Association of Coffee Drinking with Total and Cause-Specific Mortality

Image credit: Mighty Optical Illusions (moillusions.com)

I'd normally put something like this in the weekend links roundup, but it seemed particularly salient for FE readers.

Association of Coffee Drinking with Total and Cause-Specific Mortality

Freedman et al., NEJM 2012
In this large, prospective U.S. cohort study, we observed a dose-dependent inverse association between coffee drinking and total mortality, after adjusting for potential confounders (smoking status in particular). As compared with men who did not drink coffee, men who drank 6 or more cups of coffee per day had a 10% lower risk of death, whereas women in this category of consumption had a 15% lower risk. Similar associations were observed whether participants drank predominantly caffeinated or decaffeinated coffee. Inverse associations persisted among many subgroups, including participants who had never smoked and those who were former smokers and participants with a normal BMI and those with a high BMI. Associations were also similar for deaths that occurred in the categories of follow-up time examined (0 to <4 years, 4 to <9 years, and 9 to 14 years). 

Our study was larger than prior studies, and the number of deaths (>52,000) was more than twice that in the largest previous study. Whereas the results of previous small studies have been inconsistent, our results are similar to those of several larger, more recent studies, including the Health Professionals Follow-up Study and the Nurses' Health Study.

[...] 

Given the observational nature of our study, it is not possible to conclude that the inverse relationship between coffee consumption and mortality reflects cause and effect. However, we can speculate about plausible mechanisms by which coffee consumption might have health benefits. Coffee contains more than 1000 compounds that might affect the risk of death. The most well-studied compound is caffeine, although similar associations for caffeinated and decaffeinated coffee in the current study and a previous study suggest that, if the relationship between coffee consumption and mortality were causal, other compounds in coffee (e.g., antioxidants, including polyphenols) might be important.

In summary, this large prospective cohort study showed significant inverse associations of coffee consumption with deaths from all causes and specifically with deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections. Our results provide reassurance with respect to the concern that coffee drinking might adversely affect health.

Please feel free to discuss feasible instruments for coffee consumption in the comments (or not). (via bb)

New tool for interfering with malaria transmission

Geoff Johnston, a doctoral candidate at Columbia's PhD in Sustainable Development, is on the team behind this recent study in PNAS.  He's promised us a non-technical summary soon.

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

Sophie H. Adjalleya, Geoffrey L. Johnston, Tao Li, Richard T. Eastman, Eric H. Ekland, Abraham G. Eappen, Adam Richman, B. Kim Lee Sim, Marcus C. S. Lee, Stephen L. Hoffman, and David A. Fidock

Abstract: Clinical studies and mathematical models predict that, to achieve malaria elimination, combination therapies will need to incorporate drugs that block the transmission of Plasmodium falciparum sexual stage parasites to mosquito vectors. Efforts to measure the activity of existing antimalarials on intraerythrocytic sexual stage gametocytes and identify transmission-blocking agents have, until now, been hindered by a lack of quantitative assays. Here, we report an experimental system using P. falciparum lines that stably express gametocyte-specific GFP-luciferase reporters, which enable the assessment of dose- and time-dependent drug action on gametocyte maturation and transmission. These studies reveal activity of the first-line antimalarial dihydroartemisinin and the partner drugs lumefantrine and pyronaridine against early gametocyte stages, along with moderate inhibition of mature gametocyte transmission to Anopheles mosquitoes. The other partner agents monodesethyl-amodiaquine and piperaquine showed activity only against immature gametocytes. Our data also identify methylene blue as a potent inhibitor of gametocyte development across all stages. This thiazine dye almost fully abolishes P. falciparum transmission to mosquitoes at concentrations readily achievable in humans, highlighting the potential of this chemical class to reduce the spread of malaria.

From the author summary:

The scale of the malaria epidemic remains vast, causing up to 225 million symptomatic infections and ∼780,000 deaths each year, primarily in sub-Saharan Africa. Despite this sobering backdrop, there are encouraging signs that treating infected individuals with antimalarial therapies and combating the Anopheles mosquito vector with insecticides can substantially reduce the burden of disease. First-line therapies rely on pairing potent derivatives of the Chinese plant extract artemisinin with longer-lasting partner drugs in regimens referred to as artemisinin-based combination therapies. Clinical reports and mathematical models indicate that additional reductions in disease incidence will require treatments that not only cure patients but also decrease the transmission of malarial parasites to Anopheles mosquitoes (1). Here, we have investigated the ability of various antimalarial agents to inhibit transmission. This work reveals that methylene blue (MB), the first synthetic compound ever used in clinical therapy (2), has potent transmission-blocking activity superior to current first-line therapies. 

Interruption of transmission can be achieved with drugs that inhibit the development of parasite sexual forms, termed gametocytes, within red blood cells. In the case of the most lethal human malaria pathogen, Plasmodium falciparum, these gametocytes progress through five developmental stages over 10–12 d before becoming infectious to mosquitoes (Fig. P1A). Prior studies have found that some drugs that target the disease-causing asexual blood stages also inhibit early stage gametocytes (3). However, identifying compounds that inhibit the metabolically less active mature stages has proven considerably more difficult, in part because of a lack of robust experimental tools. To address this concern, we have developed recombinant parasite lines and analytical methods that enable precise measurements of drug action against gametocytes as they mature and attain infectivity. 

To investigate the abilities of known antimalarials to affect gametocyte viability at different stages, we genetically modified P. falciparum parasite lines to express GFP-luciferase reporters from gene promoters known to be active in early, mid, or late stage gametocytes. The production of gametocytes was triggered by starvation-induced stress, and their subsequent development and gametocyte maturation were monitored by quantifying luciferase activity. Measurements of the rate of action of antimalarial compounds, tested at different doses in vitro, revealed the remarkable potency of the thiazine dye MB against all developmental stages (Fig. P1A). Subsequent experiments revealed that MB almost fully blocked transmission of P. falciparum gametocytes to Anopheles mosquitoes (Fig. P1B), reducing parasite infectivity by 78–100%. The small proportion of mosquitoes that were infected had a >98% reduction in the numbers of parasites developing in the midgut. Most of the effect of MB on parasite transmission can be attributed to its potent activity against mature stage V gametocytes. Parallel studies also observed a potent effect with dihydroartemisinin, the active metabolite of artemisinin compounds, with inhibition occurring primarily against early stage gametocytes. Comparable activity against early stages was observed with key partner drugs, including amodiaquine and lumefantrine (4). 

The experimental system that we developed for these studies will enable high-throughput screening to identify additional transmission-blocking compounds. Our study also provides experimental tools to further probe gametocyte biology, including studies on the cellular processes and molecular components that dictate the formation of gametocytes and promote transmission (5). A renewed emphasis on this phase of the malarial parasite life cycle, using reporter systems such as the one described here, promises to further aid expanding efforts to roll back malaria.

Doctors Without Borders: lessons learned

This looks like a really interesting new publication by the Nobel Prize winning organization MSF. Download the book in pdf form for free here.

"Medical Innovations in Humanitarian Situations explores how the particular style of humanitarian action practiced by Doctors Without Borders/Médecins Sans Frontières (MSF) has stayed in line with the standards in scientifically advanced countries while also leading to significant improvements in the medical care delivered to people in crisis. 

Through a series of case studies, the authors reflect on how medical aid workers dealt with the incongruity of practicing conventional evidence-based medicine in contexts that require unconventional approaches."

Ideology in science

"In science, ideology tends to corrupt; absolute ideology [corrupts] absolutely"

-Robert Nisbet

That's from Mukherjee's Emperor of All Maladies, a remarkably in depth and fascinating book on the history of cancer and our attempts to treat it. That quote starts out the section detailing the push towards more empirically grounded treatments and away from surgeon preference and beliefs. Like much of the rest of the book, it manages to be frustrating, compelling, inspirational, and heart breaking all at once.

I'm finishing it up now and recommend it highly, even if your interest in oncology (or the life sciences, for that matter) is only passing. Mukherjee's subtitle is "A Biography of Cancer," but it is as much a biography of oncology itself, and all the foibles, hyped enthusiasm, and ideologically-driven resistance to change come across as uncomfortably familiar to someone working across fields.

On a side note: is it just me or does scientific writing by medical doctors sound and feel fundamentally different from all other scientific writing? It might be the reliance on narrative and case study, or it might simply be the tone; regardless, it always feels very "doctor-y" to me...

Statistical inference isn't easy, either

I was just playing around with the citation management software / website Mendeley (recommended by Amir, and worth checking out for the auto-formatting of citations alone) when I trolled over to their "most read articles in all disciplines" section and saw that the 3rd most read article was a PLoS Medicine piece titled "Why most published research findings are false: author's reply to Goodman and Greenland," by Ioannidis. Ignoring the fact that it's the response and not the original paper (huh?) and led on by the rather provocative title, I poked around and discovered that Ioannidis' work just got written up in The Atlantic and was covered in pretty nice detail by Marginal Revolution back when it came out. So blogging about it does feel a bit like trying to review a restaurant that's already been covered by Frank Bruni and Food and Wine, but I'm going to go ahead and do so anyway since the point is so worthwhile.

The crux of the paper rests on a pretty simple idea: if you're running a huge number of one-off statistical tests (i.e., not testing the same hypothesis over and over) a fraction of your results proportional to the power of your test will be false positives (i.e., type I error). This is pretty straightforward a concept for anyone doing applied work: if you're checking to make sure you've got balance across treated and controlled populations in a randomized trial, for example, having an occasional statistically significant difference between the two populations isn't a huge deal as long as the percentage of variables that turn up that way is proportional to the significance level you're setting. Yes, you should follow through as a good little applied researcher and make sure something's not hiding there, but some portion of your results will always end up that way due to random variation.

The nice step that Ioannidis takes is to look at the entire field of medical research and apply the same logic, effectively viewing the suite of randomized trials as a game where we keep picking new potential tests for the same problems over and over again, some subset of which are guaranteed to be incorrectly not-rejected. To quote Alex Tabarrok's pithy wording of it in the Marginal Revolution post:

Want to avoid colon cancer? Let's see if an apple a day keeps the doctor away. No? What about a serving of bananas? Let's try vitamin C and don't forget red wine.

Moreover, since the number of things that actually, say, help avoid colon cancer is likely small, and the number of tests being run to find things which do is large, Ioannidis concludes that a large portion ("most") results are in fast false positives and thus meaningless. It's a pretty simple premise which leads to a pretty deep statement about how we think about learning about the world.

So the solutions to this are, of course, pretty intuitive: don't trust small sample size studies; insist on retesting hypotheses; be skeptical of results in any field where a large number of researchers are pursuing solutions to the same problem. In short, demand robustness checks on everything, and make sure that what's being shown is not just an artifact of your specific data set. Good lessons that all applied researchers should have tattooed across their proverbial chests already, but nonetheless a nice thing to be reminded of.