US health inequality

"The report by Chetty et al also suggests that geography and income percentiles interact in previously unknown ways. For instance, the percentile gradient for life expectancy at 40 years of age is steeper in Detroit, Michigan, than in San Francisco, California, or New York, New York, almost entirely because being in the bottom income percentile is worse in Detroit. However, this outcome in Detroit cannot be entirely related to income because this same income percentile in Detroit has more real purchasing power than in New York. (The adjustment for race and ethnicity may be an issue here.) Beyond Detroit, it is generally true that it is at the bottom of the income distribution, not at the top, where geography matters. It is as if the top income percentiles belong to one world of elite, wealthy US adults, whereas the bottom income percentiles each belong to separate worlds of poverty, each unhappy and unhealthy in its own way. The life expectancy at 40 years of age in the top income percentile of the United States is better than the mean in any other country for life expectancy at 40 years of age. However, not by a lot, and likely not better than the top percentile in Sweden or the Netherlands. In contrast, the life expectancy at 40 years of age in the bottom income percentile of the United States is located between the mean for Pakistan and Sudan for life expectancy at 40 years of age."

That's from Angus Deaton's editorial in the latest issue of JAMA, referencing Chetty et al.'s The Association Between Income and Life Expectancy in the United States, 2001-2014.

Destruction, Disinvestment, and Death: Economic and Human Losses Following Environmental Disaster

Typhoon Haiyan as seen from space, Copyright 2013 JMA/EUMETSAT

Last spring Sol and I finished up the working paper version of our paper "Destruction, Disinvestment, and Death: Economic and Human Losses Following Environmental Disaster." Since the paper is long and fairly technical, we decided it would be worthwhile to do a shorter, more general-audience-appropriate piece for the blog, something that seems especially relevant given Typhoon Haiyan's devastating landfall this past weekend. If you'd like to take a look at the paper itself, you can find a copy of it here on SSRN; a copy of the supplemental appendix can be found here.

The motivation for "Destruction, Disinvestment, and Death" stems from the fact that we actually know surprisingly little about how people fare in the wake of natural disasters.

Toilets

Effects of Rural Sanitation on Infant Mortality and Human Capital: Evidence from India's Total Sanitation Campaign
Dean Spears

Abstract: Open defecation without a toilet or latrine is among the leading global threats to health, especially in India. Although it is well-known that modern sewage infrastructure improves health, it is unknown whether a sanitation program feasible for a low capacity, poor country government could be effective. This paper contributes the first causally identied estimates of effects of rural sanitation on health and human capital accumulation. The Indian government's Total Sanitation Campaign reports building one household pit latrine per ten rural persons from 2001 to 2011. The program offered local governments a large ex post monetary incentive to eliminate open defecation. I use several complementary identification strategies to estimate the program's effect on children's health. First, I exploit variation in program timing, comparing children born in different years. Second, I study a long difference-in-differences in aggregate mortality. Third, I exploit a discontinuity designed into the monetary incentive. Unlike many impact evaluations, this paper studies a full-scale program implemented by a large government bureaucracy with low administrative capacity. At the mean program intensity, infant mortality decreased by 4 per 1,000 and children's height increased by 0.2 standard deviations (similar to the cross-sectional difference associated with doubling household consumption per capita). These results suggest that, even in the context of governance constraints, incentivizing local leaders to promote technology adoption can be an effective strategy

How much international variation in child height can sanitation explain?
Dean Spears

Physical height is an important economic variable reflecting health and human capital. Puzzlingly, however, differences in average height across developing countries are not well explained by differences in wealth. In particular, children in India are shorter, on average, than children in Africa who are poorer, on average, a paradox called “the Asian enigma” which has received much attention from economists. This paper provides the first documentation of a quantitatively important gradient between child height and sanitation that can statistically explain a large fraction of international height differences. This association between sanitation and human capital is robustly stable, even after accounting for other heterogeneity, such as in GDP. The author applies three complementary empirical strategies to identify the association between sanitation and child height: country-level regressions across 140 country- years in 65 developing countries; within-country analysis of differences over time within Indian districts; and econometric decomposition of the India-Africa height differences in child-level data. Open defecation, which is exceptionally widespread in India, can account for much or all of the excess stunting in India.

Perhaps the most disturbing thing of all is the simple summary statistic that there are many regions where >50% of households do not have toilets.

Google search data for forensic epidemiology

Two recent papers have come out demonstrating that Google searches can provide extraordinarily rich data for forensic epidemiologists:

Urban bus pollution and infant health: how New York City's smog reduction program generates millions of dollars in benefits

Jesse and I both come from the Sustainable Development PhD Program at Columbia which has once again turned out a remarkable crop of job market candidates (see outcomes from 2012 and 2011). We both agreed that their job market papers were so innovative, diverse, rigorous and important that we wanted to feature them at FE.  Their results are striking and deserve dissemination (we would probably post them anyway even if the authors weren't on the market), but they also clearly illustrate what the what the Columbia program is all about. (Apply to it here, hire one of these candidates here.) Here is the second post.

Around the world, diesel-powered vehicles play a major role in moving people and goods. In particular, buses are heavily utilized in densely populated cities where large numbers of people are exposed to their exhaust. If bus exhaust has an impact on human health, then urban policy-makers would want to know this since it will affect whether or not it's worth it to invest in cleaner bus technologies. Upgrading the quality of public transport systems is usually expensive, but upgrading could have potentially large benefits since so many people live in dense urban centers and are exposed to their pollution. Deciding whether or not to invest in cleaner bus technologies is an important policy decision made by city officials, since buses aren't replaced very often and poor choices can affect city infrastructure for decades -- so its important that policy-makers know what the trade offs are when they make these decisions.

Unfortunately, to date, it has been extremely difficult to know if there are any effects of bus pollution on human health because cities are complex and bustling environments where people are constantly exposed to all sorts of rapidly changing environmental conditions. As one might imagine, looking at a city of ten-million people, each of whom is engaged daily in dozens of interacting activities, and trying to disentangle the web of factors that affect human health to isolate the effect of bus pollution is a daunting task. To tackle this problem, we would need to assemble a lot of data and conduct a careful analysis. This is exactly what Nicole Ngo has done.

Between 1990 and 2010,  New York City made major investments that transformed the city's bus fleet, reducing its emissions dramatically. To study the impact of this policy on human health, Ngo assembled a new massive data set that details exactly which bus drove on which route at what time every single day. Because the city's transition from dirty buses to clean buses occurred gradually over time, and because the dispatcher at the bus depot randomly assigns buses to different routes at different times, the people who live along bus routes were sometimes exposed to exhaust from dirtier buses and sometimes exposed to exhaust from clean buses.  By comparing health outcomes in households that are randomly exposed to the dirtier bus pollution with comparable households randomly exposed to cleaner bus pollution, Ngo can isolate the effect of the bus pollution on health.

In this paper, Ngo focuses on infant health (although I expect she will use this unique data set to study many more outcomes in the future) and measures the effect of a mother's exposure to bus pollution during pregnancy on a child's health at birth.  This is hard problem, since its impossible to know exactly all the different things that a mother does while she's pregnant and because Ngo has to use pollution data collected from air-quality monitors to model how pollution spreads from bus routes to nearby residences.  Despite these challenges, Ngo is able to detect the effect of in utero exposure to bus pollution on an infant's health at birth.  Fetuses that are exposed to higher levels of bus-generated Nitrous-Oxides (NOx) during their second and third trimester have a lower birthweight on average and fetuses exposed to more bus-generated particulate matter (PM) during those trimesters have a lower Apgar 5 score (a doctors subjective evaluation of newborn health).

The size of the effects that Ngo measures are relatively small for any individual child (so if you are pregnant and living near a bus route, you shouldn't panic).  But the aggregate effect of New York City's investment in clean buses is large, since there are many pregnant mothers who live near bus routes and who were exposed to less dangerous emissions because of these policies. Since its easiest to think about city-wide impacts using monetized measures, and because previous studies have demonstrated that higher birth weight causes an infants future income to be higher, Ngo aggregates these small impacts across many babies and estimates that the city's effort to upgrade buses increase total future earnings of these children by $66 million. Considering that the city upgraded roughly 4500 buses, this implies that each bus that was upgraded generated about $1,460 in value just through its influence on infant health and future earnings. Importantly however, Ngo notes:

This [benefit] is likely a lower bound since I do not consider increased hospitalizations costs from lower birth weights as discussed in Almond et al. (2005), nor could I find short-run or long-run costs associated with lower Apgar 5 scores.

and I expect that Ngo will uncover additional health benefits of New York City's bus program, which will likely increase estimates for the program's total benefits. Furthermore, I suspect that these estimates for the value of pollution control can be extrapolated to diesel trucks, although Ngo is appropriately cautious about doing so in her formal analysis.

These results are important for urban planners and policy-makers in cities around the world who must decide whether or not it is worth it to invest in cleaner public transit systems.  In addition, they are an excellent example of how great data and careful analysis can help us understand important human-environment relationships in complex urban systems.

The paper:

Transit buses and fetal health: An evaluation of bus pollution policies in New York City 

Nicole Ngo

Abstract The U.S. Environmental Protection Agency (EPA) reduced emission standards for transit buses by 98% between 1988 and 2010. I exploit the variation caused by these policy changes to evaluate the impacts of transit bus pollution policies on fetal health in New York City (NYC) by using bus vintage as a proxy for street-level bus emissions. I construct a novel panel data set for the NYC Transit bus fleet to assign maternal exposure to bus pollution at the census block level. Results show a 10% reduction in emission standards for particulate matter (PM) and nitrogen oxides (NOx) during pregnancy increased infant Apgar 5 scores by 0.003 points and birth weight by 6.6 grams. While the impacts on fetal health are modest, the sensitivity of later-life outcomes to prenatal conditions suggests improved emission standards between 1990 and 2009 have increased total earnings for the 2009 birth cohort who live near bus routes in NYC by at least $65.7 million.

In figures...

Bus routes in New York City, which Ngo links to residential exposure through geospatial analysis:

(click to enlarge)

Buses are upgraded throughout the two decades, with several large and abrupt changes in the fleet's composition:

(click to enlarge)

When dirtier buses are randomly assigned to travel a route, Ngo can detect this using air-monitoring stations near that route:

(click to enlarge)

Using her mathematical model of bus pollution (and its spatial diffusion) Ngo computes how New York City's investment in buses lead to a dramatic reduction in exposure to bus-generated pollutants:

(click to enlarge)

Exposure to bus-generated NOx during the second and third trimesters lowers birthweight, and exposure to bus-generated PM lowers Apgar5 scores:

(click to enlarge)

Strategic contamination of science by industry

I found this gem in the American Journal of Public Health. If you apply a mental "find-replace" to any of many industries, this should sound familiar.  Brandt is a science historian, for any readers who might otherwise be skeptical.

Inventing Conflicts of Interest: A History of Tobacco Industry Tactics
Alan M. Brandt

ABSTRACT: Confronted by compelling peer-reviewed scientific evidence of the harms of smoking, the tobacco industry, beginning in the 1950s, used sophisticated public relations approaches to undermine and distort the emerging science. 

The industry campaign worked to create a scientific controversy through a program that depended on the creationofindustry–academic conflicts of interest. This strategy of producing scientific uncertainty undercut public health efforts and regulatory interventions designed to reduce the harms of smoking. 

A number of industries have subsequently followed this approach to disrupting normative science. Claims of scientific uncertainty and lack of proof also lead to the assertion of individual responsibility for industrially produced health risks.

Brandt writes:

By late 1953, the tobacco industry faced a crisis of cataclysmic proportions. Smoking had been categorically linked to the dramatic rise of lung cancer. Although health concerns about smoking had been raised for decades, by the early 1950s there was a powerful expansion and consolidation of scientific methods and findings that demonstrated that smoking caused lung disease as well as other serious respiratory and cardiac diseases, leading to death. These findings appeared in major, peer- reviewed medical journals as well as throughout the general media. 

As a result, the tobacco industry would launch a new strategy, largely unprecedented in the history of US industry and business: it would work to erode, confuse, and condemn the very science that now threatened to destroy its prized, highly popular, and exclu- sive product. But this would be no simple matter. After all, in the immediate postwar years–the dawn of the nuclear age–science was in high esteem. The industry could not denigrate the scientific enterprise and still maintain its public credibility, so crucial to its success… 

 What is so upsetting is the level of intentional manipulation and coordination [emphasis is mine]:

By the early 1950s, the emerging science on tobacco’s harms documented in the elite peer- reviewed literature, especially the causal linkage to lung cancer, threatened to undo more than a half century of unprecedented corporate success. With considerable anxiety and rancor within the tobacco industry, the industry’s highly competitive CEOs came together in December 1953 at the Plaza Hotel in New York City to map a strategy. They realized that the threat they now faced was unprecedented and would require new, collaborative approaches and expertise. Not surprisingly, given their history, they turned again to the field of public relations that had served them so well in the past. They called upon John W. Hill, the president of the nation’s leading public relations firm, Hill & Knowlton. 

The public confidence the industry required could not be achieved through advertising, which was self-interested by definition. It would be crucial for the industry to assert its authority over the scientific domain; science had the distinct advantage of its reputation for disinterestedness. Hill shared with his public relations predecessor Bernays a deep skepticism about the role of advertising in influencing public perceptions of tobacco. To those schooled in public relations, advertising ran the risk of exposing corporate self-interest. Good public relations relied on scrupulous behind-the-scenes management of media. As Bernays had demonstrated in the 1920s and 1930s, the best public relations work left no fingerprints. 

Hill offered the companies powerful advice and guidance as they faced their crisis. Hill understood that simply denying emerging scientific facts would be a losing game. This would not only smack of self-interest but also ally the companies with ignorance in an age of technological and scientific hegemony. So he proposed seizing and controlling science rather than avoiding it. If science posed the principal–even terminal–threat to the industry, Hill advised that the companies should now associate themselves as great supporters of science. The companies, in his view, should embrace a sophisticated scientific discourse; they should demand more science, not less. 

Of critical importance, Hill argued, they should declare the positive value of scientific skepticism of science itself. Knowledge, Hill understood, was hard won and uncertain, and there would always be skeptics. What better strategy than to identify, solicit, support, and amplify the views of skeptics of the causal relationship between smoking and disease? Moreover, the liberal disbursement of tobacco industry research funding to academic scientists could draw new skeptics into the fold. The goal, according to Hill, would be to build and broadcast a major scientific controversy. The public must get the message that the issue of the health effects of smoking remains an open question. Doubt, uncertainty, and the truism that there is more to know would become the industry’s collective new mantra…. 

The very nature of controlling and managing information in public relations stood in marked contrast to the scientific notion of unfettered new knowledge. Hill and his clients had no interest in answering a scientific question. Their goal was to maintain vigorous control over the research program, to use science in the service of public relations. Al- though the tobacco executives had proposed forming a cigarette information committee dedicated to defending smoking against the medical findings, Hill argued aggressively for adding research to the committee’s title and agenda. ‘‘It is believed,’’ he wrote, ‘‘that the word ‘Research’ is needed in the name to give weight and added credence to the Committee’s statements.’’ a Hill understood that his clients should be viewed as embracing science rather than dismissing it…. 

Hill & Knowlton had successfully produced uncertainty in the face of a powerful scientific consensus. So long as this uncertainty could be maintained, so long as the industry could claim ‘‘not proven,’’ it would be positioned to fight any attempts to assert regulatory authority over the industry. Without their claims of no proof and doubt, the companies would be highly vulnerable in 2 crucial venues: regulatory politics and litigation…. 

In their work to control the science, the companies had also found that they had secured considerable advantages in the realms of media, law, and public opinion. All of this was dependent on maintaining the notions of controversy, uncertainty, and doubt. In 1961, Hill & Knowlton celebrated its successes on behalf of its tobacco client. The total number of cigarettes sold annually had risen from 369 billion in 1954, the company’s first full year of service to the industry, to 488 billion. Per capita consumption had risen from 3344 a year in 1954 to 4025 in 1961, the highest ever. ‘‘From a business stand- point,’’ Hill & Knowlton crowed, ‘‘the tobacco industry has weath- ered this latest spate of health attacks on its products.’’ In less than a decade, the in- dustry had been stabilized and was thriving… 

And finally, why we need to devise some kind of institution to prevent this:

The story of the tobacco ‘‘controversy’’ and the industry’s deliberative attempts to disrupt science is now, fortunately, fairly well known. In large measure, this story emerged only as a result of whistle blowers and litigation that led to the revelation of millions of pages of internal tobacco documents that both laid out this strategy and documented its implementation. But what has often gone over- looked in the assessment of the tobacco episode was the highly articulated, strategic character of seizing the scientific initiative, the engineering of science. This, however, was a factor well understood by John Hill and the public relations teams that advised the companies. They carefully documented what the scientific investment would buy and how best for the companies to protect and defend that investment. 

A wide range of other industries have carefully studied the tobacco industry strategy. As a result, they have come to better understand the fundamentals of influence within the sciences and the value of uncertainty and skepticism in deflecting regulation, defending against litigation, and maintaining credibility despite the marketing of products that are known to be harmful to public health. Also, they have come to understand that the invention of scientific controversy undermines notions of the common good by emphasizing in- dividual assessment, responsibility, and judgment.

There are so many research ideas in here that I'm not even going to bother trying to list them.  But the field is wide open. I don't think I know more than one or two people who work on the political economy of science.

Temperature, Human Health, and Adaptation

Apropos of last week's post on aggression, Marshall's post on temperature extremes, and this blog's alternate name, please see Olivier Deschênes' new NBER working paper, "Temperature, Human Health, and Adaptation: A Review of the Empirical Literature":

This paper presents a survey of the empirical literature studying the relationship between health outcomes, temperature, and adaptation to temperature extremes.  The objective of the paper is to highlight the many remaining gaps in the empirical literature and to provide guidelines for improving the current Integrated Assessment Model (IAM) literature that seeks to incorporate human health and adaptation in its framework. I begin by presenting the conceptual and methodological issues associated with the measurement of the effect of temperature extremes on health, and the role of adaptation in possibly muting these effects. The main conclusion that emerges from the literature is that despite the wide variety of data sets and settings most studies find that temperature extremes lead to significant reductions in health, generally measured with excess mortality. Regarding the role of adaptation in mitigating the effects of extreme temperature on health, the available knowledge is limited, in part due to the lack of real-world data on measures of adaptation behaviors. Finally, the paper discusses the implications of the currently available evidence for assessments of potential human health impacts of global climate change.

Diarrhoea in Bangladesh: displaying results from fixed effects models

I ran into this 2008 paper doing hurricane work with Jesse. The results are not extremely surprising, but I really liked how they displayed their result.  Many of us use high-dimensional data and multiple regression models to try and account for the many different processes that occur in social data, but it is often difficult to clearly display the effect of just one process while also being clear about all the other controls in the model. I like the approach of this team: they show predictions form the complex model (eg. with week and month fixed effects, socioeconomic controls, etc.) overlaid with the real data.


Factors determining vulnerability to diarrhoea during and after severe floods in Bangladesh
Masahiro Hashizume, Yukiko Wagatsuma, Abu S. G. Faruque, Taiichi Hayashi, Paul R. Hunter, Ben Armstrong and David A. Sack

Abstract: This paper identifies groups vulnerable to the effect of flooding on hospital visits due to diarrhoea during and after a flood event in 1998 in Dhaka, Bangladesh. The number of observed cases of cholera and non-cholera diarrhoea per week was compared to expected normal numbers during the flood and post-flood periods, obtained as the season-specific average over the two preceding and subsequent years using Poisson generalised linear models. The expected number of diarrhoea cases was estimated in separate models for each category of potential modifying factors: sex, age, socio-economic status and hygiene and sanitation practices. During the flood, the number of cholera and non-cholera diarrhoea cases was almost six and two times higher than expected, respectively. In the post-flood period, the risk of non-cholera diarrhoea was significantly higher for those with lower educational level, living in a household with a non- concrete roof, drinking tube-well water (vs. tap water), using a distant water source and unsanitary toilets. The risk for cholera was significantly higher for those drinking tube-well water and those using unsanitary toilets. This study confirms that low socio-economic groups and poor hygiene and sanitation groups were most vulnerable to flood-related diarrhoea.

Disease and Development: Some Notable Recent Findings

[This is a guest post by first year students in Columbia's Sustainable Development program]

As part of their coursework for the Human Ecology course, first years in Columbia's Sustainable Development Ph.D. program (and a few select students from the SIPA Masters programs) were asked to put together reviews of recently active areas of the broad environment/development literature. Anna Tompsett, the course's TA and sometimes guest blogger on FE, has asked the students permission to share them with us, so over the next two weeks we'll be posting them, starting with today's on disease and development. Enjoy! 

Disease and Development: Some Notable Recent Findings

by Kimberly Lai, Habtamu Fuje and Clarissa Santelmo

One of the most formidable impediments to sustainable development in low-income countries is disease. In an attempt to offer a rough sketch of the current state of research in this realm, we canvassed the past year’s worth of issues of three major journals—Nature, Lancet, and the New England Journal of Medicine—and picked out six articles that we found particularly relevant to disease, development, and global health policy.

We were especially interested in health issues that rate among the World Health Organization’s leading causes of death and global burden of disease in developing countries. (Global burden of disease measures years of healthy life lost to disability as well as death.) We selected studies based on the number of people that could benefit from the findings, out-of-sample validity (in the case of experimental studies), socioeconomic aspects, and potential policy implications.

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)

Four data points, La Niña, and the flu

Columbia's Jerry Shaman* and Harvard's Marc Lipsitch have a new paper out in PNAS that argues that La Niña events may be driving the pandemic flu cycle by changing the pattern of bird migration:

We find that the four most recent human influenza pandemics (1918, 1957, 1968, and 2009), all of which were first identified in boreal spring or summer, were preceded by La Niña conditions in the equatorial Pacific. Changes in the phase of the El Niño–Southern Oscillation have been shown to alter the migration, stopover time, fitness, and interspecies mixing of migratory birds, and consequently, likely affect their mixing with domestic animals. We hypothesize that La Niña conditions bring divergent influenza subtypes together in some parts of the world and favor the reassortment of influenza through simultaneous multiple infection of individual hosts and the generation of novel pandemic strains. We propose approaches to test this hypothesis using influenza population genetics, virus prevalence in various host species, and avian migration patterns.

Here is a BBC article summarizing the paper. Aside from the fact that this paper is, to my eye, a great argument for robust interdisciplinary training (climate + public health + microbiology), it's also a good example of a fundamental statistical truism: just because the data are sparse doesn't mean you can't say something meaningful. There have been only four pandemic influenzas in the past century, but the likelihood that they would all start at the same point in the ENSO cycle is low (Shaman and Lipsitch estimate it at P=0.069). That on its own wouldn't necessarily be meaningful, but when combined with the fairly credible potential mechanism the authors outline one ends up with a pretty plausible hypothesis. Whether it holds remains to be seen (hence the apposition in the title) but it's a lovely first paper on what might end up being a very important phenomenon.

* Jerry Shaman presented a version of this paper at the session Sol coorganized at AGU (video here).

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.