Archive for March, 2013

Rearranging the malarial deck chairs?

A friend sent this link to me, highlighting a critical comment about the future of the World Health Organization, in the context of the World Malaria Report 2012. Here’s an excerpt of the comment by William Jobin:

Their 2012 Annual Report is a very disturbing report from WHO, for at least two reasons:

1. Their program is gradually falling apart, and they offer no way to refocus, no strategy for dealing with the loss in funding, nor the brick wall of drug and biocide resistance which is just down the road. There is a label for people who keep doing the same thing, but expect different results. Do you remember what it is?

2. Because the entire top management of WHO consists of physicians, they have no idea of the opportunities they are missing for additional funding and for additional methods to add to their chemically-oriented strategy…

Concluding with:

I am not sure WHO has much of a future, nor does the UN system itself, after their failure to prevent the wars in Libya and Syria. But as long as the UN and WHO continue to operate, they must refocus their approach to face the reality of a rapidly declining budget from UN sources. Instead, I see them just re-arranging the deck chairs on the Titanic.

My friend said, “I wish these comments (and issues with the WHO and UN) were more publicised! This is not the first time I am hearing of such issues with the WHO and its demise.” I’ve certainly heard similar sentiments about the WHO from classmates and professors, but it seems there’s much less open discussion than you might expect. I’d welcome discussion in the comments…

28

03 2013

Smartphones on the cheap

Here’s a quick digression from global health that I thought might be interesting to to tech-minded folks.

nsnippets, a fascinating link blog (found via Blattman) has a post called “China’s 65 dollar smartphones” that caught my attention, because I (sort of) have one of these phones. That post is highlighting a  Technology Review piece: “Here’s where they make China’s cheap Android smartphones.” And here’s more on even cheaper phones.

Before moving to Ethiopia I was stuck in a Tmobile contract that was poor value for money with a glitchy phone. Since I’m only back in the US for about 5 months finishing my last semester of grad school I resolved to get an unlocked phone that I could use in the US or abroad, on whatever network I liked, and at a grad student price. I bought one on Amazon from “China Global Inc.” and shipped by some third party directly from China. The exact model isn’t available anymore but you can find similar phones by searching on Amazon for “Unlocked Quad Band Dual Sim Android 4.0 OS.” It gets some incredible double-take reactions because it looks almost exactly like an iPhone in front, but on the back it has the Android logo and just says “Smartphone”:

It cost just $135, and I use a $30/month prepaid plan (also Tmobile) with 100 minutes of talk (which is about right for my usage), unlimited text, and unlimited data — and I’m not locked in at all. My annual cost for this Android smartphone: $495. If you buy an iPhone 5 on Verizon your annual costs are, depending on your contract, in the $920 to $1400 range! I’m sure for some the differences between what I have and a brand new iPhone 5 with 4G (my phone is 3G) are worth $500-1000 annually, but it works for texting, email, search, Twitter, music, games, and so forth — everything I want.

I can’t imagine that everyone with the latest smartphone actually ‘needs it’ — in the sense that if they knew there were good alternatives they would think the difference is worth the value. American phone plans are generally incredibly overpriced, leaving you stuck in a cycle of buying premium products — which are nice — but ironically being locked into keeping them until they’re well past premium.  I think what is happening is that as long as most of your friends have high-priced phones with expensive contracts, that’s the norm and the price seems less absurd.

27

03 2013

This beautiful graphic is not really that useful

This beautiful infographic from the excellent blog Information is Beautiful has been making the rounds. You can see a bigger version here, and it’s worth poking around for a bit. The creators take all deaths from the 20th century (drawing from several sources) and represent their relative contribution with circles:

I appreciate their footnote that says the graphic has “some inevitable double-counting, broad estimation and ball-park figures.” That’s certainly true, but the inevitably approximate nature of these numbers isn’t my beef.

The problem is that I don’t think raw numbers of deaths tell us very much, and can actually be quite misleading. Someone who saw only this infographic might well end up less well-informed than if they didn’t see it. Looking at the red circles you get the impression that non-communicable and infectious diseases were roughly equivalent in importance in the 20th century, followed by “humanity” (war, murder, etc) and cancer.

The root problem is that mortality is inevitable for everyone, everywhere. This graphic lumps together pneumonia deaths at age 1 with car accidents at age 20, and cancer deaths at 50 with heart disease deaths at 80. We typically don’t  (and I would argue should’t) assign the same weight to a death in childhood or the prime of life with one that comes at the end of a long, satisfying life.  The end result is that this graphic greatly overemphasizes the importance of non-communicable diseases in the 20th century — that’s the impression most laypeople will walk away with.

A more useful graphic might use the same circles to show the years of life lost (or something like DALYs or QALYs) because those get a bit closer at what we care about. No single number is actually  all that great, so we can get a better understanding if we look at several different outcomes (which is one problem with any visualization). But I think raw mortality numbers are particularly misleading.

To be fair, this graphic was commissioned by Wellcome as “artwork” for a London exhibition, so maybe it should be judged by a different standard…

26

03 2013

First responses to DEVTA roll in

In my last post I highlighted the findings from the DEVTA trial of deworming in Vitamin A in India, noting that the Vitamin A results would be more controversial. I said I expected commentaries over the coming months, but we didn’t have to wait that long after all.

First is a BBC Health Check program features a discussion of DEVTA with Richard Peto, one of the study’s authors. It’s for a general audience so it doesn’t get very technical, and because of that it really grated when they described this as a “clinical trial,” as that has certain connotations of rigor that aren’t reflected in the design of the study. If DEVTA is a clinical trial, then so was

Peto also says there were two reasons for the massive delay in publishing the trial, 1) time to check things and “get it straight,” and 2) that they were ” afraid of putting up a trial with a false negative.” [An aside for those interested in publication bias issues: can you imagine an author with strong positive findings ever saying the same thing about avoiding false positives?!]

Peto ends by sounding fairly neutral re: Vitamin A (portraying himself in a middle position between advocates in favor and skeptics opposed) but acknowledges that with their meta-analysis results Vitamin A is still “cost-effective by many criteria.”

Second is a commentary in The Lancet by Al Sommers, Keith West, and Reynaldo Martorell. A little history: Sommers ran the first big Vitamin A trials in Sumtra (published in 1986) and is the former dean of the Johns Hopkins School of Public Health.  (Sommers’ long-term friendship with Michael Bloomberg, who went to Hopkins as an undergrad, is also one reason the latter is so big on public health.) For more background, here’s a recent JHU story on Sommers’ receiving a $1 million research prize in part for his work on Vitamin A.

Part of their commentary is excerpted below, with my highlights in bold:

But this was neither a rigorously conducted nor acceptably executed efficacy trial: children were not enumerated, consented, formally enrolled, or carefully followed up for vital events, which is the reason there is no CONSORT diagram. Coverage was ascertained from logbooks of overworked government community workers (anganwadi workers), and verified by a small number of supervisors who periodically visited randomly selected anganwadi workers to question and examine children who these workers gathered for them. Both anganwadi worker self-reports, and the validation procedures, are fraught with potential bias that would inflate the actual coverage.

To achieve 96% coverage in Uttar Pradesh in children found in the anganwadi workers’ registries would have been an astonishing feat; covering 72% of children not found in the anganwadi workers’ registries seems even more improbable. In 2005—06, shortly after DEVTA ended, only 6·1% of children aged 6—59 months in Uttar Pradesh were reported to have received a vitamin A supplement in the previous 6 months according to results from the National Family Health Survey, a national household survey representative at national and state level…. Thus, it is hard to understand how DEVTA ramped up coverage to extremely high levels (and if it did, why so little of this effort was sustained). DEVTA provided the anganwadi workers with less than half a day’s training and minimal if any incentive.

They also note that the study funding was minimalist compared to more rigorous studies, which may be an indication of quality. And as an indication that there will almost certainly be alternative meta-analyses that weight the different studies differently:

We are also concerned that Awasthi and colleagues included the results from this study, which is really a programme evaluation, in a meta-analysis in which all of the positive studies were rigorously designed and conducted efficacy trials and thus represented a much higher level of evidence. Compounding the problem, Awasthi and colleagues used a fixed-effects analytical model, which dramatically overweights the results of their negative findings from a single population setting. The size of a study says nothing about the quality of its data or the generalisability of its findings.

I’m sure there will be more commentaries to follow. In my previous post I noted that I’m still trying to wrap my head around the findings, and I think that’s still right. If I had time I’d dig into this a bit more, especially the relationship with the Indian National Family Health Survey. But for now I think it’s safe to say that two parsimonious explanations for how to reconcile DEVTA with the prior research are emerging:

1. DEVTA wasn’t all that rigorous and thus never achieved the high population coverage levels necessary to have a strong mortality impact; the mortality impact was attenuated by poor coverage, resulting in the lack of a statistically significant effect in line with prior results. Thus is shouldn’t move our priors all that much. (Sommers et al. seem to be arguing for this.) Or,

2. There’s some underlying change in the populations between the older studies and these newer studies that causes the effect of Vitamin A to decline — this could be nutrition, vaccination status, shifting causes of mortality, etc. If you believe this, then you might discount studies because they’re older.

(h/t to @karengrepin for the Lancet commentary.)

25

03 2013

A massive trial, a huge publication delay, and enormous questions

It’s been called the “largest clinical* trial ever”: DEVTA (Deworming and Enhanced ViTamin A supplementation), a study of Vitamin A supplementation and deworming in over 2 million children in India, just published its results. “DEVTA” may mean “deity” or “divine being” in Hindi but some global health experts and advocates will probably think these results come straight from the devil. Why? Because they call into question — or at least attenuate — our estimates of the effectiveness of some of the easiest, best “bang for the buck” interventions out there.

Data collection was completed in 2006, but the results were just published in The Lancet. Why the massive delay? According to the accompany discussion paper, it sounds like the delay was rooted in very strong resistance to the results after preliminary outcomes were presented at a conference in 2007. If it weren’t for the repeated and very public shaming by the authors of recent Cochrane Collaboration reviews, we might not have the results even today. (Bravo again, Cochrane.)

So, about DEVTA. In short, this was a randomized 2×2 factorial trial, like so:

The results were published as two separate papers, one on Vitamin A and one on deworming, with an additional commentary piece:

The controversy is going to be more about what this trial didn’t find, rather than what they did: the confidence interval on the Vitamin A study’s mortality estimate (mortality ratio 0.96, 95% confidence interval of 0.89 to 1.03) is consistent with a mortality reduction as large as 11%, or as much as a 3% increase. The consensus from previous Vitamin A studies was mortality reductions of 20-30%, so this is a big surprise. Here’s the abstract to that paper:

Background

In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2–3% die at ages 1·0–6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality.

Methods

Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200 000 IU retinyl acetate in oil, to be cut and dripped into the child’s mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs36 clusters).

The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6–72 months.  Annually, one centre per block was randomly selected and visited by a study team 1–5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100 000 visits, 25 000 deaths at ages 1·0–6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547.

Findings

Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6% vs13%, decrease 7% [SE 1%]), as was that of Bitot’s spots (1·4% vs3·5%, decrease 2·1% [SE 0·7%]).

Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89–1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected.

Interpretation

DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20–30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5–16, p=0·00015), reliably contradicting the hypothesis of no effect.

Note that instead of just publishing these no-effect results and leaving the meta-analysis to a separate publication, the authors go ahead and do their own meta-analysis of DEVTA plus previous studies and report that — much attenuated, but still positive — effect in their conclusion. I think that’s a fair approach, but also reveals that the study’s authors very much believe there are large Vitamin A mortality effects despite the outcome of their own study!

[The only media coverage I’ve seen of these results so far comes from the Times of India, which includes quotes from the authors and Abhijit Banerjee.]

To be honest, I don’t know what to make of the inconsistency between these findings and previous studies, and am writing this post in part to see what discussion it generates. I imagine there will be more commentaries on these findings over the coming months, with some decrying the results and methodologies and others seeing vindication in them. In my view the best possible outcome is an ongoing concern for issues of external validity in biomedical trials.

What do I mean? Epidemiologists tend to think that external validity is less of an issue in randomized trials of biomedical interventions — as opposed to behavioral, social, or organizational trials — but this isn’t necessarily the case. Trials of vaccine efficacy have shown quite different efficacy for the same vaccine (see BCG and rotavirus) in different locations, possibly due to differing underlying nutritional status or disease burdens. Our ability to interpret discrepant findings can only be as sophisticated as the available data allows, or as sophisticated as allowed by our understanding of the biological and epidemiologic mechanisms that matter on the pathway from intervention to outcome. We can’t go back in time and collect additional information (think nutrition, immune response, baseline mortality, and so forth) on studies far in the past, but we can keep such issues in mind when designing trials moving forward.

All that to say, these results are confusing, and I look forward to seeing the global health community sort through them. Also, while the outcomes here (health outcomes) are different from those in the Kremer deworming study (education outcomes), I’ve argued before that lack of effect or small effects on the health side should certainly influence our judgment of the potential education outcomes of deworming.

*I think given the design it’s not that helpful to call this a ‘clinical’ trial at all – but that’s another story.

20

03 2013

Note to job seekers

The first question I’ve had in several recent job interviews/conversations was “do you speak French?” (I don’t.) Not that it’s impossible to find work if you don’t — but it certainly seems to be a major asset. If you want to work in global health, take note.

20

03 2013

Monday miscellany

11

03 2013