Isaacson

That's rather the point. Any odds ratios worked out by comparing an exposed group to an unexposed control where the sample size was large enough to include a full (and fairly equal) range of "lifestyle" factors, would (if lifestyle factors have a significant effect) be totally inapplicable to anyone but the "average" person and, depending on the size of the effect, could be whole orders of magnitude out. As we already have some very useful drugs which have to carry a "do not use if pregnant" or "not suitable for under 12s" warning because of the specific vulnerabilities of those groups, there could theoretically be medicines which are useful but might carry a "do not use if you eat less than 5 fruit and veg a day", or "do not use if you do less than 20 minutes exercise a day" warning. Similarly, levels of toxins such as benzene in certain work environments might be so well tolerated by those who eat well and exercise regularly that such a requirement of workers might be a demonstrably useful control measure.

Yes, the model would be slightly different because I'd be using Odds Ratios rather than standard variables, but it would not differ substantially from models attempting to use multiple interaction terms. I did consider doing this, but found that all I was modelling was the potential change in disease risk, in the light of certain lifestyle factors without being able to control for things like the fact that a person who was otherwise fit and healthy probably wouldn't smoke 20 a day, lowering the sample size beyond significance. Of more significance was the lack of comparable data (that I have access to anyway) which is mainly why I posed the question. I'd ideally want data on the risk from some environmental disease causing variable (or drug side effect) and the lifestyle factors in cohorts that are reasonably comparable. Unless someone with the budget to design studies has actually deliberately done this, I don't think it's going to happen. As far as interest is concerned though, I'm quite surprised it's not been done. The significance as I see it would be that if there was a correlation, there could be a threshold above which the toxin is not toxic, or the otherwise useful drug's side effects are insignificant. Say for example (and forgive my basic grasp of biology), that a certain toxin had its effect by production of free oxide radicals, and that a good diet improved one's health partly by containing anti-oxidants. It could well be that if the quantity of oxides in a given toxin were below the quantity of anti-oxidants in a good diet, one would not have simply lowered one's chances of getting said disease, one would be immune entirely to it at that dose. Quite a significant difference in statement.

Thanks for the link it's certainly interesting reading along the same lines and it's linked to a whole load of other studies of a similar type. The trouble is, studies on this topic seem to be of two camps; one studying the effects of lifestyle factors on some given condition, and the other studying the effects of some environmental/genetic factor on said disease. What I'm really interested in is the effect of lifestyle factors on the effect of environmental factors on some given disease. Take smoking for example, unless I'm mistaken studies have shown that smoking causes a risk of lung cancer (say 1:100 for the sake of argument). Studies have also shown that certain lifestyle factors (such as obesity, stress and anti-oxidant levels in the diet) have an impact on cancers (presumably including lung cancer). What it would be interesting to know then, is what the result is from putting them together. I.e. what is the risk of lung cancer to an otherwise ideally healthy person who for some crazy reason decides to smoke 20 a day.

A glance at any official health bodies advice will show that we are entreated to eat more healthily, take more exercise and reduce stress. Presumably, there is some reasonable evidence that these factors play a relatively significant role in disease formation and response (otherwise, one would presume they would not be within the remit of such organisations). In what little opportunity I've had to read primary research on medical testing, however (I'm a statistician, not a biologist), I've not come across any attempt at stratification for these factors. If one is, say, testing the response to a new medicine, presuming these factors will promote recovery in your test subjects, then the apparent efficacy of the medicine might be effected by the distribution of these "lifestyle" factors within your test and control groups. Similarly, on the other side of the coin, if you are testing the response to a new health threat by epidemiological study, a quoted Odds Ratio of 1.2 might be quite radically different for individuals of different general health, yet (in the studies I've read) there seems to be simply a presumption that the control group and the test group will have a similar spread of lifestyles. It certainly seems to be a relevant factor in some cases as individuals with a history of smoking are almost always controlled for in such epidemiological studies (especially related to lung conditions), but I have never come across similar treatment of individuals in high stress jobs, eating fewer than 5 fruit and veg per day, taking less than three hours exercise a week etc. For large effects, these factors would probably be insignificant, but where the effect is small (say a slightly efficacious new treatment, or a low risk environmental contaminant), failure to take account of these factors could theoretically lead to the conclusion that the drug is a slight improvement on what we have, or the threat requires some moderate mitigation, when if fact the drug is virtually ineffective in people who are otherwise unhealthy, or the threat is actually zero to a healthy individual, which would be really important conclusions for public health. My limited interaction with epidemiological studies was quite a few years ago now, so my question is, have things moved on to start controlling for these factors now we have a better idea of their impact, and more significantly, if they have, have any studies from the past been revised in the light of such controls? Also, does anyone know of any accessible studies on the impact of these factors on epidemiology in general?

If I understand correctly, low doses of most viruses initiate an immune response, which is how vaccines work, I also think I've read somewhere that low doses of some bacteria can help to "train" the immune system to make it more capable of dealing with larger exposures later on. I was wondering if this was true of any other potential causes of disease like carcinogens or poisons, where a very small dose over time actually makes the body more capable of defending against a larger dose later on. With regards to poison, I'm not referring here to the fact that some poisons are good for you in low doses and poisonous in high doses. I'm specifically asking about ways in which small doses of a thing actually help protect you against larger doses later on. Thanks.

Thank you, that's exactly what I was looking for, I don't know why that didn't turn up in the many Google searches I did. I never used the term 'susceptibility', and that must have been the key. I've only been posting here for a while, but I've never had a post answered so entirely in one go, thanks.

I don't wish to underestimate the impact that Mesothelioma has on those who have worked with Asbestos, but I'm curious from a scientific point of view as to why it has affected so few people. I know generally reports are shocked by the large number of people affected, but given that Asbestos was pretty much ubiquitous for nearly 40 years, is present in almost every home and public building, and has no lower threshold of carcinogenesis, I'm more surprised at the low number of people who actually end up with the disease. Even among workers exposed to huge doses for 30 years, the rate of Mesothelioma is about 1 in 10. What is that is protecting the 9 out of every ten workers who have managed to breathe in doses of a carcinogenic fibre at 1000 times the safe level for 30 years with no ill effect, and vice versa, what is it about a person who breathes in 0.02f/ml (just above the safe threshold) and is unfortunate enough to contract the disease? All of the research I've been able to track down on the internet seems to focus on the fact that Asbestos causes Mesothelioma in 1 in ten workers (closer to 1 in 1000 more moderately exposed people), and how this happens and what can be done to prevent it. Very noble and necessary work, but there is a notable absence of research on the fact that it doesn't seem to affect 9 out of ten workers and 999 out of every 1000 people more moderately exposed. Surely the key to helping people through the last few decades of an Asbestos riddled environment would be to find out what the majority of people have got that the unfortunate minority seem to lack and seeing if we can pass it over in some way. Links to any research of this nature would be gratefully received.

You may be on to something, both experiments were at room temperature, quoted as 27-30C in one paper (quite hot for room temperature I thought). Would it make a difference to how the chlorine works, or just the organism itself?

We seem to have got caught up in a discussion about the UK's climate, hygiene etc., which is not really the query I had. What I'm asking about are the physiological factors. I thought of an example which will eliminate all the other factors and I would be curious to see if anyone could answer. Rodents getting into the cold water tank is a problem described by various plumbing books as "frequent" and "quite common" (I can reference if you like but I thought that could be taken for granted). People, wash, bathe, brush teeth and occasionally drink this water. The incidence of Leptospirosis from unknown sources in the UK is fewer than ten (eliminating foreign travel, water-sports and occupational exposure). So the question is, how do we get from a "quite common" situation which provides direct water-bourne exposure to rodents, in a country of 70,000,000, to fewer than ten (if any) case of Leptospirosis? No issues of climate, hygiene, contact, flooding events, aridity or any previously mentioned factor plays a part here. I've found two studies cultivating Leptospires in tap-water, so it doesn't seem to be the chlorine (though it's still a possibility I suppose, if those studies were flawed in some way). Any ideas?

According to the WHO recommendations for drinking water safety http://www.who.int/water_sanitation_health/dwq/guidelines/en/ it says under residual chlorine that to achieve a log2 reduction in bacteria you need "Ct99 = 0.04–0.08 min·mg/l; 5 °C; pH 6-7)" By my understanding at 0.5mg/l (normal tap water) you would need less than 1 tenth of a minute contact (0.5 x 0.1 = 0.05). That can't be right, it would make tap water an effective disinfectant within minutes, can anyone explain why?

This is part of the aspect which puzzles me. The disease is so much more prevalent in the tropics which would correlate with the case studies you mention. The problem is, nowhere in the literature can I find any reference to Leptospires being unable to survive below a certain temperature. The pathogen safety sheets only mention inactivation above 50C no lower limit. A low tolerance of low temperatures would certainly explain literally all of the anomalies I've found, but it just doesn't seem to have any physiological evidence that I can find.

That seems to be what most authors suggest, I just can't quite see it. Take a farm for example. Leptospira can live in mud or water for weeks, on a farm you can be pretty sure a rat's been almost everywhere at some time over the last few weeks and rats are incontinent, so it's definitely urinated on that surface, in winter everything can stay wet for days. About 40% of rats have leptospires and about 10% of cases are severe enough to need hospital treatment. That should mean that everyone who has any contact with any wet surface that a rat has visited at any point in that past few weeks should have an 4% (40%x10%) chance not just of contracting Leptospirosis, but of contracting a version serious enough to require hospitalization. Even if we were to take a very conservative estimate that only 10% of the 500,000 people employed on farms in the UK ever found themselves in this situation, we should see 2,000 severe case a year, instead we see fewer than 10, nearly half of which are contracted abroad. I can't seem to get around that fact that actual incidence is several thousand times less than the published risk factors would appear to suggest.

I'm curious as to why Leptospirosis is so rare in the UK (under 70 cases a year). It's physiology and mode of transmission do not seem to provide an explanation. It's survival in the environment would imply that any wet surface, puddle or patch of mud that has been visited by any rodent at any time in the past few weeks has at about a 40% chance of being contaminated (using the upper estimate of prevalence in the rodent population). In farmyards and dense urban areas this could well be just about every puddle, patch of mud etc.. The case studies would seem to suggest that low doses are infectious (urine diluted by an entire lakeful of water in America, a single hedgehog polluting a water fountain in Italy). Case studies also suggest that such doses do not require any immune suppression or physiological weakness to be infectious (an Olympic athlete having succumbed in Britain recently). I imagine how many times children living on a farm might fall over in a muddy puddle and graze their hands, how many farmers and land worker must forget, or not bother to wash their hands when they should? It seems to compare to something like Norovirus; a large carrier population (humans/rats), lots of contact opportunities (public surfaces/muddy puddles), high environmental survival rates (12 days/several weeks), and low infectious dose. Yet the difference between them in terms of epidemiology is 4-5 orders of magnitude (several hundred thousand/<40). Can anyone explain what it is about Leptospira which explains the extremely rare and sporadic nature of cases in the UK?

I'm not in general an advocate of the Hygiene Hypothesis nor of ignoring proper hygiene, But what those who so strongly advocate conventional hygiene practices fail to address is that these too have the same lack of statistically significant epidemiology trials to support them. Most evidence for practices such as hand-washing and food hygiene come from either laboratory culture of bacteria or from hospital settings (where indeed there is a massive amount of evidence in favour of good hygiene). They do not constitute proof that good hygiene will make any difference to the total number of infections you will contract in your lifetime. As many commentators have pointed out, there simply is no evidence one way or the other as to the long term effect of hygiene practices on normal healthy individuals. We must therefore accept that both conventional hygiene advice and the Hygiene Hypothesis/Immune conditioning are theories supported by a limited amount of evidence.