Monday, October 31, 2011

The China Study II: Gender, mortality, and the mysterious factor X

WarpPLS and HealthCorrelator for Excel were used to do the analyses below. For other China Study analyses, many using WarpPLS as well as HealthCorrelator for Excel, click here. For the dataset used, visit the HealthCorrelator for Excel site and check under the sample datasets area. As always, I thank Dr. T. Colin Campbell and his collaborators for making the data publicly available for independent analyses.

In my previous post I mentioned some odd results that led me to additional analyses. Below is a screen snapshot summarizing one such analysis, of the ordered associations between mortality in the 35-69 and 70-79 age ranges and all of the other variables in the dataset. As I said before, this is a subset of the China Study II dataset, which does not include all of the variables for which data was collected. The associations shown below were generated by HealthCorrelator for Excel.


The top associations are positive and with mortality in the other range (the “M006 …” and “M005 …” variables). This is to be expected if ecological fallacy is not a big problem in terms of conclusions drawn from this dataset. In other words, the same things cause mortality to go up in the two age ranges, uniformly across counties. This is reassuring from a quantitative analysis perspective.

The second highest association in both age ranges is with the variable “SexM1F2”. This variable is a “dummy” variable coded as 1 for male sex and 2 for female, which I added to the dataset myself – it did not exist in the original dataset. The association in both age ranges is negative, meaning that being female is protective. They reflect in part the role of gender on mortality, more specifically the biological aspects of being female, since we have seen before in previous analyses that being female is generally health-protective.

I was able to add a gender-related variable to the model because the data was originally provided for each county separately for males and females, as well as through “totals” that were calculated by aggregating data from both males and females. So I essentially de-aggregated the data by using data from males and females separately, in which case the totals were not used (otherwise I would have artificially reduced the variance in all variables, also possibly adding uniformity where it did not belong). Using data from males and females separately is the reverse of the aggregation process that can lead to ecological fallacy problems.

Anyway, the associations with the variable “SexM1F2” got me thinking about a possibility. What if females consumed significantly less wheat flour and more animal protein in this dataset? This could be one of the reasons behind these strong associations between being female and living longer. So I built a more complex WarpPLS model than the one in my previous post, and ran a linear multivariate analysis on it. The results are shown below.


What do these results suggest? They suggest no strong associations between gender and wheat flour or animal protein consumption. That is, when you look at county averages, men and women consumed about the same amounts of wheat flour and animal protein. Also, the results suggest that animal protein is protective and wheat flour is detrimental, in terms of longevity, regardless of gender. The associations between animal protein and wheat flour are essentially the same as the ones in my previous post. The beta coefficients are a bit lower, but some P values improved (i.e., decreased); the latter most likely due to better resample set stability after including the gender-related variable.

Most importantly, there is a very strong protective effect associated with being female, and this effect is independent of what the participants ate.

Now, if you are a man, don’t rush to take hormones to become a woman with the goal of living longer just yet. This advice is not only due to the likely health problems related to becoming a transgender person; it is also due to a little problem with these associations. The problem is that the protective effect suggested by the coefficients of association between gender and mortality seems too strong to be due to men "being women with a few design flaws".

There is a mysterious factor X somewhere in there, and it is not gender per se. We need to find a better candidate.

One interesting thing to point out here is that the above model has good explanatory power in regards to mortality. I'd say unusually good explanatory power given that people die for a variety of reasons, and here we have a model explaining a lot of that variation. The model  explains 45 percent of the variance in mortality in the 35-69 age range, and 28 percent of the variance in the 70-79 age range.

In other words, the model above explains nearly half of the variance in mortality in the 35-69 age range. It could form the basis of a doctoral dissertation in nutrition or epidemiology with important  implications for public health policy in China. But first the factor X must be identified, and it must be somehow related to gender.

Next post coming up soon ...

28 comments:

Anonymous said...

If you are a man don't rush to get hormones but donate blood regularly and get rid of excess iron. So far nothing new under the sun, not even in China. The name of the game remains iron peroxidation.

Ned Kock said...

Hi Anon. Interesting and intriguing hypothesis. Just to be sure, you are saying that the results in this post are explained by iron overload in men, but not in women, right?

Beth@WeightMaven said...

Anon beat me to it. Anthony Colpo has had a couple of interesting posts on the benefits of reducing iron by phlebotomy. Here's a review of a book he says is a must read on this subject.

Beth@WeightMaven said...

One other thing. Alas for women, the association of increased CVD after menopause led to the theory it was estrogen that was protective thus we got HRT. Interesting to consider that it might have been iron instead!

Ned Kock said...

One problem with this iron overload theory is the still very strong effect of gender on mortality in the 70-79 age range.

Women would have long ceased to undergo “natural phlebotomy” by then.

Ned Kock said...

Here is another problem with this iron overload theory. The strength of the gender-mortality effect seems a lot stronger in this dataset than others I’ve seen, even in modern urban contexts. And menstruation seems to start earlier and end later in modern urban contexts, compared with non-urban traditional societies.

Still, I will be reviewing some statistics on gender-mortality effects this week, which I hope to be able to summarize in my next post.

That will come most likely during the coming weekend, and the factor X will be revealed!

Or at least what I think the factor X is …

David Isaak said...

Yep--Mike Eades has been recommending that men donate blood some time now.

Alas, I can't. The last time I tried to give blood they sent me away because I had more than two weeks of cumulative time in the UK in the last couple decades...not to mention having been in Papua New Guinea and other verboten places.

Most people I know who travel internationally on business are unable to give blood. You also can't give blood if you have been in jail. Or had a tattoo in the last six months.

If you got tattoed in jail in the UK, you aren't even allowed to fill out the forms.

Ned Kock said...

Yet another problem with the iron overload theory. It would have to assume that paleo men would be bleeding on a regular basis.

Anyone who has been through a “survival in the wild” situation knows that even a small cut is a serious threat to survival.

Only urbanites go into the wild and start bleeding all over the place. Natives don’t.

Anonymous said...

Ned it is the other way round. It is not paleo hunters bleeding like in a splatter movie. It is women's bleeding being extraordinary high by mammal standards because of all-year-long menstruation. Women are the only mammal females I am aware of where iron levels are much lower than in males. Even in China apparently. Maybe even lower than in the West due to poor consumption of red meat in their diet.

Ned Kock said...

I get it Anon, but paleo men would have to have some mechanism to prevent iron overload, if this theory is correct.

Blood banks are arguably a new invention, in evolutionary terms.

And I don’t see many men around addicted to the sensation of having leeches all over their bodies.

Anonymous said...

No there is none in human metabolism. Even today iron storage keeps naturally increasing the older you get. Turning to uric acid is the antioxidant mechanism carnivores adopt to cope with the problem. Probably because of its superior chelation property compared to herbivore ascorbate. Women are simply given some extra years as an unintended side effect of a peculiar fertility mechanism.

Ned Kock said...

These are very interesting points Anon, but they do not address the other counter-arguments I presented.

For example, if iron overload is a good candidate for factor X, how come we see a VERY strong protective effect associated with being female on mortality in the 70-79 age range?

As I said, women would have long ceased to undergo “natural phlebotomy” by then.

If that were a residual benefit from the pre-menopausal period, it would have to be weaker.

I hope I can illustrate this with some data in my next post.

David Isaak said...

I don't think iron explains everything about longevity differences between genders. But I think it may well be a factor in the equation.

Look at it this way. Take the age of menarche to be 13 and menopause to be 50. Assume both men and women have an arbitrary concentration of iron in their bodies of 100 at age 13. Now assume that both accumulate more iron at 1% per annum, but that women stay at 100 from 13 to 50.

In that case, a man would have nearly 50 percent more iron in his body at age 50.

Although the woman would have more iron in her body at 79 than she did at 50 (133 units vs 100), the man would still have almost 50% (46% to be precise) more iron than the woman (146 at age 50, 195 at age 79).

That doesn't mean iron is Factor X. But it does mean that if accumulated iron is bad for you, men have a bigger problem than women do, even post-menopause.

Nick said...

Hi Ned, how are you defining 'paleo man' in the context of the iron overload comments? If you are being literal, there would be very few people of that time who lived long enough to really find out how iron overload might play out after age 50.

Nick said...

Beth, have you read the book on iron overload? The review you link to pretty much implicates excess iron for just about every malady. Whew. Really curious what the sources might look like for the conclusions, as well as how someone like Ned or Peter D. might deconstruct how well done they might be.

I just had a doc tell me he thinks I may have iron overload based on lifelong symptoms that appear unrelated to anything in particular. He is running various tests. Hemochromatosis can be hereditary that is caused by a recessive gene.

Interesting that reducing vitamin C was listed as a way to reduce iron overload.

Anonymous said...

Ned, you underestimate the importance of cumulated damage already achieved at age 70. What happens after is almost irrelevant. It is a chronic mechanism not an acute one. Look at the way hemosiderin builds up in the cell. The Fenton reaction remains a poorly understood process including effects of ph on it. And I am not 100% sure it always does harm. It remains the fact that when you supplement vit c beyond a certain threshold your body desperately tries to get rid of it as quick as possible. Pity it cannot with vit e. But if you are a man and really like to add damage to damage just prop up the Fenton reaction with "antioxidant" vitamin supplementation.

Ned Kock said...

Hi Anon. Your counter-arguments are getting better. I assume that are coming all from the same Anon?

Ned Kock said...

Hi Nick. I don’t think our ancestors would have lived such short lives that an enormous effect like this would not have exerted selection pressure and thus adaptation.

As you can see from this analysis, the strength of the effect in the 35-69 range is so high (beta=-0.65) that it even suggests the possibility of lateral collinearity (between gender and mortality in that range).

I already tested for it, and collinearity can be safely ruled out.

Ned Kock said...

A reasonable test of whether the factor X is iron overload or not would be to compare the strength of the gender effect observed here (with this China Study II dataset) with the gender effects in other populations.

If the difference is large, we would have to look for another difference between the men and women participating in the China Study II and in other populations. That other difference would lead us to the factor X.

I am working on it, but slowly. My day job keeps me busy.

Lerner said...

Well, let's see... wheat and iron. In 1975, I walked into a Biology class where the professor was writing on the blackboard: "Can Wonder Bread make you dead?" He was referring way back then (36 years ago) to the danger of iron fortified foods. Maybe there's something to be mined about comparisons between Chinese iron-rich-meat eaters versus iron fortified or non-fortified wheat eaters.

Ironically, green tea is said to be a good chelator of iron, so there's another possible China angle.

Whether it's a problem or not, I don't know - but I still do always make it a point to buy only the multivitamins without iron. Regardless, the topic screams out for a mention about the curious "ironjustice", a prolific usenet poster since at least 2004 with over 100,000 posts about how iron causes almost all ills. You couldn't go anywhere without him popping up.

http://groups.google.com/groups/search?hl=en&qt_s=1&q=ironjustice

Clicking on "sort by date" shows that he posted again just 3 hours ago, so I guess he hasn't given up on it :)

Lerner said...

that's 164,000 hits for "ironjustice" anyway...

Under his current account, he apparently has about 3,000 posts per year:

http://groups.google.com/groups/profile?hl=en&enc_user=OCu7ZRQAAAChwOar_afLMXwAD53NQsfVOPANdqfI6prRsqjc7uCt1A

KathyAC said...

Maybe iron accumulation is a problem now a days because we got rid the gut parasites? Probably used to be quite advantageous to be good at hanging onto iron in that context...

Anonymous said...

What really happens with iron excretion is largely a matter of speculation, as the subject has been very poorly studied. Although this goes against official science received wisdom, there could be some feedback mechanisms to excrete excess iron, at least in rats http://www.ncbi.nlm.nih.gov/pubmed/10921422.
Gluten is often associated to poor iron absorption, but as it down-regulates transferrin it could also play a role in locking the exit door. Who knows. Green tea by the way is a very good chelator just in case. Also red wine for the booze lovers.

Anonymous said...

To come to your point KathyAC, if this excretion mechanism exists, a big IF indeed, it goes without saying that anything interfering with the mucosa could play a role. And bacteria are the obvious candidates of choice.

Anonymous said...

Now I am really thinking aloud and this is imaginative science bordering science fiction. But ... you could reasonably conceive a scenario where gluten-related iron malabsorption is not malabsorption but is non-bound iron overstorage and limited bioavailability (celiacs often have liver diseases). Transferrin mucosal down-regulation would then explain both apparent anemia, liver toxicity and lack of excretion is any exists. This is science-fiction, but I wouldn't be surprised to find one day it is not.

Justin Cain said...

What is the best way to check iron status? I have heard of some kind of special MRI that can quantify iron content of the liver, just not sure what it is called.

Thanks,
Justin

Karn said...

Being a man is inherently more dangerous, of the top 20 most dangerous jobs, 100% of them are primarily performed by men.

Anonymous said...

You mean this I suppose. http://bloodjournal.hematologylibrary.org/content/105/2/855.full?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&title=Noninvasive+measurement+and+imaging+of+liver+iron+concentrations+using+proton+ma&andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT
As a rule of thumb if you have a serious iron overstorage in the liver ALT and AST will give you a warning sign.