What do rising mortality rates tell us?

When I was a student at a school of public health in the late '70s, the focus was on chronic disease. This was when the health and disease establishment was full of the hubris of thinking they'd conquered infectious disease in the industrialized world, and that it was now heart disease, cancer and stroke that they had to figure out how to control.  Even genetics at the time was confined to a few 'Mendelian' (single gene) diseases, mainly rare and pediatric, and few even of these genes had been identified.

My field was Population Studies -- basically the demography of who gets sick and why, often with an emphasis on "SES" or socioeconomic status.  That is, the effect of education, income and occupation on health and disease.  My Master's thesis was on socioeconomic differentials in infant mortality, and my dissertation was a piece of a large study of the causes of death in the whole population of Laredo, Texas over 150 years, with a focus on cancers.  Death rates in the US, and the industrialized world in general were decreasing, even if ethnic and economic differentials in mortality persisted.

So, I was especially interested in the latest episode of the BBC Radio 4 program The Inquiry, "What's killing white American women?" Used to increasing life expectancy in all segments of the population for decades, when researchers noted that mortality rates were actually rising among lower educated, middle-aged American women, they paid close attention.

A study published in PNAS in the fall of 2015 by two economists was the first to note that mortality in this segment of the population, among men and women, was rising enough to affect morality rates among middle-aged white Americans in general.  Mortality among African American non-Hispanics and Hispanics continued to fall.  If death rates had remained at 1998 rates or continued to decline among white Americans who hadn't more than a high school education in this age group, half a million deaths would have been avoided, which is more, says the study, than died in the AIDS epidemic through the middle of 2015.

What's going on?  The authors write, "Concurrent declines in self-reported health, mental health, and ability to work, increased reports of pain, and deteriorating measures of liver function all point to increasing midlife distress."  But how does this lead to death?  The most significant causes of mortality are "drug and alcohol poisonings, suicide, and chronic liver diseases and cirrhosis."  Causes associated with pain and distress.

Source: The New York Times

The Inquiry radio program examines in more detail why this group of Americans, and women in particularly, are suffering disproportionately.  Women, they say, have been turning to riskier behaviors, drinking, drug addiction and smoking, at a higher rate than men.  And, half of the increase in mortality is due to drugs, including prescription drugs, opioids in particular.  Here they zero in on the history of opiod use during the last 10 years, a history that shows in stark relief that the effect of economic pressures on health and disease aren't due only to the income or occupation of the target or study population.

Opioids, prescribed as painkillers for the relief of moderate to severe pain, have been in clinical use since the early 1900's.  Until the late 1990's they were used only very briefly after major surgery or for patients with terminal illnesses, because the risk of addiction or overdose was considered too great for others.  In the 1990's, however, Purdue Pharma, the maker of the pain killer Oxycontin, began to lobby heavily for expanded use.  They convinced the powers-that-be that chronic pain was a widespread and serious enough problem that opioids should and could be safely used by far more patients than traditionally accepted.  (See this story for a description of how advertising and clever salesmanship pushed Oxycontin onto center stage.)

Purdue lobbying lead to pain being classified as a 'vital sign', which is why any time you go into your doctor's office now you're asked whether you're suffering any pain.  Hospital funding became partially dependent on screening for and reducing pain scores in their patients.

Ten to twelve million Americans now take opioids chronically for pain.  Between 1999 and 2014, 250,000 Americans died of opioid overdose.  According to The Inquiry, that's more than the number killed in motor vehicle accident or by guns.  And it goes a long way toward explaining rising mortality rates among working-class middle-aged Americans.  And note that the rising mortality rate has nothing to do with genes.  It's basically the unforeseen consequences of greed.

Opioids are money-makers themselves, of course (see this Forbes story about the family behind Purdue Pharma, headlined "The OxyContin Clan: The $14 Billion Newcomer to Forbes 2015 List of Richest U.S. Families;" the drug has earned Purdue $35 billion since 1995) but pharmaceutical companies also make money selling drugs to treat the side effects of opioids; nausea, vomiting, drowsiness, constipation, and more.  Purdue just lost its fight against allowing generic versions of Oxycontin on the market, which means both that cheaper versions of the drug will be available, and that other pharmaceutical companies will have a vested interest in expanding its use.  Indeed, Purdue just won approval for use of the drug in 11-17 year olds.

In a rather perverse way, race plays a role in this epidemic, too, in this case a (statistically) protective one even though it has its roots in racial stereotyping.  Many physicians are less willing to prescribe opioids for African American or Hispanic patients because they fear the patient will become addicted, or that he or she will sell the drugs on the street.

"Social epidemiology" is a fairly new branch of the field, and it's based on the idea that there are social determinants of health beyond the usual individual-level measures of income, education and occupation.  Beyond socioeconomic status, to determinants measurable on the population-level instead; location, availability of healthy foods, medical care, child care, jobs, pollution levels, levels of neighborhood violence, and much more.

Obviously the opioid story reminds us that profit motive is another factor that needs to be added to the causal mix.  Big Tobacco already taught us that profit can readily trump public health, and it's true of Big Pharma and opioids as well.  Having insinuated themselves into hospitals, clinics and doctors' offices, Big Pharma may have relieved a lot of pain, but at great cost to public health.

Playing the Big Fiddle while Rome burns?

We've seemed to have forgotten the trust-busting era that was necessary to control monopolistic acquisition of resources.  That was over a century ago, and now we're again allowing already huge companies to merge and coalesce.  It's rationalized in various ways, naturally, by those on the gain.  It's the spirit and the power structure of our times, for whatever reason.  Maybe that explains why the same thing is happening in science as universities coo over their adoption of 'the business model'.

We're inundated in jargonized ways of advertising to co-opt research resources, with our  'omics' and 'Big Data' labeling.  Like it or not, this is how the system is working in our media and self-promotional age.  One is tempted to say that, as with old Nero, it may take a catastrophic fire to force us to change.  Unfortunately, that imagery is apparently quite wrong.  There were no fiddles in Nero's time, and if he did anything about the fire it was to help sponsor various relief efforts for those harmed by it.  But whatever imagery you want, our current obsession with scaling up to find more and more that explains less and less is obvious. Every generation has its resource competition games, always labeled as for some greater good, and this is how our particular game is played.  But there is a fire starting, and at least some have begun smelling the smoke.

Nero plucks away.  Sourcc: Wikipedia images, public domain

The smolder threatens to become an urgent fire, truly, and not just as a branding exercise.  It is a problem recognized not just by nay-saying cranks like us who object to how money is being burnt to support fiddling with more-of-the-same-not-much-new research.  It is an area where a major application of funds could have enormously positive impact on millions of people, and where causation seems to be quite tractable and understandable enough that you could even find it with a slide rule.

We refer to the serious, perhaps acute, problem with antibiotic resistance.  Different bugs are being discovered to be major threats, or to have evolved to become so, both for us and for the plants and animals who sacrifice their lives to feed us. Normal evolutionary dynamics, complemented with our agricultural practices, our population density and movement, and perhaps other aspects of our changing of local ecologies, is opening space for the spread of new or newly resistant pathogens.

This is a legitimate and perhaps imminent threat of a potentially catastrophic scale.  Such language is not an exercise in self-promotional rhetoric by those warning us of the problem. There is plenty of evidence that epidemic or even potentially pandemic shadows loom.  Ebola, zika, MRSA, persistent evolving malaria, and more should make the point and we have history to show that epidemic catastrophes can be very real indeed.

Addressing this problem rather than a lot of the wheel-spinning, money-burning activities now afoot in the medical sciences would be where properly constrained research warrants public investment.  The problem involves the ecology of the pathogens, our vulnerabilities as hosts, weaknesses in the current science, and problems in the economics of such things as antibacterial drugs or vaccinations.  These problems are tractable, with potentially huge benefit.

For a quick discussion, here is a link to a program by the statistical watchdog BBC Radio program MoreOrLess on antibiotic resistance  Of course there are many other papers and discussions as well.  We're caught between urgently increasing need, and the logistics, ecology, and economics that threaten to make the problem resistant to any easy fixes.

There's plenty of productive science that can be done that is targeted to individual causes that merit our attention, and for which technical solutions of the kind humans are so good at might be possible. We shouldn't wait to take antibiotic resistance seriously, but clearing away the logjam of resource commitments in genetic and epidemiological research to large weakly statistical efforts well into diminishing returns, or research based on rosy promises where we know there are few flowers, will not be easy...but we are in danger of fiddling around detecting risk factors with ever-decreasing effect sizes until the fire spreads to our doorsteps.

QC and the limits of detection

It’s been a while since I’ve blogged about anything – things have been quite busy around SMRU and I haven't had many chances to sit down and write for fun [i] (some press about our current work here, here, here and here). 

Today I’m sitting in our home, listening to waves of bird and insect songs, and the sound of a gentle rain.  It is the end of another hot season and the beginning of another rainy season, now my 5^th in a row here in Northwestern Thailand and our (my wife Amber and son Salem, and me) 3^rd rainy season since moving here full time in 2013.  The rains mean that the oppressive heat will subside a bit.  They also mean that malaria season is taking off again. 

Just this last week the final chapter of my dissertation was accepted for publication in Malaria Journal.  What I’d like to do over a few short posts is to flesh out a couple of parts of this paper, hopefully to reach an audience that is interested in malaria and infectious diseases, but perhaps doesn’t have time to keep up on all things malaria or tropical medicine.  This also gives me a chance to go into more detail about specific parts of the paper that I needed to condense for a scientific paper. 

The project that I worked on for my dissertation included several study villages, made up of mostly Karen villagers, on the Thai side of the Thailand-Myanmar border. 

This particular research had several very interesting findings. 

In one of the study villages we did full blood surveys, taking blood from every villager that would participate, every 5 months, for a total of 3 surveys over 1 year.  These blood surveys included making blood smears on glass slides as well as taking blood spots on filter papers that could later be PCRd to test for malaria.  Blood smears are the gold standard of malaria detection (if you're really interested, see here and here).  A microscopist uses the slides to look for malaria parasites within the blood.  Diagnosing malaria this way requires some skill and training.  PCR is generally considered a more sensitive means of detecting malaria, but isn’t currently a realistic approach to use in field settings[ii]. 

Collecting blood, on both slides (for microscopic detection of malaria)
and filter papers (for PCR detection of malaria)

The glass slides were prepared with a staining chemical and immediately read by a field microscopist, someone who works at a local malaria clinic, and anyone who was diagnosed with malaria was treated.  The slides were then shipped to Bangkok, where an expert microscopist, someone who has been diagnosing malaria using this method for over 20 years and who trains other to do the same, also read through the slides.  Then, the filter papers were PCRd for malaria DNA.  In this way we could look at three different modes of diagnosing malaria – the field microscopist, the expert microscopist, and PCR. 

And basically what we found was that the field microscopist missed a whole lot of malaria.  Compared to PCR, the field microscopist missed about 90% of all cases (detecting 8 cases compared to 75 that were detected by PCR).   Even the expert microscopist missed over half of the cases (34 infections). 

What does this mean though? 

Lets start with how this happens.  To be fair, it isn’t just that the microscopists are bad at what they do.  There are at least two things at play here: one has to do with training and quality control (QC) while the other has to do with limits of detection.

Microscopy requires proper training, upkeep of that training, quality control systems, and upkeep of the materials (regents etc.)  In a field setting, all of these things can be difficult.  Mold and algae can grow inside of a microscope.  The chemicals used in microscopy, in staining the slides, etc. can go bad, and probably will more quickly under very hot and humid conditions.  In more remote areas, retraining workshops and frequent quality control testing are more difficult to accomplish and therefore less likely to happen.  There is a brain drain problem too.  Many of the most capable laboratory workers leave remote settings as soon as they have a chance (for example, if they can get better salary and benefits for doing the same job elsewhere – perhaps by becoming an “expert microscopist”?)

Regarding the second point, I think that most people would expect PCR to pick up more cases than microscopy.  In fact, there is some probability at play here.  When we prick someone’s finger and make a blood smear on a glass slide, there is a possibility that even if there are malaria parasites in that person’s blood, there won’t be any in the blood that winds up on the slide.  The same is true when we make a filter paper for doing PCR work.  However, the microscopist is unlikely to look at every single spot on the glass slide and there is also some probability at play here too.  There could be parasites on the slide, but they may only be in a far corner of the slide where the microscopist doesn’t happen to look.  These are the ones that would hopefully be picked up through PCR anyway. 

Presumably, many of these infected people had a low level of parasitemia, meaning relatively few parasites in their blood, making it more difficult to catch the infection through microscopy.  Conversely, when people have lots of parasites in their blood, it should be easier to catch regardless of the method of diagnosis.  

These issues lead to a few more points. 

Some people have very few parasites in their blood while others have many.  The common view on this is that in high transmission[iii] areas, people will be exposed to malaria very frequently during their life and will therefore build up some immunity.  These people will have immune systems that can keep malaria parasite population numbers low, and as a result should not feel as sick.  Conversely, people who aren’t frequently exposed to malaria would not be expected to develop this type of “acquired” (versus inherited or genetic) immunity.  Here in Southeast Asia, transmission is generally considered to be low – and therefore I (and others) wouldn’t normally expect high levels of acquired malaria immunity.  Why then are we finding so many people with few parasites in their blood? 

Furthermore, those with very low numbers of parasites may not know they’re infected.  In fact, even if they are tested by the local microscopist they might not be diagnosed (probably because they have a “submicroscopic” infection).  From further work we’ve been doing along these lines at SMRU and during my dissertation work, it seems that many of these people don’t have symptoms, or if they do, those symptoms aren’t very strong (that is, some are “asymptomatic”).

It also seems like this isn’t exactly a rare phenomenon and this leads to all sorts of questions:  How long can these people actually carry parasites in their blood – that is, how long does a malaria infection like this last?  In the paper I’m discussing here we found a few people with infections across multiple blood screenings.  This means it is at least possible that they had the same infection for 5 months or more (people with no symptoms, who were only diagnosed by PCR quite a few months later, were not treated for malaria infection).  Also, does a person with very few malaria parasites in her blood, with no apparent symptoms, actually have “malaria”?  If they’re not sick, should they be treated?  Should we even bother telling them that they have parasites in their blood?  Should they be counted as a malaria case in an epidemiological data system?

For that matter, what then is malaria?  Is it being infected with a Plasmodium parasite, regardless of whether or not it is bothering you?  Or do you only have malaria when you're sick with those classic malaria symptoms (periodic chills and fevers)?  

Perhaps what matters most here though is another question: Can these people transmit the disease to others?  Right now we don’t know the answer to this question.  It is not enough to only have malaria parasites in your blood – you must have a very specific life stage of the parasite present in your blood in order for an Anopheles mosquito to pick the parasite up when taking a blood meal.  The PCR methods used in this paper would not allow us to differentiate between life stages – they only tell us whether or not malaria is present.  This question should, however, be answered in future work. 

*** As always, my opinions are my own.  This post and my opinions do not necessarily reflect those of Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, or the Wellcome Trust. For that matter, it is possible that absolutely no one agrees with my opinions and even that my opinions will change as I gather new experiences and information.  

    

---

[i] Shoklo Malaria Research Unit – a field station of the Mahidol Oxford TropicalMedicine Research Unit

[ii]  PCR can be expensive, can take time, and requires machinery and materials that aren’t currently practical in at least some field settings

[iii] In a high transmission area, people would have more infectious bites by mosquitoes per unit of time when compared to a low transmission area.  For example, in a low transmission area a person might only experience one infectious bite per year whereas in a high transmission area a person might have 1 infectious bite per month.  

Common ground

By Eric Sannerud

Note:  We know Eric through our connection with a remarkable group of farmers, philosophers, economists, geneticists, innovators, writers, both academic and not, who share a concern for how we humans are mismanaging our place in the biosphere, and how we might make it better.  Eric describes himself as a farmer, thinker, and entrepreneur in Ham Lake, Minnesota. He is the Director of Sandbox Center for Regenerative Entrepreneurship and a member of the Minneapolis Hub of the Global Shapers. Connect with him on Twitter @ericsannerud.   Here are his thoughts:

As a 23 year-old American farmer who studies the US food system from the field I have a unique perspective on the serious challenges it faces. From drainage tiles that evacuate nutrient laden water to the nearest public water source, to obesity rates that cost untold lives, livelihoods, and money, the US food system is badly in need of regeneration.

Source: Wikipedia

Food and health policy in the United States.
In the United States food policy is a collection of local and national priorities that concern the supply of food. US food policy sets supports for certain crops that lead to a higher supply (and therefore lower price) of these crops in the market. Crops that are insured by the US government, against too much rain or too much drought, for example, such as corn, soy, and wheat, are more attractive to farmers than “non-insurable” crops, leading to greater production of insured crops.

United States Health policy is a collection of state and national regulations meant to minimize occupational and recreational dangers and to improve health. Seat belts, MyPlate.gov, the newest iteration of the government recommended diet, FDA regulations, and food labeling mandates are examples of health policy. The intended purpose of many of these regulations, as they relate to food, is to educate consumers to make informed decisions about what they eat. MyPlate identifies proper serving sizes for Americans (though it is not without criticism1). Food labels provide even, consistent criteria for comparing two different items (even if less than half2 of Americans read them).

The trouble is this...
On one hand we have food policies, such as government crop insurance, that encourage environmentally damaging fence row to fence row crop production, or government support for drain tile, drainage systems for fields that shuttle nutrient rich runoff to the nearest water body to be rushed downstream. On the other hand are well-meaning health policies. One can imagine that in the minds of the crafters of health policy each consumer carefully reads the food label on each product, compares the serving size of their meals against the MyPlate recommendations, and eats just the right amount of calories for their BMI each day. Real life food decisions are more complex and price is a big factor in purchasing. Price is where food policy gets involved. Government support makes certain crops cheap. These cheap crops can be used to create cheap food products (corn into chips and soda, for example). But chips and soda are shunned by health policy, and do not have healthy nutrition labels or a formal home on MyPlate.

Due to this disconnect between food policy and health policy the US food system is malfunctioning. A food system that creates historic rates of obesity3 while continuously exploiting the resources humans require for life, soil4 and water5, requires change. However, since the left hand doesn’t know what the right hand is doing, any efforts made, positive or negative, will be hindered by inefficiencies and ineffectiveness.

There is no one elegant solution to reducing the negative effects of such disconnected policies. Anyone claiming to have a trump card is lying: GMOs will not solve all of our problems, neither will organic production nor sin taxes on fizzy drinks and new government serving size suggestions. When dealing with interconnected systems solutions require a full deck of answers.

Three cards to add to the deck

1. Regenerating Health
US consumers shop with their wallets while health policy targets their minds. Health policy that acts on this fact will be moving in the right direction. The question for the discerning health policy strategist then is how to make healthy food price competitive?

One argument that I find persuasive as a low-paid, full-time change maker is the prudence of home cooking. Too often on the run I need food that is grab and go. Frozen burritos at the store cost me $2.00 each, I can make similar quality, though I must say, far tastier, burritos at home for just $.75.

A more aggressive strategy than home cooking promotion is artificially adding cost to unhealthy food. The reasoning goes that if that 76oz soda costs $5.00 instead of $1.00 less people will imbibe. Unfortunately, according to a recent US Supreme Court ruling all Americans have the right to drink cheap soda.6

One inventive way that communities across the United States are improving the cost competitiveness of healthy food is by offering “bonus bucks” to Electronic Benefits Transfer (EBT), government food support, purchases. Spend $20 of EBT at a participating farmers market and get $5 additional “market bucks” good for any fresh produce at the market.

2. Regenerating Land
More healthy food in the market will make healthy food cheaper and more accessible. A benefit of coordinated food and health policy is an increase in the overall supply of healthy food.

Farm fields: Wikipedia

For starters, imagine if US food policy aligned what farmers were incentivized to grow with what health policy encourages Americans to consume. The landscapes of rural America, and the tables of all Americans, could change drastically. This map7, by Emily Cassidy at the University of Minnesota’s Institute on the Environment, shows the caloric efficiency of crop production across the world. Caloric efficiency is the ratio of calories produced on a landscape to the number of produced calories consumed directly by humans. Developed countries producing commodities show horrendous caloric efficiency. Globally just 41% of calories produced are consumed by humans. According to Cassidy, maximizing caloric efficiency could feed an additional 4 billion people. In the US, food policy structures that support big commodity production could be amended to support crops, meat, and production methods of higher caloric efficiency including growing more crops for direct human consumption and more caloric efficient animal proteins such as chicken and fish.

Photo by Eric Sannerud

Private actors have their own part to play in addressing this disconnect. Non-governmental actors can work to aggregate and add scale to local food systems: decreasing prices of the freshest produce by harvesting efficiencies of scale.

Photo by Eric Sannerud

Two up and coming projects, Urban Oasis in St.Paul, Minnesota and New Moran in Burlington, Vermont, are examples of private sector innovation. By serving as aggregation, processing, and distribution hubs for local farmers these projects can increase the scale of healthy local food systems.

3. Regenerating Governance
Solutions also exist in state and local governments that can induce dialogue between government food and health policy makers.

At the state level food policy councils are popping up across the nation. These food policy councils are often created with the express purpose of increasing dialogue between state departments of agriculture, natural resources, and health. The Iowa Food Systems Council is one of the most longstanding and studied State food councils.

City level food councils are also developing. Similar to the state level councils these organizations are made up of a diverse group of stakeholders from across the food system including farmers, nutritionists, academics, and entrepreneurs. In Minneapolis, Minnesota “Minneapolis Homegrown” is a food policy council made up of appointed community members who serve an advisory role to the elected city council on food and health policies.

Hand, eye coordination

Food and health policies in which the left hand doesn’t know what the right is doing are only effective at continuing the failing status quo. At their best, food policy attempts to tackle resource issues in food production while health policy encourages healthy grocery store purchases. Discontinuity contributes to the symptomatic nature of present day solutions and thinking. A focus on symptomatic solutions leaves the underlying disease untouched. In order to cure the cause the US needs a new coordination between food and health policy. Thankfully, there are many luminaries across public, private, and government sectors who understand the underlying problem and are generating bold ideas to address it. 

1 The Nutrition Source. (2014): Healthy Eating Plate vs. USDA’s MyPlate. Harvard School of Public Health [online]. -URL: http://www.hsph.harvard.edu/nutritionsource/healthy-eating-plate-vs-usda-myplate/

2 The NPD Group. (2014, Feb 27): U.S. Consumers’ Interest in Reading Nutrition Facts Labels Wanes as Time Goes On, Reports NPD. NPD Group [online]. -URL: https://www.npd.com/wps/portal/npd/us/news/press-releases/u-s-consumers-interest-in-reading-nutrition-facts-labels-wanes-as-time-goes-on-reports-npd/

3 Centers for Disease Control and Prevention. (2012): Overweight and Obesity, Centers for Disease Control and Prevention [online]. - URL: http://www.cdc.gov/obesity/data/adult.html

4 Lang, S. (2006, Mar 20): ‘Slow, insidious’ soil erosion threatens human health and welfare as well as the environment, Cornell study asserts, by Cornell University [online]. - URL: http://www.news.cornell.edu/stories/2006/03/slow-insidious-soil-erosion-threatens-human-health-and-welfare

5 Bielle, D. (2008, Mar 14): Fertilizer Runoff Overwhelms Streams and Rivers, in Scientific American [online]. - URL: http://www.scientificamerican.com/article/fertilizer-runoff-overwhelms-streams/

6 Klepper, D. (2014, Jun 26): Drink Up NYC: Ban on Big Sodas Canned, in ABC News [online]. -URL: http://abcnews.go.com/Health/wireStory/court-reinstate-york-citys-big-soda-ban-24314227

7 Cassidy, E. (2013): Hotspots of inefficiency Mapping the difference between crop production and food calorie delivery. Institute on the Environment [online]. -URL: http://gli.environment.umn.edu/wp-content/uploads/2013/04/EmilyCassidy_AGU_small.pdf

More on IRBs and restraint on science

Stories over the last couple of days lead us to interrupt our series on natural selection with this brief post on research and ethical conundrums. It's a continuation of a couple of posts from last week (here and here) about IRBs (ethical review committees), bioethics and the idea of societal restraints on what scientists do or are permitted to be funded to do.

Nobody likes restraint, but science is supported by the public and science also has important public implications.  Nothing human is perfect or without potential down sides, including risks.  If society expects to benefit from new knowledge, it will have to pay for things that go nowhere and will also have to assume some risk.  The problem is how to assess work that shouldn't really be done, or paid for, and how to assess risk.

Our posts last week were about the indomitable scientist whose controversial work on engineering viruses--gain-of-function experiments--to make them dangerous went on despite disagreement about the public health consequences of the work.  Is it more important to protect public health by exploring the viruses in greater detail and thus enable the manufacture of better vaccines, or to do absolutely everything possible to prevent the public health disaster that could ensue if the viruses were to escape the lab?  That is, not make the organisms in the first place. 

Again, scientists are basically no more or less honorable than others in our society, and our society isn't exactly famous for its collective unity.  To the contrary, in a selfish society like ours, and when scientists have an idea and there may be money to be made (commercially or in grant funds), or potentially great public benefit, they are going to do what they can think up to get around rules that might stymie the objects of their desires.  That may include shading on honesty or not being as clear or forthcoming, or obfuscating.  Whatever works.  We're great at that--as can be seen in research papers (often, buried in the massive 'Supplemental' material!).  If you think that's not how things work, what planet do you live on?

But by coincidence, just since our posts about IRBs, infectious disease and science ethics, several significant and relevant events have come to light.  Six vials of smallpox virus were found buried in a lab freezer at the NIH in Washington, having been there since the 1954 (as reported by infectious disease writer Maryn McKenna in one of her fine series on this issue) when research into vaccines against the disease was underway, and before smallpox was eradicated; the last case on Earth was seen in 1978.  The vials were sent to the Centers for Disease Control in Atlanta (CDC), where it was discovered that 2 of them contained viable virus; McKenna reports that the samples will be destroyed after they've been thoroughly analyzed.

Officially, only 2 labs in the world still have smallpox samples; the CDC and a lab in Siberia.  The rationale for maintaining these stockpiles is that this would quickly enable whatever research would be necessary if the disease were to reappear -- presumably through biological warfare or terrorism rather than accidental release, but this does now put the latter possibility on the table.

But then in a widely reported story, the CDC found a 'lapsed culture' in infectious disease laboratories, the lax control potentially exposing workers to anthrax and shipping dangerous flu viruses.  The labs have been closed at least temporarily and external review requested.  No one hurt--this time.

Researchers do need to send potential dangerous samples to collaborators, and to work on them in their own labs (where, of course, employees do the actual work, not investigators).  The problem is that if or when an accident does occur, it could be of massively awful proportions.  The problem isn't new -- indeed, McKenna links to a 2007 piece in the USA Today reporting a long list of accidents in US labs handling "deadly germs".  Where is the line, and how do we draw it, to balance between the self- or selfish interest of scientists, the proper concern of government for public health measures, the potential for personal or corporate gain, the potentially major benefit to society, and the risks due to culpable avoidance of ethical standards (such as getting around the IRBs) or ordinary human fallibility?

Life involves risks as well as gains.  But unfortunately, risky research requires regulatory decisions about these issues by insiders, those with the knowledge but also conflict of interest, because it involves regulating themselves.  This is an area in which the public doesn't seem to have adequate means to be the guardians of our own interests.  No obvious solution comes to mind.

elimination now

In last years’ presidential address at the American Association of Tropical Medicine and Hygiene meeting, now published here, David H. Walker asks: “After malaria is controlled, what’s next?”  I find this to be a peculiar but illustrative question for several reasons.  I’ll return to that in a bit, but first a few terms that are frequently thrown around:

Control: reducing the numbers of new infections to an acceptable low level

Elimination: getting rid of a pathogen in the human populations within a defined region

Eradication: completely ridding a defined region, or the entire world, of a particular pathogen

In his presidential address Walker noted that “control is not easy to accomplish…” and he is mostly correct in this statement.  I say mostly correct because I’ve typically found that by having simple health care facilities available to people, malaria can be controlled quite well.  Maintaining such simple facilities, however, is the real trick because of factors such as funding shortages, corruption and other political problems, and in very remote areas it can be difficult to maintain supplies.  Furthermore, populations move around, new generations are born meaning naïve generations are subsequently exposed to diseases, the goal of keeping the numbers of cases down to a low number requires constant effort.  In the absence of such constant attention and effort, the disease can wind up taking over again.     

If you asked most malaria researchers and medical workers if they would like to see malaria eliminated, they would probably give you a resounding “yes”.  Whether or not it would be the truth, I think, is another story altogether.  Later on in Walker’s address he adds: “I do not know what the ultimate outcome of the efforts to control and eliminate malaria will be.  If malaria were to be eradicated, a large portion of our society’s membership would have to find other scientific problems to address.”

I don’t actually believe that Walker is lamenting the potential loss of one of the greatest killers in the history of mankind at the expense of economic considerations.  In fact, this post is not at all an attack on Walker’s speech, but I think it beautifully illustrates some issues that keep arising in my own mind as I’ve spent the last several years in malaria research and work.   

Recently I’ve moved out of what I think was a pure research role (as a PhD student) and into one where I help plan and execute malaria health care in areas that are quite difficult to reach, because of both the physical and political terrain in Karen State, Myanmar.  Research is still a fundamental aspect of what I do, but there is one big difference in what I do now versus what I used to do.  That is, my/our research findings directly affect our actions in the field, almost immediately.  Publishing is still important, both for my own career and for malaria science in general, but it has a secondary importance in my new position.  The goal is public health first and papers second.  I assure you that this isn’t necessarily the case in many academic settings.  

Currently there are lots of malaria researchers that spend all of their time generating and analyzing data, then writing papers on those analyses, many of which never wind up in the hands or minds of people who actually work with the disease in the field.  I see this as a failure in the dissemination of scientific findings.  Open Access efforts partially help with this problem, since many of the people who work in endemic countries don’t have the personal or institutional ability to afford journal fees.  But this is just a part of the problem.  

I find two even larger issues with what I call the malaria world (the malaria research communities plus malaria medical communities, including public health workers):

Issue 1: Economics (at the expense of public health?)

Malaria work provides a livelihood for many, many people, including me (myself?).  It means careers, salaries, wages, a way of life, for those who enter or develop a career in tropical medicine and malaria research.  What I find potentially problematic with this aspect of the malaria world is that when the control of malaria becomes an economic institution, supporting the livelihoods of people who are mostly not at risk of malaria infection themselves, doesn’t the goal become maintenance rather than elimination or even eradication?  Doesn’t the current system discourage people from really fixing the malaria problem?  I detect a little bit of worry in Walker’s presidential address, related to this very issue, and I think that this points at a major ethical flaw in the current malaria research and medicine community.  Economics is certainly important, it is even tied to malaria epidemiology and ecology in some ways, but it is not more important than wellbeing and lives. [note – I’m not saying that Walker thinks that jobs are more important, but I think his statements address a concern (in the malaria community) about the potential loss of an industry if we were actually able to get rid of malaria.]

Issue 2: Control versus elimination

As I previously discussed, malaria control in itself takes a lot of effort.  You must build up a medical infrastructure of some type for it to work, then you must staff it, and keep it maintained for it to continue to work. This has been the goal now in some areas for decades.  

But if elimination efforts are anywhere near as complicated or expensive to set up and maintain as are control efforts, and if (IF) the elimination efforts are successful, then isn’t the end result much more rewarding?  Isn't that the right thing to do?    

Now that I'm actually part of a team that is working toward elimination, I'm face to face with some of the challenges inherent in elimination versus control strategies.  Elimination really does requires a different mind set.  Given that basically everyone has been doing the control bit for the last 5 decades, there isn't much collective knowledge in what does and doesn't work with regard to elimination.  We're having to figure much of this out as we go.  

Returning to Walker’s question though, (“After malaria is controlled, what’s next?”), it appears to me that all too often, nothing is next.  Control turns into maintaining the disease, rather than actually progressing in our public health efforts.  People get used to what they're doing and frequently don't like to change, even when it is the right thing to do.  It is time for change.  In at least some places right now, and everywhere in the near future, it’s time to move toward elimination.  Don’t worry; there are other bad diseases out there to worry about afterward.   

*** My opinions are my own!  This post and my opinions do not necessarily reflect those of Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, or the Wellcome Trust.  

Walker, David H. (2014) "After malaria is controlled, what's next?" Am J Trop Med Hyg 91(1): 7 - 10. 

Universal statins: scam....or just honest good luck for Pharma...or what?

The American Heart Association and American College of Cardiology issued new guidelines on Tuesday for reducing risk of heart disease and stroke (the first of five explanations of these new recommendations is offered here).  If you've got a 7.5% risk of heart disease or higher, as measured by their risk calculator (downloadable here), they recommend you go on statins.  This means, according to the panel, that 70 million Americans should now be considering taking these drugs.  This is perhaps 70% more than the number who now take them, and would put at least one third of all adults in the US on this drug.  For life. 

These recommendations have caused quite a ruckus, but perhaps for the wrong reasons. Before Tuesday, people were put on these drugs to lower their LDL cholesterol levels beyond a given threshold, but, confusingly to many, that threshold which we had supposed was a well-established rock-solid risk factor, has now been eliminated!  Before Tuesday, the indication for going on statins was high LDL, but the indications have now been broadened to include other risk factors such as diabetes and obesity.  So, people now taking statins wonder if they should continue, and others wonder if they need to start.  Some doctors commenting on these changes hasten to add that the most important protection against heart disease is a healthy lifestyle -- don't smoke, exercise, lose weight -- but if these can't be accomplished, statins are recommended (see Dr Harlan Krumholz on "The Newshour" on PBS, e.g.).

Wikipedia

But the new recommendation seems strange. First, a word about statins, drugs designed to control circulating lipids (fats), which confer heart-disease risks. They inhibit an enzyme called 'HMG-CoA reductase' which is expressed in liver cells as they produce cholesterol from raw ingredients and secret it into the blood stream.  Lower enzyme activity, lower circulating lipids.  But in fact, there is evidence that for some reason statins target inflammation in irritated arteries and veins, which may be what reduces risk of heart disease rather than any effect on cholesterol, so there is mystery even in the supposed reason for their supposed effectiveness.


Now, according to John Abramson and Rita Redberg in an editorial in the Thursday New York Times, statins aren't actually effective at preventing heart disease.

Statins are effective for people with known heart disease. But for people who have less than a 20 percent risk of getting heart disease in the next 10 years, statins not only fail to reduce the risk of death, but also fail even to reduce the risk of serious illness — as shown in a recent BMJ article co-written by one of us. That article shows that, based on the same data the new guidelines rely on, 140 people in this risk group would need to be treated with statins in order to prevent a single heart attack or stroke, without any overall reduction in death or serious illness.

If the recommendation is not based on evidence that everyone can agree is reliable then, where is it coming from? Partly, we think, it's a reflection of our belief that we're immortal, partly a general belief in the benefits of drug intervention.... and partly it's a reflection of the fact that some of the recommendation-makers have a vested interest in statins.

The first reason, our belief in immortality, is cultural, and of course very natural.  Few of us, even apparently those with strong religious belief in life hereafter, want to test out that belief.  Heart disease is the number 1 killer in the US and most of us don't want to die of it.

The second reason is more problematic. The most reliable way to lower heart disease risk is through diet, exercise and not smoking.  Indeed, lean, fit, non-smoking individuals whose only risk factor is high LDL are generally at low risk of heart disease.  Until this week, the purpose of statins was to lower LDL cholesterol, but that doesn't reliably lower risk of heart disease. So, are statins a good replacement for life-style?  The answer is No.

But what about the vested interest issues?  As Abramson and Redberg say:

The process by which these latest guidelines were developed gives rise to further skepticism. The group that wrote the recommendations was not sufficiently free of conflicts of interest; several of the experts on the panel have recent or current financial ties to drug makers. In addition, both the American Heart Association and the American College of Cardiology, while nonprofit entities, are heavily supported by drug companies. 

This kind of conflict of interest means that one must be highly suspicious.  One might argue that industry reps are the most knowledgeable about the benefits of their product.  If you want to know how to cure a toothache, ask a dentist, after all.  But how are we to judge the motive behind the recommendations?  Corporate-sponsored research is notoriously biased toward findings favoring their sponsor.  This doesn't mean the bias is intentional, but the evidence suggests that often it is.  At least, the corporate-sponsored research the corporate sponsors tell us about is that which favors their product, since they aren't in fact required to report all their results, and often don't.  (This is why Ben Goldacre, physician, writer and epidemiologist, started the AllTrials campaign to require that all clinical trials be registered, and all results be reported, positive and negative.)  So, when the science isn't convincing, and vested interests are involved in decision-making, it's not unreasonable to be suspicious.

Contingency and context
In addition, the related roles of context and contingency are fundamental and important to understand here.  Risk of heart disease is based on the context--genomic and environmental exposures affect the levels of statins and their consequences.  The risk in an individual is contingent on his/her situation at present, and that can change.  This seems so hard for the established system to understand!

Statins have side effects.  Risk of statin-related disease is estimated in the context of current culture.  If that culture changes, then the risks will change and by all that we know, they'll change dramatically.  If the major contexts change--better diets and so on, things we know a lot about--then the overall risk of heart disease will change.  Models can only do so well at estimating the interaction among the various factors (as the above quote suggests).  If people live healthier lives and if physicians actually pay attention to risk calculations, many may be able to go off their statins, or not start on them, as a result.

But how many will actually risk going off?  Will they keep taking, or their physicians not dare to recommend stopping, for various subjective, inertial, or even emotional reasons?  Will drug companies recommend cessation if, say, body weight goes below some value?  Will they fully advertise the fact that if other factors are favorable, to stop buying their product?  What does history--including their history--suggest to you?

And 10 years from now, how accurate will the predictions have been on which lifelong medications are now being recommended?  Will results be contingent, for example, on the current recommendations themselves?   For example, if you're on statins, will you be more likely to take that second helping of fries, feeling protected by the drug?  The Times Op-Ed puts it this way:

Perhaps more dangerous, statins provide false reassurances that may discourage patients from taking the steps that actually reduce cardiovascular disease. According to the World Health Organization, 80 percent of cardiovascular disease is caused by smoking, lack of exercise, an unhealthy diet, and other lifestyle factors. Statins give the illusion of protection to many people, who would be much better served, for example, by simply walking an extra 10 minutes per day.

These are not secret or new issues by any means, but they tend to be overlooked or minimized by a system that tries to be 'objective' based on current data.  The Op-Ed is written by respectable authors, but they are also known skeptics of the over-medicating problem, with its built-in conflicts of interest as we noted above.  So is their skepticism itself a disqualifying issue--does it mean they bias their views in a similar way to having Pharma-supported people on the panel that made the new recommendations?

Clearly, the issues are complex as so many issues related to late-onset disease are.  After all, you don't get a heart attack even at a young age like 40, unless you live to be 40.

Like second-hand smoke?  The real beneficiaries
Smokers get all sorts of diseases, because of the direct effects of the ugly weed.  But those who live in the same house also get diseases, indirectly, courtesy of their smoking cohabitant.  We have just the opposite story here.  The vendors of statins will get filthy rich as a direct result of their recommendations, whether or not they actually prevent heart disease.  And if they do, some other people--maybe the same people--will get even richer as an indirect result of the same recommendations!

If we don't die of heart disease or its associated diseases, we may live longer but that means more of us will get the slower, nastier, very expensive lingering ailments of old age.  The surgeons, retirement homes, cancer and dementia drug-makers will rake it in big-time!

We've written a few times about the subtle, surreptitious problem of competing causes, and this is another manifestation of the problem.  It's largely unavoidable that if you survive the quick-hitting earlier causes of death, you'll last and linger in service to the slower causes.  They're even more expensive.

We would not credit (nor blame) the statin-promoters for the diabolical scheming that would be involved in salivating over the indirect benefits of statin use.  That takes more perception and a longer view than most people, even scientists, usually have.  It is clear that most drug companies, not to mention the scientific research community itself, as we often write, are in for the quick kill, so to speak.

The US Health Disadvantage

 Mobilization of an unprecedented kind is now necessary in the United States. It requires a campaign to remove the public veil of ignorance about the evidence.

So states the public health Policy Forum in the Aug 30 issue of Science ("Confronting the Sorry State of U.S. Health," Bayer et al.*), which raises some important questions about health and sickness in the United States.  The authors are commenting on a recent report published by the U.S. National Research Council and Institute of Medicine, "US Health in International Perspective: Shorter Lives, Poorer Health," (Jan, 2013) which asks why the US is among the richest nations in the world, and yet the health of its people is far down the list.  The report is the outcome of 18 months of work by a panel charged with exploring the problem and identifying causes and solutions.

The panel compared health outcomes of Americans with those of 16 other wealthy countries.  They found that Americans have had a shorter life expectancy than people in the comparable countries for many years, and that the differential is growing, especially for women.  The health disadvantage affects everyone up to age 75, it's worse among poorer Americans but exists even in the wealthy, and includes multiple diseases, risk factors and injuries. 

It's worth quoting the panel's findings in detail.

1. Adverse birth outcomes: For decades, the United States has experienced the highest infant mortality rate of high-income countries and also ranks poorly on other birth outcomes, such as low birth weight. American children are less likely to live to age 5 than children in other high-income countries.

2. Injuries and homicides: Deaths from motor vehicle crashes, nontransportation-
related injuries, and violence occur at much higher rates in the United States than in other countries and are a leading cause of death in children, adolescents, and young adults. Since the 1950s, U.S. adolescents and young adults have died at higher rates
from traffic accidents and homicide than their counterparts in other countries.

3. Adolescent pregnancy and sexually transmitted infections: Since the 1990s, among high-income countries, U.S. adolescents have had the highest rate of pregnancies and are more likely to acquire sexually transmitted infections.

4. HIV and AIDS: The United States has the second highest prevalence of HIV infection among the 17 peer countries and the highest incidence of AIDS.

5. Drug-related mortality: Americans lose more years of life to alcohol and other drugs than people in peer countries, even when deaths from drunk driving are excluded.

6. Obesity and diabetes: For decades, the United States has had the highest obesity rate among high-income countries. High prevalence rates for obesity are seen in U.S. children and in every age group thereafter. From age 20 onward, U.S. adults have among the highest prevalence rates of diabetes (and high plasma glucose levels) among peer countries.

7. Heart disease: The U.S. death rate from ischemic heart disease is the second highest among the 17 peer countries. Americans reach age 50 with a less favorable cardiovascular risk profile than their peers in Europe, and adults over age 50 are more likely to develop and die from cardiovascular disease than are older adults in other
high-income countries.

8. Chronic lung disease: Lung disease is more prevalent and associated with higher mortality in the United States than in the United Kingdom and other European countries.

9. Disability: Older U.S. adults report a higher prevalence of arthritis and activity limitations than their counterparts in the United Kingdom, other European countries, and Japan.

It's not all bad -- if an American reaches 75, s/he has a higher survival rate thereafter; the US has higher cancer screening and survival rates, blood pressure and cholesterol are better controlled, we're more likely to survive a stroke, we smoke less and our average household income is higher, suicide rates aren't higher than comparison countries (faint praise, that), and the health of recent immigrants is better than that of people born here. Otherwise, and even though health care spending per capita is much higher in the US than the comparison countries, health outcomes here are significantly worse. Though, of course, we're ahead of the curve in some respects, obesity rates e.g., with other countries fast catching up.  

So, why the dismal picture in the US?  The panel considered this at great length (it's a 400 page document).  You'd think it might be because we have more people without access to health care than other countries, but the disadvantage holds even for those with access to care.  We smoke and drink less, but eat more.  We have more accidents and have more guns.  Our educational attainment is lower than other countries, and poverty rates and income inequality higher. and social mobility lower.  And, the panel also points out, a less effective social safety net.  But, even those of us with "healthy behaviors" are more likely to get sick, and have accidents, than our counterparts in other wealthy countries.

So, understanding what's behind the sorry state of health in this country is not straightforward.  Indeed, the panel seemed sorely tempted to describe unhealthy social and environmental conditions in the US, and ascribe our health conditions to the whole sorry mess.

Potential explanations for the U.S. health disadvantage range from those factors that are commonly understood to influence health (e.g., such health behaviors as diet, physical inactivity, and smoking, or inadequate access to physicians and high-quality medical care) to more “upstream” social and environmental influences on health (e.g., income, education, and the conditions in which people live and work). All of these factors, in turn, may be shaped by broader national contexts and public policies that might affect health and the determinants of health, and therefore might explain why one advanced country enjoys better health than another.

That's of course not very helpful in policy terms because public health measures must be directed at something specific, like cleaning dirty water or vaccinating against disease. The situation reminds us of too many attempts to explain complex disease with simple, enumerable factors -- for example, we dream of simple genetic causes, but in fact it's multiple gene and environment interactions.  Here, the Affordable Care Act won't be the answer, nor would gun control be, nor enforcing seat belt laws, nor banning supersize drinks or increasing the availability of fresh fruits and vegetables in poor neighborhoods.  It's complicated.  And surely a combination of many factors, social and environmental.
 
The panel recommends, though, more data collection, more refined analytic methods and study design, and more research.  They recommend focusing on children and adolescents, because early life experiences and habits can affect the whole life span. They also recommend that research should be on the entire life course rather than more localized cause and effect.    But the study urges that the situation is so critical that action must be taken while research is ongoing, and they provide a long list of actions they believe should be taken, from increasing the use of motorcycle helmets to increasing the availability of public transport to improving air and water quality and increasing the proportion of adolescents who don't use illegal drugs.  More generally, they recommend:

(1) intensify efforts to pursue existing national health objectives that already target the specific areas in which the United States is lagging behind other high-income countries, (2) alert the public about the problem and stimulate a national discussion about inherent
tradeoffs in a range of actions to begin to match the achievements of other high-income nations, and (3) undertake analyses of policy options by studying the policies used by other high-income countries with better health outcomes and their adaptability to the United States.

But what kind of issue is this?  A public health issue?  Public policy?  Economic, educational?  Here we come to a fundamental question of causation. What, we might ask, causes AIDS? Is it HIV?  Needle sharing?  Poverty?  A confluence of factors at all levels?  Epidemiology has long struggled to take multi-level causation into account, acknowledging the role of many different kinds of factors including biological and social determinants (see Nancy Krieger's old but seminal and still good 1994 paper on this, "Epidemiology and the web of causation: has anyone seen the spider?"), but once the web extends into social causes, the field of public health is pretty much stymied when it comes to fixing things.  And throwing this into the political arena is a sure recipe for a lot of grandstanding but not much else.

Is more research really needed into why Americans are sicker than our counterparts in other wealthy countries?  No doubt it is a serious problem, and very costly in both human and monetary terms.  But of course the request will be for more mega-scale, long-duration highly technological studies--more grant money.  You'd expect us to say that.  But is the plea for more funding a reflex or is it really the answer? 

It does not seem obviously so, except for the many small factors that would be found.  We know enough to know that the answer is going to be complicated, and causal factors changeable.  Indeed, we surely will be found to be leading the pack in some measures, and other countries will catch up.  And, whether the fix is deemed to be personal behavior or political, or a mix of many approaches, once we go beyond requiring vaccines or seat belts, we are the master of none of them. And they're always changing.  Perhaps research money should be going into things like how to improve health education (that is, how to get people to do things they'd rather not do, like exercise or eat less fat). 

If history is any guide, we're betting that when another such study is done in the future, we'll be better than we are now in some measures and worse in others.  And we won't know why.  And we'll say that 'more research is needed'.  Cardiovascular disease rates have risen and fallen over the past 60 years or so, and we still don't know why -- and that's just one disease.  A serious question is how to deal with phenomena that are so changing, and so subtly complex, that we have to keep surveying to understand them.  Could there be some better way, a different approach?
 

---------------------
*Thanks to Bob Ferrell for bringing this to our attention.

Collecting data is easy; making sense of it is not

Big Data
More Big Data is on the horizon -- a new estimate of the number of viruses in known mammal species harbor is generating excitement over the plausibility of sequencing them all.  A paper in mBio ("A Strategy To Estimate Unknown Viral Diversity in Mammals," Anthony et al.) reports that sequencing the Indian Flying Fox, a bat, the first species whose 'virodiversity' was characterized, found 58 viruses, 50 of them previously unknown.  Extrapolating from this, researchers estimated that with 5,500 known mammals, mammals harbor at least 320,000 viruses.

The majority of viruses that infect humans come to us from wild life, so if we sequence them all, which now seems feasible, or at least imaginable in principle, we'd have at least some handle on the kinds of epidemics that might be in our future.  And this for a mere $6.3 billion, trivial compared with the cost of a pandemic, assuming that's what would be in store otherwise. And it would be even less costly if only 85% of all viruses were characterized.

If annualized over a 10-year period, the discovery of 85% of mammalian viral diversity would be just $140 million/year, which is both a one-off cost and a fraction of the cost of globally coordinated pandemic control programs such as the “One World, One Health” program, estimated at $1.9 to 3.4 billion per year, recurring.  While these programs will not themselves prevent the emergence of new zoonotic viruses, they will further contribute to pandemic preparedness by enhancing our understanding of viral ecology and the mechanisms of disease emergence and by providing sequences and other insights that reduce the morbidity, mortality, and economic impact of emerging infectious diseases by expediting recognition and intervention. 

This all sounds extremely valuable to global public health.  But, will it be?  We have known about the mode of transmission of influenza for decades, and have developed vaccines which we're all encouraged to get each fall, but we are unable to eliminate the virus in its animal reservoirs.  And it mutates every year, and it's yet another virus that medicine is unable to treat, and it still kills tens of thousands every winter.

MERS coronavirus; Wikimedia Commons

We know everything we need to know about HIV and it's still killing people.  We worry about avian flu, and mutations that will make it easily transmissible between humans, and are unable to prevent that, even though the virus has been well characterized.  Even when the reservoir for MERS is discovered, we'll not be able to treat it, nor prevent its transmission to humans, nor prevent its mutation.  Sequencing a virus is easy, it's what gets done after that that's hard.  And having 320,000 viral sequences won't change that.

Another Framingham -- alas
At least one commenter on this project, here, likens its potential to that of the Framingham Project, a decades long study of heart disease which many believe has been responsible for a sharp decline in  cardiovascular disease in the West.  But in fact incidence of CVD began to fall before any Framingham-related interventions became widespread, and indeed the underlying reason is still not understood.  And some of the fundamental Framingham findings have not been born out by subsequent research. So, if the project is similar to Framingham it may well be in collecting huge amounts of data that may not make much difference to public health.

The project has the potential to be similar to Framingham in another major way, and that is in tying up money for decades.  The investigators are already talking about ten years of funding.  And ten years from now, the project will be too big to defund.

And of course this project will have a lot in common with human genetics -- let's just collect the data, and then it will tell us what it means.  Science has gotten very very good at collecting loads of data.  But that doesn't always correlate with asking the right questions, or understanding what it means.

There seems to be a clear pattern that investigators get together to hatch ever larger, longer and costlier projects, argued on fanciful promises that often boil down to fear tactics (horrible epidemic if you don't fund us!!!).  That is the 'Big Data' worldview.  Time has already proven that these are very costly, difficult to terminate after they reach diminishing returns, compete with focused individual investigator research, and are a big grab on shrinking or limited funds.

So the very first question one should ask, after filtering out the excess verbiage, is would this, at this time, given other problems being faced, be worth investing in?  Or should the investigators be told to focus on more immediate or real problems, or areas of virology and epidemiology with more likely short-term relevance?  After all, some years, say ten, from now, technology costs may have plummeted and this could be more affordable, given a recovered economy.  But affordability is not necessarily the same as guaranteed progress. 

Adding the human context to disease ecology

Sometimes there exist subregions where, for a variety of reasons, diseases just tend to lurk and persist regardless of what is occurring in the surrounding regions.  An excellent example can be seen in Southeast Asia, where there exists malarious pockets surrounded by malaria free regions.  In Southeast Asia, these places tend to be hilly, forested regions and international borders.  For example, both Thailand and China have been relatively successful at eradicating malaria from much of their nations while continuing to have a malaria problem along their borders with Myanmar (also known as Burma).

So what is it about these places that make malaria eradication so difficult, at least on the China or Thai sides of the border?  Well, the simple answer is that it’s complicated.

This last summer I made a trip to the border between China and Myanmar to visit one of the field sites we are using in our malaria research.  My trip to Nabang, China began in Kunming (the capital of Yunnan Province), where I caught a plane to Tengchong and then caught a five hour ride through steep mountains to the relatively small border town called Nabang.

Directly across the China-Myanmar border from Nabang is a town called Laiza which at one point was a tourist attraction for wealthy Chinese, offering a legal gambling outlet.  Today the fancy new gambling halls are still up and running in Laiza and there are several relatively nice hotels in Nabang, both mostly empty and waiting for the tourists to come.  Lining the streets of much of Nabang are brand new, fancy looking street lights, none of which have ever been turned on.  Nabang has the feel of a Wild West gold mining town after the gold is all gone.

So what happened to this place?  Basically, war happened.

Downtown Nabang, with Laiza in the distance.

Laiza, which is in Kachin state, is named after the indigenous group (the Kachin) that has historically lived in this region of Northern Myanmar.  The Kachin are known for their fighting skill, they were our allies in this region during WWII, and they have historically been at odds with the ruling national government.  In 2011, after a 17 year truce, civil war broke out between the Kachin and the government military.  Unless you’re familiar with this region though, you’ve probably never heard of this war.  This isn’t the type of shock and awe war that we all saw when the U.S. went to war with Iraq or even the high-level shelling currently occurring in Syria.  Villages get burned in the middle of the night, women and children are kidnapped, raped and forced into labor, and military camps are occasionally ambushed.  It is a low grade, slow-and-steady war that claws at the psyche of the people living in this area.   

The KIA (Kachin Independence Army) is currently located in the Laiza Hotel, right in the middle of what was once a tourist retreat.  

What does this mean for the human ecology of the place?  

For one, it means that many people are clustering up near the border in make-shift camps for ‘internally displaced persons’ (what you’re called when you’re a refugee in your own nation).  When I was there, the people living in camps were working together in preparation for many more people to arrive.  

Villagers preparing for new people to arrive.

It also means that the population has a very unique composition, made up mostly of women, children, and the elderly.  Working aged men were mostly absent, except for the occasional young adults that would zip by on their motor bikes, donning camouflage and carrying AK47s.  Instead of helping out with household chores and working in the near-by agricultural fields, the men are moving covertly through the mountainous and forested landscape, engaged in warfare with the Burmese military.    

A KIA soldier riding through town.

And what does this mean for the disease ecology of the place?

By disrupting the everyday lives of populations, conditions are primed for disease.  Close-quarters mean that easily transmittable diseases will almost certainly move through the population rather than be confined to individual households.  Diarrheal diseases that are common in children may become a problem for everyone.  The same is true for airborne diseases such as influenza and tuberculosis.  For already stressed and sometimes malnourished people, this is an added threat.

Furthermore, vector borne diseases are an increased threat.  Newly cleared fields easily form water puddles when it rains, making excellent breeding grounds for mosquitoes.  Dengue fever could easily thrive in these camps.  And for a variety of reasons, malaria is already a growing problem.  

Some preliminary research in this area has indicated that working-aged males appear to disproportionately acquire falciparum malaria infections.  Given that most of these working aged males are living in the conditions of war, moving through the jungles at night, sleeping out-doors, and almost constantly being exposed to a range of mosquito vectors, perhaps this is no surprise.  

And what happens when they are too sick to fight?  One could imagine that they then come home, with a thriving population of parasites swimming in their blood.  A potential real danger, and one that my research is particularly aimed at, is that these individuals could then pass the disease on to their families and neighbors. 

Also, given that artemisinins have been available in Myanmar and China for decades, and since there clearly is no regulation of their use in Myanmar (especially in this part of the nation), conditions are also primed for drug-resistant parasites.  We are already seeing this on the Thai-Myanmar border, it isn’t a stretch to expect to find it in this region next.  

And if these pretty terrible conditions weren’t bad enough, there is another disease that has predominated in this area for some time.  It is a hotspot for HIV/AIDS –because there are thriving sex and opium trades.  (Note: The sex and opium trade bring in problems of their own, even outside of infectious disease.)  Much of the world has been privy to the knowledge about where HIV/AIDS comes from, how it is spread, and how to keep from becoming infected.  However, Myanmar has been largely closed to the world until the last several years, meaning that such educational campaigns are unlikely to have reached many outside of the wealthy, urban, or elite of this nation.   

What does this all of this mean for public health efforts?  

Clearly this isn’t an easy place to work.  It isn’t even an easy place to get to.  Our collaborators at Kunming Medical University have sent several teams of graduate students to the field sites here in order to collect demographic and epidemiological data.  Many of them don’t stay for long.  It is a depressing environment, there are frequent earthquakes, the heat is almost unbearable and AC units don’t work when the electricity is out.  Oh… and it’s a war zone.   This makes getting data difficult, and given the fluctuating population size and composition, it makes epidemiological modeling difficult.  This means it is really hard to fully understand the disease situation.  

The hospital in Nabang, China has been badly damaged by earthquakes.  Here it is being repaired and expanded.  This hospital sees a lot of malaria cases as well as wounded soldiers from the fighting.

Not all malaria endemic places in Southeast Asia are the same but there certainly are some commonalities.  Another malaria endemic border zone, along the Thai-Myanmar border, was until very recently also a site of ethnic tensions and occasional war.  The Thai-Cambodian border zone was a strong-hold for the Khmer Rouge up until the 1990s.  It was also a site of heavy, informal mining efforts, which led to living conditions that appeared very similar to the refugee camps I’ve seen in Northern Myanmar on the Chinese border.  Perhaps a common theme across these regions is the disruption of ‘normal’ human ecology.  These are places where people haven’t had the chance to settle in, to develop their homes and villages, and to fix problems associated with sanitation and hygiene.  

Perhaps it is too much to think that some of these regions will ever be malaria free.  But I can’t help but think that conditions would be much more controllable, perhaps even with a low, maximally acceptable, background level of malaria, if only the socio-economic and political conditions weren’t as they are.  And while it’s easy for me to say that if we could just stop warfare and fix poverty that we’d have a lot more success at controlling disease, clearly doing these things isn’t anywhere near easy.  However, these challenges can’t even begin to be approached until there is a widespread realization that these are in fact the underlying, downstream conditions that lead to bad human health outcomes.  

Main road through one of the study villages near Laiza, Myanmar.