months after delivery. The cod liver oil  
    contained 1183 mg/10 mL DHA, 803 mg/10 mL eicosapentaenoic acid (20:5 n-3), and a 
    total of 2494 mg/10 mL summation operator n-3 PUFAs. The corn oil contained 4747  
    mg/10 mL linoleic acid (18:2 n-6) and 92 mg/10 mL alpha-linolenic acid (18:3 
    n-3). The amount of fat-soluble vitamins was identical in the 2 oils (117 micro 
    g/mL vitamin A, 1 micro g/mL vitamin D, and 1.4 mg/mL dl-alpha-tocopherol). A 
    total of 590 pregnant women were recruited to the study, and 341 mothers took 
    part in the study until giving birth. All infants of these women were scheduled 
    for assessment of cognitive function at 6 and 9 months of age, and 262 complied 
    with the request. As part of the protocol, 135 subjects from this population were 
    invited for intelligence testing with the Kaufman Assessment Battery for Children 
    (K-ABC) at 4 years of age. Of the 135 invited children, 90 came for assessment. 
    Six children did not complete the examination. The K-ABC is a measure of 
    intelligence and achievement designed for children aged 2.5 years through 12.5 
    years. This multisubtest battery comprises 4 scales: Sequential Processing, 
    Simultaneous Processing, Achievement (not used in the present study), and 
    Nonverbal Abilities. The Sequential Processing and Simultaneous Processing scales 
    are hypothesized to reflect the child’s style of problem solving and information  
    processing. Scores from these 2 scales are combined to form a Mental Processing 
    Composite, which serves as the measure of intelligence in the K-ABC. RESULTS: We  
    received dietary information from 76 infants (41 in the cod liver oil group and 
    35 in the corn oil group), documenting that all of them were breastfed at 3 
    months of age. Children who were born to mothers who had taken cod liver oil (n = 
    48) during pregnancy and lactation scored higher on the Mental Processing 
    Composite of the K-ABC at 4 years of age as compared with children whose mothers  
    had taken corn oil (n = 36; 106.4 [7.4] vs 102.3 [11.3]). The Mental Processing 
    Composite score correlated significantly with head circumference at birth (r = 
    0.23), but no relation was found with birth weight or gestational length. The 
    children’s mental processing scores at 4 years of age correlated significantly 
    with maternal intake of DHA and eicosapentaenoic acid during pregnancy. In a 
    multiple regression model, maternal intake of DHA during pregnancy was the only 
    variable of statistical significance for the children’s mental processing scores  
    at 4 years of age. CONCLUSION: Maternal intake of very-long-chain n-3 PUFAs 
    during pregnancy and lactation may be favorable for later mental development of 
    PMID: 12509593 [PubMed - indexed for MEDLINE]