Malaria Atlas Project: Data visualization or special effect?

A map from the Malaria Atlas Project, modified and superimposed on a photograph of Maarten Vanden Eynde’s “IKEA Vase

The Malaria Atlas Project (MAP) found that human interventions this century averted fully 663 million cases of the disease. “Malaria in Africa,” according to MAP, “has halved since the turn of the millennium.”

MAP’s interactive application visually depicts human triumph over disease, malaria driven back, year after year. But is the triumph real or a special effect? More broadly, is malariology accurately representing reality or is it giving malaria a makeover?

Both the visual aspects and the science of MAP invite scrutiny and raise questions. What the maps show sometimes diverges from what the data actually say, for example. And MAP's data sometimes contradict the World Malaria Report when they ought to be nearly the same. It is doubtful that MAP accounted for age shifting while it is certain that MAP did not model the impact of an epidemic of insecticide resistance on the effectiveness of insecticide-treated bed nets. Both decisions might lead to an overestimate of human progress against malaria. Indeed, a different set of choices might show malaria is now resurgent rather than falling.

Images and science are being tweaked elsewhere in the malaria world. A paper in the Lancet on insecticide resistance presents a map that may have been improperly manipulated. In a separate study of insecticide resistance, a senior author "muted" the finding that resistance substantially reduced the protective benefit of bed nets. In addition, estimates from malaria researchers of the economic benefits of malaria have jumped implausibly from $0 in 2010 to $4 trillion today. Malariaologists are also going as far as saying that artemisinin-resistant malaria is spreading in Southeast Asia and threatens a leap to Africa when current published evidence does not support this contention. 

A Lancet ombudsman fended off criticism of one publication saying: “the paper conveys information that suffices for the message,” a philosophy that mis-informs too much malaria research.

These dissimulations may be well-intentioned, but they are not science.

Malaria Atlas Project (MAP)

Modelers make choices that shape the model. A few shards from an IKEA coffee mug became an amphora (pictured above) by the hands of artist Maarten Vanden Eynde. Similarly, the actual shape of malaria’s burden is ambiguous. Shards of malaria incidence data are so scarce that the World Health Organization (WHO) said it can't tell if cases are rising or falling in 32 of the 45 countries in the Africa region.

The MAP visualization mostly displays modeled estimates, not data. Importantly, MAP relies not on reports of malaria cases (which tend to be few and dubious) but parasite prevalence surveys. These surveys test for malaria parasites in blood samples taken from people in numerous different locales over time. MAP combines geo-located survey information with many other factors, like satellite weather data, all processed by minutely engineered statistical methods. Along with the visualization, MAP and other malaria researchers (Bhatt et al.) produced a numerical summary, published in Nature last September: “The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.”

But for countries like Madagascar, the map and the numbers used in the paper disagree. MAP displays malaria cases estimated from parasite prevalence surveys while, behind the scenes, the aggregate statistics for malaria cases in Bhatt et al. are based on country data.

Maps of Madagascar that should show about the same amount of malaria, based on the bar graph (top), but do not

According to the bar graph, average malaria incidence in Madagascar was roughly 69 cases per thousand people in both 2005 and 2014. The map for 2014, however, clearly shows far less malaria than in 2005. Peter Gething, corresponding author for Bhatt et al., confirmed the disparity, saying it is “entirely correct that there is a mis-match between the time series and the map.”

More than mis-matched, the map and data tell contradictory stories. Visually, malaria in Madagascar appears to be getting crushed. But the data—considered by the researchers as more reliable—say malaria has been rising since 2008, approaching the same level seen in 2000. Malaria in Madagascar looks much better than scientists believe it really is.

Gething, who leads the MAP effort, explained that for some countries “it makes far more sense to base estimates of cases on the country-reported data.” He added: “The list of countries for which the second approach was used is listed in the paper if you are interested.” But the list is not in the paper. Gething did not reply to multiple email requests for the list. However, after the editors of Nature intervened, the MAP tool was changed to list the 11 countries handled like Madagascar where the country data “may not correspond to the parasite-rate derived maps.”

The text in red is a post-publication clarification for MAP (Source: Malaria Atlas Project)

Gething said the 11 countries had smaller malaria burdens and better health systems, leading to more reliable reporting. “Many were unambiguous but inevitably some were borderline situations where arguments could be made for either approach.” But the position of the borderline might have decided the conclusions of the paper. Based on WHO-published country data, reported malaria cases appear to be rising in up to 28 African countries. If some or all of those 28 countries had been chosen, Bhatt et al. might have found a malaria resurgence. Gething would not further detail the criteria used to select the 11 countries.

In concussion research, the NFL stands accused of cherry picking data to produce a milder picture of head trauma. As one critic put it, in excluding unflattering data, “You’re not doing science here; you are putting forth some idea that you already have,” like Maarten Vanden Eynde choosing to make an amphora from fragments of a coffee mug.

Of concern, MAP used country reporting for Gambia, Mauritania and Senegal, three countries which WHO categorized as not having assessable country data. Also puzzling, Senegal has a relative abundance of parasite prevalence surveys. (See figure 2 in the Bhatt et al. supplement.) Senegal even contributed to the much more rarefied data used to transform parasite prevalence into malaria case estimates.

There are presumably good reasons to use country data for Senegal, but Gething would not say what they were. Also, it is not clear if MAP used all the available parasite prevalence surveys or, NFL-style, an unspecified subset. Again, Gething would not say. (He answered 2 of 13 emails which I sent over a three-month period.)

More concerning, what Gething described as “official country-reported data” used by MAP differs radically at times from similar data published by WHO in the 2015 World Malaria Report (WMR). Gething said “some adjustments for known under-reporting or missing data” were applied to the country data. But for Rwanda in 2014, MAP and the WMR present very different pictures of what is happening, although both are based on some form of national reporting.

WHO shows malaria surging in Rwanda (top graph, orange line) whereas MAP (bottom graph) shows malaria tailing off in recent years. (Note: The time axis for the MAP chart runs from 2000 to 2015, one more year than the WHO chart.)

A press account corroborates a sizable malaria resurgence in Rwanda: “Malaria cases in Rwanda rose at 68.6% last year [2014] to reach 1,598,076, against 947,689 cases last year; According to figures released by the Rwandan Ministry of Health.”

It’s not just Rwanda. For 2014, of the 11 nations for which MAP used country reporting, MAP figures undershoot WHO confirmed cases in five: Botswana, Namibia, South Africa, Swaziland and Rwanda.

(Swaziland, as a side note, is not mapped but shows as gray for all years, indicating either intermittent malaria transmission or none. Intentional or not, a gray Swaziland slyly promotes the strategy of “shrinking the malaria map.”)

MAP does not use country data for Burundi. MAP’s survey-based algorithms, however, produce estimates that directly contradict WHO-reported country data.

Malaria incidence in Burundi: Rising sharply according to WHO-reported country data (top, orange line) but falling steadily to its lowest point this century according to the Malaria Atlas Project (bottom).

“We are not sure why the estimates exceed the reported number of cases,” said WHO’s Richard Cibulskis who is also a co-author of Bhatt et al. Cibulskis was uncertain “whether this reflects some double counting of cases or the estimates are just off.” Double counting can be excluded, unless it also afflicts previous versions of the WMR which show much the same chart for Burundi. WHO has not corrected the 2015 edition, so the MAP estimates are “just off.” While data and estimates must be expected to differ in a modeling exercise, the degree of divergence in Burundi might raise proportional concern regarding the model’s validity.

Gaussian process models and reconstruction paste

Maarten Vanden Eynde’s amphora mostly took its shape from reconstruction paste, with just a few pieces of the original blue coffee mug. Similarly, the malaria map for Chad is almost all model. Over the 2000-2015 period, MAP had only a single 2004 study of 960 people.

Red arrow points to the single data fragment, during the 2000-2015 period, to map malaria for all of Chad. (Adapted from Bhatt et al. supplement, Figure 2.)

MAP fills in this data void with exquisite math, computing power and data borrowed from elsewhere to find a steady decline of malaria in Chad, from a peak in 2006 to a low in 2015.

But an amphora is not a coffee mug and malaria in Chad is differently shaped in the eyes of other academics. According to Foster et al., “616,722 malaria cases were reported in 2012, an increase of over 200,000 cases since 2006.” The World Malaria Report also sees malaria in Chad very differently. (Graph not shown.)

Richard Cibulskis suggested that greater use of rapid diagnostic technology possibly increased detection of cases, although “this does not necessarily reflect a true increase in malaria incidence, just an increase in diagnostic effort.”

But Cibulskis acknowledged there were true increases: “Some countries such as Uganda have experienced a resurgence in cases.” To distinguish signal from noise, researchers consider malaria hospital admissions, deaths, diagnostic practices and test positivity rates. I asked Cibulskis if, after taking those factors into account, “can an increase in cases be ruled out for any of the [28] countries which are showing increasing confirmed cases?” In other words, can the possibility that malaria is actually on the rise across most of Africa be excluded? Cibulskis did not reply.

Paying it forward: shifting malaria to older age groups

Malaria interventions frequently target very young children who lack immune protection which develops over time—and by becoming infected with malaria. Averting malaria in the very young reduces cases and overall malaria transmission, but it also prevents acquisition of immunity. As children get older, even where malaria transmission has been pushed down, some will become clinically ill with malaria because of reduced immunity. Overall, cases are greatly diminished but some are “shifted” to older age groups.

Bhatt et al. report parasite prevalence estimates for a cohort aged from 2 to 10. But it is unclear if they adjusted their estimates for the age shifting effects of malaria interventions. If not, their estimates might overstate progress against malaria by leaving the effects of age shifting off the books.

Best scientific practice seems to require accounting for age shifting. According to Briët & Penny (2013): “Many malariological studies limit themselves to examining malaria in children under ten or under five years of age...” However, “analyses for the whole population are preferred as the analyses for children under five do not capture the shifts of morbidity and mortality to older age groups...” I asked Melissa Penny, a co-author of Bhatt et al., whether that paper did as she recommended.  Penny deputized Peter Pemberton-Ross to answer my question, but he didn’t. He said the software used “certainly includes the possibility for age-shifting through its immunity submodel.” He also said that inferring incidence data from prevalence data “may implicitly assume some age-shifting.” But Pemberton-Ross would not say, yes or no, if the Bhatt et al. estimate of 663 million cases averted accounted for age shifting. Peter Gething did not reply to my inquiry about age shifting.

Bed Nets

Spatial only Gaussian Markov random field

Bed nets were “by far the largest contributor,” to averting those estimated 663 million cases, blocking 68% or 450 million malaria episodes, according to Bhatt et al. However, although the MAP interactive application shows the distribution of insecticide-treated nets (ITNs) changing in both space and time, the Bhatt et al. paper used a spatial only model for bed nets. The paper’s supplement states that a spatial only model for bed nets “was preferred over the spatio-temporal model.” Researchers made do with “national means estimated previously” for nets, published in the 2013 World Malaria Report.

Conceivably this creates a mismatch between the maps of bed nets shown by the interactive application and the data used to estimate cases averted, perhaps like the mismatch  of map and data for Madagascar. But a spatial only model for nets might mean a mismatch for all countries.

According to Pemberton-Ross, the spatial only model is just “a technical issue… This choice will have affected the results, but not necessarily by making them less accurate.”

The issue might be fundamental rather than technical, but Peter Gething did not reply when I asked if the conclusion that nets averted 450 million cases of malaria since 2000 rested on a comparatively crude, spatial only model. I also asked Gething whether the interactive mapping tool was displaying spatio-temporal bed net data when, behind the scenes in the Bhatt et al. paper, calculations for cases averted were actually based on a static, spatial only model. Gething did not reply.

I raised these issues to Nature. The editors were responsive to the Madagascar map discrepancy, and appear to have occasioned MAP’s listing of the 11 countries treated like Madagascar “in the interests of transparency,” said Rebecca Walton, Nature’s Senior Press Manager. But the other issues were met with pro forma dismissal: “The paper was rigorously peer reviewed as part of our usual editorial procedures.”

Insecticide resistance—and intransigence

Although bed nets are thought to have stopped 450 million cases of malaria, Bhatt et al. urged that maintaining their effectiveness in the face of insecticide resistance “should form a cornerstone” of future control strategies. But this grave threat to bed nets is entirely absent from the model, as if it’s solely a future concern. (Peer reviewers presumably agreed.)

However, the very distribution of hundreds of millions of nets sparked a proportionally vast rise of resistant mosquitoes, “a worsening situation that needs urgent action to maintain malaria control,” as the subtitle of a recent paper put it. Only a single class of insecticide, pyrethroids, is used to treat nets. Unsurprisingly, mosquitos have developed multiple genetic escape mechanisms, very much as they did when faced with DDT, the primary weapon used in earlier, mid-20th century efforts to eradicate malaria.

Mosquito resistance to DDT increased gradually, ultimately rendering it ineffective and leading to the failure of eradication efforts. With pyrethroids, we seem to be watching a brutal remake of the DDT story. But researchers raise more questions than they answer about pyrethroid resistance: "Is it a problem? How do you know?" asked David Smith, a member of MAP and co-author of Bhatt et al.

In addition to doubting if insecticide resistance is a problem, Smith suggested that dispelling such doubts is nearly impossible: “The experimental unit is the population,” he contended, and “we would need to start collecting data from across the continent,” meaning Africa. A second study, also at continent scale, would be needed to measure the “attributable effect of resistance.” Even more remarkably, Smith said he “would expect the effect size of ITNs to go up overall,” if these two massive studies were somehow completed.

Smith is not alone in denial and casuistry. In Strode et al., researchers set out to investigate “the evidence that resistance is attenuating the effect of ITNs.” But instead, the scientists declared “ITNs are more effective than [untreated nets] regardless of resistance,” which is tautological. Until 100% of mosquitoes are 100% resistant to pyrethroids, an insecticide-treated net will always be more effective than an untreated one.

“Agreed with respect to the tautology,” acknowledged first author Clare Strode. “The ability of ITNs to kill insecticide resistant mosquitoes was significantly reduced when faced with resistance mosquitoes,” but, this message was “muted” in the paper according to Strode. “I originally included a much stronger statement of fact that ITNs kill fewer resistant mosquitoes than susceptible counterparts,” she continued, “but the statistician and Cochrane expert recommended a less bold statement.”

The Cochrane expert, Paul Garner, did not dispute Strode’s account or explain why he recommended a less bold statement. (Also at Garner’s suggestion, the Strode et al. review excluded 914 studies without explaining why.) In 2004, Garner was involved in the Cochrane Review of bed nets that provided much of the basis for the massive scale-up that intervention. Muting the conclusions of Strode et al. might serve to protect the conclusions of the earlier review and the subsequent, massive, bed net intervention that seems to have gone awry.

Many malariaologists demand proof that pyrethroid resistance reduces the impact of nets, a stance akin to the tobacco lobby’s denial that cigarettes cause cancer. According to Clare Strode, “I cannot see how increasing resistance would NOT impact ITN efficacy.” It’s undeniable: “There is no biological basis to argue otherwise,” said Strode.

Nick Hamon agrees: “Yes, resistance compromises efficacy. That is no longer in question.” Hamon runs IVCC, a consortium tasked with developing new insecticides.

Nonetheless recent peer-reviewed papers still ignore resistance. A paper in the Lancet estimating how much malaria might be reduced by further expanding interventions “assumed no loss of effect due to drug or insecticide resistance.” In fact, the authors almost doubled the killing effect of nets in their model, adapted from Menach et al. (2007). Senior and corresponding author, Azra Ghani, did not reply to emails asking how to reconcile today’s stronger insecticide resistance with an assumption of greater killing power than nine years ago.

Insecticide resistance has been modeled. Brady et al. found that resistance cuts the effectiveness of nets by half or as much as two thirds, depending on how swiftly resistance develops. (See Figure 3D.)

In 2013, Penny & Briët determined that introducing nets in high transmission areas with insecticide resistance only reduced transmission by 75% instead of 90%. Penny went on to co-author Bhatt et al., but that paper ignored insecticide resistance even though one third of the population of Africa lived in high transmission settings in 2000.

I am not aware of any papers estimating increased malaria cases and/or deaths resulting from insecticide resistance. IVCC’s Nick Hamon made recourse to “two respected, independent malaria scientists” for a crude estimate of the number of deaths that would be averted if there were a new insecticide to replace failing pyrethroids. According to Hamon: “One scientist gave me a range of 141,000 – 228,000 and another 125,000.” Adding even part of 125,000 to WHO’s estimated 395,000 malaria deaths in 2015 would make for a very sizeable increase in mortality.

Hamon cautioned that “these are ‘back of envelope calculations’ and should be treated as such,” adding that “nobody wanted to be quoted, and for good reasons.” He would not say what the good reasons were. Nonetheless, among themselves, malaria experts countenance disturbingly large increases in malaria deaths resulting from insecticide resistance.

Another mostly insider conversation is the effect of resistance on the infectivity of mosquitos. Against hope and expectation, early indications are that the genetics of resistance also increase mosquito susceptibility to infection by malaria parasites. (See Ndiaith et al. and Alout et al.) Conceivably, not only has the scale-up of bed nets sparked a massive wave of resistant mosquitos, those mosquitos are also more likely to become infected with malaria and thus are potentially more likely to transmit the disease.

Averting the appearance of a malaria disaster: Possible image manipulation in Hemingway et al.

Another paper this year in the Lancet, “Averting a malaria disaster,” drew attention to mounting insecticide resistance and the need to develop new chemicals to replace those that are failing.

However, the map (Figure 2B) accompanying the paper might have understated the extent of the resistance problem. According to the caption, Figure 2B was “reproduced” from an online tool called IR Mapper. However, Figure 2B includes a number of green dots, indicating no resistance, that are not found on IR Mapper, in Sudan, for example. Some yellow dots in IR Mapper, showing possible insecticide resistance in Angola, appear as green dots in Figure 2B, indicating no resistance.

Figure 2B (left) from Hemingway et al. shows a green dot in Sudan but IR Mapper (right) does not although Figure 2B was “reproduced” from IR Mapper. Also, dots in Angola show as green in Figure 2B but are yellow in IR Mapper. (Purple triangles added to identify discrepancies)

I found at least seven such discrepancies between Figure 2B and IR Mapper. In addition, Figure 2B does not display any yellow dots. IR Mapper has been displaying red, green and yellow dots since its inception in 2012, according to Duncan Kobia Athinya of Vestergaard Frandsen, which oversees IR Mapper. Said Athinya: “I cannot speak as to why the Lancet figure does not feature possible resistance (yellow) points, but IR Mapper has followed WHO criteria since its launch in 2012.”

Also unexplained is the green dot in Sudan in Figure 2B. Said Vestergaard’s Melinda Hadi: “I still do not have an answer regarding the green susceptible point in Sudan.” Figure 2B was created in October of 2014 but not published until April of 2016. Studies, and thus dots, have been added subsequently. Also, some might have been removed. But regarding the green dot in Sudan, Hadi said:  “I can confirm a publication was not removed from IR Mapper.”

Perhaps explaining these and other discrepancies, according to Hadi: “the maps in the Lancet article were reproduced. The IR Mapper database was provided to the Liverpool School.” Of possible relevance, IR Mapper includes a “View own data” facility that allows users to create a map from a database.

Hadi explained that yellow dots were left out: “Data points that were classified as possible resistance (90-97% mortality) were not presented in Figure 2.” In addition, Figure 2B “only included data from peer-reviewed publications, so you will note other data points available on the platform (e.g., PMI data) were excluded.” PMI, the President’s Malaria Initiative, collected data in 18 countries.

Asked about issues regarding Figure 2B, first author Janet Hemingway said: “the figure is a screen shot downloaded back in 2014…” Hemingway is Director of the Liverpool School of Tropical Medicine. The discrepancies resulted from the passing of time, according to Hemingway: “Lancet have sat on the paper for almost a year since submission and acceptance so I guess it is possible over this period that IR mapper has been updated for historical data, but we made no alterations to the download.”

Hemingway declined to answer any more questions:  “I have no intention of responding further on this, as there is no further explanation…”

However, the passing of time did not explain the discrepancies such as the missing yellow dots and the presence of a green dot in Sudan and half a dozen other anomalies that surfaced in a non-exhaustive analysis.

I raised these issues with Figure 2B to the attention of Lancet editor-in-chief, Richard Horton. Horton did not reply.

Prompted by the intervention of the Committee on Publication Ethics (COPE), Lancet editor Zoë Mullan relayed an explanation from Hemingway (who had earlier declined to answer questions). Hemingway said: “The single green dot in Sudan he refers to, I suspect is a point that was subsequently corrected if GPS co-ordinates had been incorrectly allocated for example.” Hemingway did not say where the dot could now be found.

Regarding the absence of yellow dots, Mullan explained, perhaps implausibly: “IR Mapper was clearly not showing any yellow dots on the day the authors downloaded the screenshot that became their figure.” Besides the unfortunate timing, Mullan’s explanation would also seem to require that the authors, who are experts on insecticide resistance, didn’t notice the absence of yellow dots that indicate possible resistance, nor did peer reviewers.

In addition to being an editor at the Lancet, Mullan is a trustee of COPE, perhaps creating a conflict of interest in responding to COPE-initiated inquiries. (Mullan’s role at COPE was not disclosed to me; I happened upon it later by chance.)

I also asked Richard Horton directly: “Is Figure 2B a screen capture or reproduced from the IR Mapper database? Why does Figure 2B not show any yellow dots?”

However, Horton only replied that the editors “feel confident that the data reported” in the paper “are accurate and reliable.” He vouched, to some degree, for the data but not for the accuracy of Figure 2B. He did not address the absence of yellow dots.

COPE declined to press the Lancet further. Wrote COPE’s Iratxe Puebla: “Given that the issues relate to a specific figure, we do not feel this falls within COPE’s remit to evaluate...” Furthermore, “COPE considers it beyond its remit to comment on… how facts are presented in individual publications.”

Richard Horton recently criticized COPE for not intervening sufficiently in a controversy regarding statins, bemoaning “the lack of a central institution where scientists who wish to question the actions or ethics of other scientists or scientific institutions can go.”

COPE suggested that I contact “the authors' institution so that they can review and consider what follow up may be appropriate.” Via transatlantic mail, I contacted LSTM board secretary R.E. Holland inquiring about a possible institutional investigation. Holland replied, also by letter: “Having reviewed the issue thoroughly, and having spoken to several experts in respect of resistance incident imaging, I have concluded there is no case for the authors to answer in respect of your complaint.”

Holland’s review assumed that Figure 2B was a screen shot. His letter said: “it is impossible to compare a snapshot of image data from one period to that of another and therefor there is no case to answer.” Holland’s answer was essentially the same as LSTM’s Director, Janet Hemingway. Holland did not explain the absence of yellow dots or the green dot in Sudan. He touted LSTM’s “rigorous research misconduct policy” which had been used in this case.

“[T]he paper conveys information that suffices for the message” 

Figure 2B and the statements by the authors and editors of the Lancet also passed muster with Lancet ombudsman, Malcolm Molyneux. However, Molyneux acknowledged the possibility that Figure 2B was not a screen capture. 

The word ‘reproduced,’ according to Molyneux, “can mean either of the possibilities - a screen-shot or a figure re-drawn from data.” He added: “I really do not think it matters.” In his view, if the authors changed the figure to suit their purposes—including adding dots—they were within their rights: “the paper conveys information that suffices for the message - removing or adding yellow dots or (a few) other dots would make no difference at all to that message.”

Molyneux's statement, “the paper conveys information that suffices for the message,” nicely captures the philosophy that is mis-informing too many papers in malaria.

Placing a green dot in Sudan or anywhere appears to be legitimate in the eyes of the Lancet ombudsman, as long as the number of dots added does not exceed "a few.” Leaving dots out is no infraction, according to Molyneux because “the legend to Fig 2 says ‘reproduced from...’ - it does not say ‘with no subtractions’.” 

He distinguished “falsification of data” from “simplification for purposes of clarity.” However, adding green dots that do not actually represent studies of insecticide resistance means those dots are fake, while changing the color of dots misrepresents the findings of actual studies. It is hard to see how that would not be falsification of data.

Continued Molyneux, “if the authors had been trying to manipulate the figure in order to make their case more compelling, we would expect them to err towards the red in the later time-period (2b)… In every single case you mention of a difference between the IRMapper and Fig 2b, the difference is from red to green, not the other way round.” 

Image manipulation requires no explanation. However, as I wrote to Molyneux, “the title of the paper is ‘Averting a malaria disaster.’ Unless the map shows that there is a disaster to avert then the title doesn't fit… A sea of red and yellow dots might lead readers to conclude that mosquitoes had already won.”

As it stands, figures “reproduced” in the Lancet may differ in unspecified, undisclosed ways from the source in order to convey the authors' message, which might differ from their scientific findings.

Tale of two resistances

If the malaria research community is downplaying insecticide resistance, it is exaggerating the threat of drug resistance in Southeast Asia spreading to Africa. Resistance to artemisinin is not spreading even in Southeast Asia and faces scientifically demonstrated obstacles to overtaking Africa. It’s not happening, but researchers are saying it is.

Arjen Dondorp heads malaria research at the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok. He laid out an accurate chronology of the discovery of resistance to artemisinin-based malaria treatments. Resistance was first found in Western Cambodia, then at the Thai-Myanmar border, in Myanmar, Northern Cambodia, Northeastern Thailand, Eastern Cambodia, Southwestern Vietnam, and Southern Laos.

“Out of the ‘epicentre’ of Western Cambodia,” said Dondorp, “over time the resistant parasite has spread westward, northward, and eastward.” He concluded: “This is spread.”

However, Dondorp’s statement, if not simply false, is not scientifically supported. He described the spread of surveillance, a trick that could equally demonstrate that broken arms or bad breath are “spreading” in Southeast Asia just by conducting surveys in the same places and order he described for artemisinin resistance.

Genetic sequencing has, against expectation, found that nearly every artemisinin resistance hot spot emerged independently, not as a result of spread. Future research might change the current understanding of the epidemiology of artemisinin resistance, but the most comprehensive survey found only three instances of spread out of 112 samples from across the region.

More word play and dissembling are on view in a Lancet paper on resistance in Myanmar that included the word “spread” in its title but adduced little evidence and no claims for it. I wrote two of the authors, saying “the title of your paper, ‘Spread of artemisinin-resistant Plasmodium falciparum in Myanmar’ seems belied by the evidence actually in the paper (and other papers).” I asked them if they would correct “any misperceptions on my part,” but neither Mallika Imwong nor Charles Woodrow replied.

François Nosten, who runs a clinic in Mae Sot near the Thai-Myanmar border, also claims resistance is spreading. “Resistance to artemisinin,” according to Nosten, “has emerged in different places in SEA [Southeast Asia] but then it has spread.” I asked: “Can you describe unpublished data or point to papers where spread is documented?” Nosten, regarded by many as a public health hero, replied not with science but anecdote and sophistry: “We find that over 80% of our patients with malaria have parasites that are resistant to artemisinin. It did not emerge in each and every one independently, did it?” Nosten is correct it did not emerge in each patient independently but that is not at all the same as spread. To establish spread requires DNA sequencing from at least two places; Nosten claims spread based on a single cohort and no sequencing data.

A malaria press tour to Southeast Asia, funded by Malaria No More, featured journalist visits and interviews with Nosten and Dondorp. Stories in Slate and other outlets told readers artemisinin resistance was spreading and threatened a malaria apocalypse in Africa.

Distorted science is creating distorted journalism. An AFP story suggested that the reason artemisinin resistance hadn’t spread to Africa was that “international efforts to contain the spread of resistant parasites have been effective.” It is more the case that biologically it is difficult or impossible to install the multiple genetic changes required to create artemisinin resistance. However, the international containment efforts, by increasing drug pressure, might be forcing malaria down evolutionary pathways which could result in a more compact genetic form of resistance that could be more easily exported to Africa.

Meanwhile, the actual spread of insecticide resistance in Africa is ignored. Another journalist field trip funded by Malaria No More featured Tanzania as the destination. Insecticide resistance might have been among the briefing topics, but it did not appear once in an article for Vice written by one of the journalists on the trip.

No one has died from drug-resistant malaria. “As far as I know,” said Nosten, “there has been no confirmed fatal case.” Meanwhile, according to Nick Hamon’s sources, some part of 125,000 people (or more) have died from malaria because insecticide resistance has reduced the effectiveness of bed nets.

Debasing the currency: $4 trillion drawn on the account of science

Worth less than the paper it’s printed on (Source: Wikimedia)

In 2010, researchers concluded that malaria eradication was unlikely to break even and advised that “financial savings should not be a primary rationale for elimination.” But a few years later, an overlapping constellation of researchers discovered that eradication would quickly generate $4.1 trillion in economic benefits, in just 15 years.

The paper touting a $4.1 trillion windfall “is an advocacy document rather than an academic analysis,” according to Rima Shretta at the University of California, San Francisco (UCSF). Shretta is part of the UCSF group which led development of the 2010 Lancet series which found no cost savings from eradication. Shretta also served on the Action and Investment for Malaria task force that developed the advocacy document projecting $4.1 trillion in benefits.

To reconcile the academic analysis of the 2010 Lancet paper with the later discovery of trillions of dollars in benefits, Shretta seems to suggest scientists are free from the standards of science if they are engaged in advocacy. And functionally, it appears malaria advocacy has detached from science, although much of the advocacy comes from scientists.

The End: Malaria Goes Hollywood

Images, which can surreptitiously mislead, end up exposing a conscious mis-shaping of malaria research. Authors are making undisclosed and perhaps improper choices regarding the visual elements in their papers. However, within the papers, the same authors are free to make any number of choices that can decisively influence findings and there is little or no possibility of suggesting impropriety. The sources of data, how they are processed, type of model and parameters partly or entirely decide the research results. Authors can “mute” statements about the loss in bed net effectiveness caused by pyrethroid resistance. Editors can entitle a paper “spread of resistance” when there is none mentioned in the paper and the evidence contradicts the spread hypothesis. But when the philosophy of managing reader beliefs extends to choices about visual elements, the curtain is drawn aside and we see not a scientist but the Wizard of Oz.

World drops type 2 polio vaccine as Nigeria reports type 2 vaccine-derived virus

A spot of bother in Maiduguri district, Nigeria (Source: Wikimedia)

Worldwide, in all but three of 155 countries, the trivalent oral polio vaccine has been replaced with bivalent oral vaccine. The bivalent formulation includes only attenuated versions of type 1 and 3 of poliovirus. The type 2 component has been dropped because, far more than the other types, it sometimes mutates back into virulent form. Also, type 2 polio was eradicated in 1999.

But just as the world moved to the bivalent vaccine, Nigeria reported finding a type 2 vaccine-derived virus in a sewage sample. Consequently, right on the heels of the vaccine switch, the type 2 vaccine is being immediately pressed back into service, although it will be used by itself, in monovalent form, according to the Global Polio Eradication Initiative.

Sequencing indicates the Nigerian virus has been circulating undetected since May of 2014. The sample comes from Maidaguri district, an area contested by government forces and Boko Horam, making vaccination problematic. 

Last September, WHO removed Nigeria from the list of polio-endemic countries. However, the CDC continued to advise that US travelers to Nigeria be immunized against polio.

Initially, the polio eradication project envisioned stamping out all type 2 vaccine-derived virus transmission before dropping the type 2 vaccine component. But plans to switch vaccines ultimately went ahead despite the likelihood of continued circulation of type 2 vaccine-derived virus somewhere in the world.

There are now multiple hotspots. Besides Nigeria, according to the CDC's Steve Wassilak, "We consider [the] Guinea and Myanmar outbreaks still active." In addition, Brazil reported what researchers described as a "highly evolved" type 2 vaccine-derived virus found in sea water off São Paulo. Found in January 2014, sequencing indicates the virus has been circulating undetected for eight years. Brazil has very high population immunity to polio, so this virus likely came from somewhere else, according to Wassilak. 

Eight years of undetected circulation suggests a perhaps large and as yet undiscovered surveillance gap somewhere in the world. Asked whether eight years set the record for undetected circulation, Wassilak answered: "Nigeria had documented circulation for 10 years." However, in Nigeria, there were multiple transmission chains, and it is not clear from Wassilak's answer if any one chain circulated eight years. The Brazilian isolate also had mutations at antigenic sites, suggesting possible evolution of resistance. However, researchers reported that type 2 antibodies still killed the virus.

The process of switching to the bivalent formulation also risks creating new type 2 vaccine derived virus. The switch was synchronized globally because if use of the trivalent vaccine continues anywhere, it might potentially infect children who have only been immunized with the bivalent vaccine. According to WHO:

"The primary risk associated with the cessation of use of type 2 OPV [oral polio vaccine] is the re-introduction of disease-causing type 2 poliovirus into a population with increasing susceptibility to type 2 poliovirus. The switch from tOPV to bOPV must therefore be globally synchronized to minimize the risk of new cVDPV type 2 emergence."

The precision of the large and un-rehearsable switch remains to be seen. Globally, susceptibility to type 2 vaccine derived virus is now rising given the switch to bivalent vaccine and the slow (and arguably belated) introduction of the injected vaccine, which includes all three virus types in a form in which mutation is not possible. Also, while the injected vaccine protects against paralysis caused by poliovirus, it does not prevent infection nor halt transmission. Polio circulated in Israel without causing any cases of paralysis because coverage with the injected vaccine was so high. Eventually, however, circulation might find someone missed by vaccination or with a compromised immune system, resulting in polio's hallmark acute flaccid paralysis.

The success in beating back wild poliovirus bodes well for the eradication effort to also smash outbreaks from vaccine-derived virus. But, out of the gate in the post-trivalent world, the race is already on. And, in Nigeria at least, type 2 vaccine-derived virus circulation has gone uninterrupted for a decade.

Why you might think like Bill Gates about global health

Video still of Bill Gates during a Washington Post interview

Perhaps you read some of the same publications as Bill Gates, like the New York Times or Slate. You tune into NPR and watch the PBS NewsHour, part of the sacred ritual of thoughtful Americans becoming informed citizens.

From Slate, we know time is running out to eliminate drug-resistant malaria. The Gates Foundation believes this too. But is the foundation’s logic irresistible or did Slate run an infomercial for the foundation funded by a $40,000 grant? The story (including a trip to Thailand) was paid for by Malaria No More which has received $20 million in Gates Foundation grants.

Media matter. As Bill Gates observed, even Theodore Roosevelt’s reform program “wasn’t really successful until journalists at McClure’s and other publications had rallied public support for change.” Now Gates has rallied public support for malaria eradication in Slate, and President Obama tentatively endorsed it in the State of the Union.

It’s not just Slate or only global health. Carefully restricted Gates Foundation grants to NPR, the PBS NewsHour, the Pulitzer Center on Crisis Reporting and other news organizations shape what gets covered, what doesn’t, when and how.

The Gates-funded PBS NewsHour just began a new series on education called “Making the Grade.” The first episode is difficult to distinguish from an earlier Gates Foundation video on postsecondary education. In the NewsHour version, Gates-funded journalists and academics deliver the messages of the foundation’s postsecondary strategy, but neither the foundation nor its funding role are mentioned. 

Trusted media organization receiving Gates Foundation grants are not following good journalistic practices. And like improper food labeling, undisclosed funding misleads news consumers about what they are actually getting.

Readers got nothing on Ebola from the Gates-funded Pulitzer Center for Crisis Reporting until more than half a year after the crisis broke. Pulitzer Center stories appear in an array of top-shelf outlets like the New York Times, Nature, and the Economist, where the center’s first article on Ebola eventually came out. Although restricted Gates funds paid for 59 of 240 Pulitzer Center stories over a 30-month period, neither readers nor perhaps even the editors publishing them could tell which were actually Gates-funded. 

NPR, with its Gates grant, cut staffing for covering climate change in order to expand and transform its global health coverage into an upbeat, advocacy-oriented approach, the opposite of muckraking. Gates funding of this specific initiative is not disclosed. While NPR gives the impression that the Gates Foundation just writes a check to support all of NPR’s good work, it doesn’t.

NPR’s restricted Gates grant actually requires NPR to contribute unrestricted money towards Gates-initiated projects. Ironically, listener donations might be funding broadcast of the Gates Foundation’s news values on public radio.

Which is perhaps why you think like Bill Gates when it comes to global health.

Slate: not so clean

In late December, CNN ran an op-ed advocating malaria eradication, written by the CEO of the advocacy group Malaria No More. In January, a week later, Slate too proclaimed “The World Can Eliminate Malaria.” The article delivered Malaria No More’s messages but was written by a Slate staff writer—funded by the Gates-backed Malaria No More. Jackpot: advocacy runs as news from a credible source.

Nightline veteran Dan Green orchestrates the Gates Foundation’s media and communications grant portfolio. Speaking in 2011 on the “media metamorphosis,” Green observed that with the demise of old media, many news organizations “don’t have a global health reporter anymore.” Consequently, when journalists cover global health, “they need more guidance.” For advocacy groups, according to Green, this created “an enormous opportunity for you to educate those reporters about what it is they need to be thinking about.”

The Malaria No More grant provided reporters with ample guidance:

During the tour, participants will conduct site visits to clinics and treatment centers, attend briefings with health officials and disease experts, hear from organizations working to eliminate the disease and meet with local journalists covering the issue.

In return:

Participants will be expected to produce stories based on the information gathered and contacts made during the tour.

Slate staff writer, Joshua Keating, while possessed of formidable reporting chops, focuses on international affairs and does not appear to write much about malaria for Slate. When domain expertise is short, journalists are at the mercy of their sources. When a journalist’s sources are curated by an advocacy group, the result is not journalism.

Technically, Keating’s trip wasn’t directly funded by Malaria No More. Indeed, it is unlikely Slate would have accepted money straight from an advocacy group. Instead Malaria No More funded the International Center For Journalists (ICFJ). Passing the money through ICFJ, which called the five-day trip a “fellowship,” seemed to overcome any journalistic scruple. As Slate science editor, Laura Helmuth, wrote me:

Josh Keating’s editors were all fully aware of his trip and how it was funded, and we fully support him and the reporting that came out of his trip and his story in Slate.

I asked Executive Editor Josh Levin about  Slate’s policy on accepting funding from advocacy groups. Levin did not reply.

Drug resistant malaria is undoubtedly important. But for Thailand, is it more important than dengue? Globally, multidrug-resistant tuberculosis might be far more urgent and deadly, with half a million cases a year. CDC Director Thomas Frieden believes “There can be no delay” in combating drug resistant TB. But Frieden’s views appear on the CDC blog, not in Slate. (Slate has covered the media’s neglect of TB.)

Slate’s malaria piece takes for granted that a single-disease approach to public health is best, without considering whether health systems might be more effective. In addition, current scientific evidence suggests drug-resistant malaria has not spread even within Southeast Asia and faces surprising barriers to taking over in Africa.

For malaria’s considerable importance, neither Slate nor perhaps any media outlet has written about why Rollback Malaria, the global consortium responsible for combatting malaria, disbanded itself in 2015.

For its grant to Slate, Malaria No More got a narrowly focused piece getting out its key messages. Indeed there were four other ICFJ fellowships, so Slate participated in an orchestrated news boomlet. ICFJ would not disclose the names of the other publications, so the impact (and degree of funding disclosure) are untrackable.

The over $200,000 spent on these trips could go a long way towards putting a journalist on the global health beat. But who needs global health reporters if it’s possible to generate “news” that faithfully delivers an advocacy message?

Structural changes in the news industry have made this easier. Said the foundation’s Dan Green, back in 2011: “You have now media organizations that are far more open to innovative partnerships.” Why? Because “their resources are stretched.” As revenue streams for traditional media dried up, enter the world’s wealthiest foundation as innovative partner.

Promise to say you’re independent

With much solemnity, the foundation and its media partners proclaim the full editorial independence of Gates grantees. But Green acknowledged a “fear” felt by Gates-supported news organizations:

...that fear that as my grant ends, will I get renewed and will any foundation funder, or any outside philanthropic funder, say, ‘Hmm. I looked at the stories and they weren’t all that positive, and they weren’t filled with success. Maybe we don’t want to fund that anymore.’

Green insisted it would be short-sighted for funders to take such an approach. And yet the Gates Foundation seeks demonstrable results, according to Green: “We as funders try to think in terms of outcomes. What would be the outcomes we’re hoping for by telling these stories, by engaging with the content creator?”

The foundation engages with content creators not to give readers a puzzle to solve thoughtfully but to deliver pre-specified, actionable messages. “We really think a lot about ‘Is it reaching an audience that we think is an important audience we need to reach?’ ” Green opined in 2013.  “And, if it is, does it have the credibility and the trust so when it puts out evidence-based information that people say, ‘I believe that. I’ll follow what that says?’ ”

Wearing his journalist hat, Green said, “Now you come from journalism and we don’t sit around talking about messaging. Messaging makes us cringe. Because then it makes us feel that you’re using all the journalists as tools for your messages.” Green concluded, forthrightly: “You might say, ‘Yeah, we are.’ ”

Green defended using journalists as tools because “it’s a mistake to think that if your subject that you care about is getting talked about, and stories are being told and information is out there, that is incredibly valuable.” Journalists get to cover global health; the price is carrying the foundation’s messages. It’s painting by numbers, but it’s still painting.

The dissolution of traditional media, according to Green, brought fragmentation and proliferation of information outlets, and created a news environment with fewer facts and more opinions. Some digital media consultants, said Green, recommended that “the louder and stronger your opinion is, sometimes the more people gravitate to you…” However, even Theodore Roosevelt’s  bully pulpit did not suffice to create change. Regarding the loud opinion strategy, Green said “I’m not a huge fan of that necessarily.” Far better that the foundation’s opinions appear as news.

Like Slate’s malaria piece.

The Pulitzer Center—presented by the Gates Foundation

The Pulitzer Center for Crisis Reporting frowns on free trips. Pulitzer Center-funded articles appear in elite publications like the New Yorker, Nature, the Economist, the Washington Post, Slate, Foreign Policy, National Geographic etc.

But regarding trips, the Pulitzer Center’s ethics policy says journalists “should not normally accept free travel, with the exception of military embeds and other situations in which travel assistance is essential to the reporting.” To further protect its integrity, the center counsels writers to “avoid activities that might interfere with your ability to function as a journalist.” Otherwise, “you may be precluded from working on certain topics for the Pulitzer Center if you're personally involved.”

Although the center closely polices the integrity of worker bee journalists, different standards apply to donors. Many donors write a check with no strings attached, leaving the Pulitzer Center with full editorial discretion. “In recent years,” said Executive Director, Jon Sawyer, “we have consistently gotten 50 percent or more of our budget from unrestricted donations…”

However, the other 50 percent of donations have strings, although the center’s ethics policy seems to guard against any improper influence. The policy asserts: “Donors will not dictate in any way the editorial products of the Pulitzer Center.” But restricted donors, like the Gates Foundation, restrict their grants because they do not believe the Pulitzer Center would, by itself, create the desired editorial products. Influencing the Pulitzer Center’s editorial products is the only reason restrictions exist.

“Over a four-year period our Gates funding has totaled approximately $2.4 million,” said Sawyer. “These were restricted grants but the terms were broad, with funding for a broad range of global health/development topics and educational outreach and full autonomy as to the selection of specific projects, news-media placements and outreach activities.” But the center’s “full autonomy” is over selecting specific projects. The Gates Foundation draws the big picture and contracts out for the needed words and images.

Recall that the Pulitzer Center will disqualify journalists from writing on subjects in which they are personally involved. To guard against donor bias, the center’s ethics policy asserts: “We do not accept donations that raise the possibility, or the appearance, of a conflict of interest.” However, the center’s Gates funding, at minimum, creates the possibility of a conflict. The Gates Foundation is the largest in the world. Most of its donations go to global health and development, the same subjects funded by its grants to the Pulitzer Center. The foundation, far from being policy-agnostic, funds research into policy and advocates for specific approaches to global public health.

This possible conflict of interest is not disclosed to readers nor perhaps even to editors of the publications running stories from the Pulitzer Center. Slate at least disclosed the funding of its story on malaria. Slate didn’t just name the funding intermediary, the International Center for Journalists, it named (sort of) the funder, Malaria No More. Anyone wanting to dig further could discover the Gates Foundation’s $20 million funding of Malaria No More, which advocates for the foundation’s malaria policy, eradication, set by the foundation in 2007.

The Pulitzer Center, with its Gates funding, produced a substantial amount of global health coverage. Over the 30 months of its most recent Gates grant, “we applied Gates funds to support a total of 59 projects,” said Sawyer. “For purposes of comparison, over that same 30 month period we supported some 240 projects overall.” These stories ran with the disclosure of funding provided by the Pulitzer Center. However, one in four is actually the Pulitzer Center presented by the Gates Foundation.

Which 59 projects were Gates funded? Sawyer would not say. He previously mentioned “On some of those [Gates] projects we also drew on funds from other donors.” He emphasized the point: “Also, as point of clarification, our grants to journalists often mix restricted/unrestricted funds.” Sawyer perhaps was suggesting that mixed funding mitigates conflicts of interest. The idea might be that if funding from interested donors passes through intermediaries who stir in some amount of disinterested money, then journalism is not compromised and disclosure is unnecessary.

From the Gates Foundation perspective, however, adding unrestricted funds to those of its restricted grant leverages the foundation’s investment. (It’s possible the grant stipulated that the Pulitzer Center contribute additional funds.) The restricted Gates grant shifted Pulitzer Center resources to more closely match the news values of the Gates Foundation. Maybe not by much; maybe a lot.

Initially, Sawyer wrote me: “Happy to discuss this further. Complicated numbers and we're eager to have it reported accurately.” But when I asked for a spreadsheet listing Gates-funded projects and the funding mix for each, Sawyer did not reply.

Sawyer defended the center’s work: “I hope you'll take the time to read some of the reporting,” he wrote me. “It's quite good!” Read the stories; don’t ask where they came from. But Sawyer is right about quality: the center’s production values are top-shelf, and the finely wrought stories bring attention to a broad array of important but neglected subjects. Slate’s article on the neglect of TB, for example, was supported by the Pulitzer Center. Nonetheless, reporting loses the name of journalism when it comes from restricted funding.

The Pulitzer Center website quotes Joseph Pulitzer: “We will illuminate dark places and, with a deep sense of responsibility, interpret these troubled times.” But Sawyer shed very little light on funding of stories bearing Pulitzer’s name. “Ebola, malaria and other health projects relied in part on Gates, in part on other funding sources,” he said, perhaps again suggesting that mixed funding ameliorated conflicts of interest not disclosed by the Pulitzer Center.

It is true that finding such conflicts is much harder when 59 restricted projects are mixed with 201 that are not. However, in a far from exhaustive search, I came across a speech in which Bill Gates advocated an intervention called seasonal malaria chemoprevention. Later, there is Pulitzer Center article about it, indeed a multi-article project on the subject. Whatever the merits of seasonal malaria chemoprevention, there is no way to determine if its coverage was funded by an interested party.

The Pulitzer Center tells its reporters: “Let the audience know any information about yourself or your sources that might affect its understanding of your work.” Brick-laying journalists are closely scrutinized but the audience has no idea even of the existence of restricted donors shaping the overall news architecture.

The void: Why no Ebola coverage for half a year?

If Gates Foundation influence on malaria, for example, is worrisome, evidence on Pulitzer Center coverage of Ebola raises far more serious concerns: The Pulitzer Center supported no stories on Ebola for more than half a year.

The outbreak began in March of 2014 but no Pulitzer Center stories appeared on Ebola until mid-December. The center’s full name is the Pulitzer Center for Crisis Reporting, and Ebola is the most important global health crisis since HIV/AIDS. Although funded by the Gates Foundation to cover global health, the Pulitzer Center produced nothing on Ebola for the better part of a year.

I conducted my search for “Ebola” articles using the center’s website. (I asked Jon Sawyer for confirmation of my results. He did not reply.) The first article I found is dated December 13, 2014, “The Fight Against Ebola: Donating the Cure,” appearing in the Economist.

According to Sawyer, the Pulitzer Center received what he described as an “extension” grant of $300,000 from the Gates Foundation. It is possible that the timing of the grant coincides with the onset of Pulitzer Center stories about Ebola.

In difficult to parse grammar, Sawyer said: “Gates extension was continuation of previous grant, support for reporting/outreach on broad range of global health/development issues: choice of projects, journalists and outlets left to us.”

Unsure whether that meant “no,” the extension grant did not fund the center’s Ebola coverage, I asked Sawyer again, several times, if the grant was to cover Ebola. I sought details on timing and who approached whom. Sawyer did not reply.

When I inquired of the Gates Foundation’s Bryan Callahan whether the extension grant was for Ebola, he did not reply. Callahan is the foundation’s Senior Program Officer for Program Advocacy & Communications.

Back in 2011, the foundation’s Dan Green, claimed: “We want people to say ‘We get our money from the Gates Foundation.’ ” Later, writing on the foundation’s blog, Green put transparency first among the guiding principles for media grants. Green also promised “in the coming weeks I’ll post another blog listing all of our current investments in this portfolio.” I asked Green for the listing of the foundation’s current media grants. He did not reply.

I asked Amy Maxmen, who wrote stories on Ebola for the Pulitzer Center, whether she knew if her efforts had been Gates funded. “I don't know where the Pulitzer Center gets their funding,” answered Maxmen, without saying yes or no. “I admit I don't ask.”

Maxmen did assert: “I independently came up with the idea for my reporting on Ebola.” However, Maxmen thinks a lot like the Gates Foundation.

The Pulitzer Center’s Ebola project is entitled “Disaster Science During the Ebola Outbreak.”  The center took care to explain this odd-seeming focus: “Research during a disaster can seem frivolous when there aren’t enough resources to handle the immediate response. But in the Ebola outbreak it's become clear that data collection must happen now.” The Pulitzer Center had ignored Ebola for more than half a year and now focused not on an Ebola response but Ebola research—rather like the Gates Foundation.

Had Médecins Sans Frontières (MSF) been the funder of the Pulitzer Center’s Ebola coverage, the stories would likely have come sooner, indeed immediately, and with a different emphasis: the need to act.

In contrast to MSF, the Gates Foundation remained silent on Ebola for months until moments before WHO’s belated declaration of an emergency. Barely beating WHO to the punch, the foundation announced an Austin Powers-sized $1 million dollar grant to “help address the immediate need on the ground.” One day after its token grant, the foundation blogged that meningitis, “could end up being far more destructive than the current Ebola epidemic.” Remarkably, the foundation moved on from Ebola before WHO even declared it to be an emergency.

The crisis worsened. As it reached increasingly apocalyptic scale and the world belatedly mobilized billions of dollars, the foundation chipped in $50 million. The announcement committed $10 million to “emergency operations” but also to “R&D assessments.” For the remaining $40 million, “the foundation will provide further details on its funding commitments to on-the-ground operations and to research and development for Ebola drugs, vaccines, and diagnostics.” The foundation was not going to fund the operational response costing billions but research costing millions. The Pulitzer Center’s Ebola coverage, when it finally came, also focused on research.

The center’s Ebola coverage can be seen as favorable to the Gates Foundation which funded the stories, at least in part. Maxmen’s first article, for example, appearing in the Economist, focused on the silver bullet of blood transfusions potentially curing Ebola. It turned out not to work, and new research contributed little to containing the epidemic. However, one of Maxmen’s stories, appearing in Newsweek, criticized the Ebola response as wastefully managed. Undoubtedly. But the foundation had mostly not contributed to on-the-ground efforts which, in the end, worked. 

In the pages of Nature, Maxmen reminded readers of the importance of malaria and that Ebola was disrupting mass administration of anti-malarial drugs.

Another Maxmen piece provided a reporter's timeline of the world's “plodding attack on Ebola.” It pummeled bureaucratic organizations “bogged down in democratic decision-making processes and bureaucratic policies,” perhaps meaning the World Health Organization. The timeline doesn’t mention the inaction of the Gates Foundation. Nor does the article examine the role of the CDC, which only declared Ebola a top-level emergency one day before WHO.

Latest of all, however, was the Gates-funded Pulitzer Center.

The Economist: “We do not publish articles 'supported' by any organisation”

Maxmen's article in the Economist runs without disclosure of Pulitzer Center funding. I asked Economist science editor, Geoffrey Carr, whether the Pulitzer Center disclosed to the Economist any funding of its work by the Gates Foundation.

Carr replied: “We do not publish articles 'supported' by any organisation, and we certainly do not publish anything funded by anyone.” The Economist is journalism at its purest, or at least proudest.

I pointed out that the Ebola story appearing on the Pulitzer Center site was identical to the one appearing in the Economist. (The Pulitzer Center lists 25 articles and 1 photo as published by the Economist.)

Carr changed tunes: He described Maxmen as “a freelance who seems to have some sort of travel and support grant from the Pulitzer Centre.” Carr added: “I don't see any impropriety in this, since we pay our freelances a market rate for their copy.” 

The Economist  does publish articles supported by other organizations, but without disclosing that support to its readers. (In this regard, the Economist is perhaps the perfect vehicle for maximally credible stories with undisclosed conflicts of interest.) Regarding the question of whether any Gates funding of the Ebola article was disclosed to the Economist, Carr wrote: “I will pass your thoughts on to the Editor of the Middle East and Africa section, whose section this story appeared in.”

NPR: Gates and Soda

Think of your brain as a pie chart, the slices representing the subjects you pay attention to, and the size of the slice indicating how much. If NPR programming influences your pie chart, then your slice on climate change might have shrunk like a receding glacier.

In 2014, NPR cut its environment team to one reporter, according to Inside Climate News, with resources reassigned to “the outlet’s global health and development coverage, which includes a new project launched this summer using a grant from the Bill and Melinda Gates Foundation.”

NPR will not say how much of that project, called Goats and Soda, is Gates-funded. One report said it would “likely not exist” absent Gates funding. But NPR’s Isabel Lara said: “Goats and Soda is possible in large part due to the Gates Foundation grant but it isn't accurate to say that it wouldn't exist otherwise.” Lara is NPR’s Media Relations Director. When asked for details, Lara would only repeat the amount and duration of the grant. “Cannot get more specific than that,” Lara said.

The Gates Foundation’s funding relationship with NPR goes back 15 years. Its most recent grant in 2013 provided $4.5 million to “advance global health and development coverage.”

The Gates initiatives at NPR, however, are not 100%-funded by the foundation. According to Lara: “As is common with many foundation grant agreements, our Gates agreement references NPR’s proposed budget for the initiative which included other resources beyond their investment.” More plainly, the Gates grant requires NPR to help fund the foundation’s projects.

I asked Lara if the “other resources” contributed by NPR included listener donations. She did not reply. However, as at the Pulitzer Center, a restricted Gates grant might be drawing unrestricted funds into the support of the foundation’s news values. Conceivably, listeners are funding NPR’s Gates-designed presentation of global health news.

NPR does not disclose Gates Foundation support for Goats and Soda on its website except, it seems, when Gates or his foundation are the subject. A commentary applauding BIll Gates’ views on solar power, for example, parenthetically disclosed: “As our readers may know, the Gates Foundation is a funder of NPR.” But readers of the laudatory piece on Bill Gates do not know that the Goats and Soda enterprise is mainly and specifically funded by Bill Gates.

Goats and Soda might even be preferentially covering its funder. I asked the author of the commentary, Michael Hayden, if he approached Goats and Soda or vice versa, but he would not say. “Sorry,” Hayden wrote back, “what are you trying to do exactly?”

Unlike NPR’s Goats and Soda, the Guardian puts the Gates Foundation’s logo on all the pages appearing in its Gates-funded development section. Guardian readers do not have to guess what is Gates-funded and what is not. Whether foundation influence extends beyond what it pays for is another question. But a dedicated page describes the funding relationship including the declaration that “content is editorially independent.”

I wrote to Goats and Soda editor, Vikki Valentine, asking whether Gates funding was properly disclosed. Valentine did not reply.

Solutions journalism: turn that frown upside down

Goats and Soda represents not just a switch in coverage from climate to global health. The news production line now turns out a very different editorial product based on a new template, solutions journalism.

In 2012, the Gates Foundation issued a challenge to “find ground-breaking ways to gather and share stories of aid working well.” In the foundation’s view, “The media seems full of stories of corruption, waste and broken systems.”

Responding to the challenge, New York Times writer David Bornstein and colleagues won an initial $100,000 grant from the foundation for an idea called “solutions journalism.” As Bornstein explained:

So much of what we do as journalists is aimed at holding powerful people accountable and identifying failure, which is very important and valuable. But if we stop there, with just identifying failures and the bad actors, it becomes frustrating to people. It’s a broken narrative.

The foundation has supported Bornstein’s efforts with a further $1 million.

Solutions journalism, according to Bornstein, “has more in common with a Harry Potter novel, a quest or struggle, than the traditional journalism narrative.” Harry Potter, of course, is fiction.

Traditional journalists on the global health beat, like Tom Paulson, questioned the solutions emphasis: “A number of journalists, including me, remain concerned that making reporters responsible for emphasizing solutions – along with this Gates push for ‘success stories’ – could undermine basic watch-dogging.”

Paulson leaned toward what he called “cranky” stories. The blog Paulson edits, Humanosphere, ran a story entitled “How Tanzania failed to fix its water access problem.” The piece delivers a very cranky, evidence-based beatdown of the World Bank. The story held powerful people accountable and identified failure. The story was not solutions journalism.

By contrast, a Goats and Soda article on water featured a solution: Bill Gates drinking water “made from poop.” The Gates-funded piece stars Gates and promotes a Gates-funded project. The article’s solutions journalism style, favored and funded by the Gates Foundation, leaves readers with gee whiz wonderment, a sense that there’s an app for the water crisis.

Although the water-from-waste system appears to be the size of small refinery, the story does not delve into what it costs to construct or operate. The price of a gallon of water and whether the system works where there is no sewage system or electricity are not addressed. Broken narratives about the water crisis, however, are avoided.

Change the perception, change the reality

Sally Struthers, circa 1992, told television viewers: “Every year, 10 million third world children don’t live to see their third birthday.” Ten million avoidable child deaths, said Struthers—and that’s on you, viewer. Look: tiny bodies, bloated bellies, skeletal ribs, eyes outlined in flies.

Global Health, 1992 Source: YouTube

Today, moralizing and macabre messages are out. Even the news category “global health” has been left behind. NPR buried its old Twitter handle @nprglobalhealth, pointing followers instead to the new @nprgoatsandsoda. In place of 1990s-era, grim scenes of despair, a Goats and Soda music video shows the modern day “bliss” of living in low-income rural India.

Goats and Soda, 2015

Source: NPR Goats and Soda

Struther’s moral importuning came in television commercials clearly paid for by the Christian Children's Fund. By contrast, what Goats and Soda presents appears as NPR-certified reality, a perception unspoiled by disclosure of Gates Foundation funding.

Very few Struthers-like sermons have appeared in Goats and Soda. Indeed, a story about ethics and the making of blue jeans argued against moralizing. The piece concluded with a quotation from a researcher: “To get people to be more ethical, do not ever present your message as, 'If you're not doing this, you're a bad person...'”

And instead of counting dead children, today we count those who have been saved. Said Melinda Gates at Davos recently, “When we look at the fact that since 2000, childhood deaths have been cut in half, a big percentage of that is because of vaccines.” Quite reasonably, Melinda describes the glass as half full. And the world is doing great on vaccinating children, right?

Omission of bad news is bad journalism—or worse

There is one hiccup: measles vaccination is “falling behind,” according to a story in Goats and Soda. Not to worry, though. Annual measles deaths have fallen from 546,800 to 114,900 since 2000. That’s fantastic—except measles progress actually flattened back in 2007. The good news stopped eight years ago but is still being reported.

More than just measles vaccination is falling behind. Of six targets set in 2010 for global child vaccination, “Just one of these six is on track to be achieved,” according to a report from WHO’s Strategic Advisory Group of Experts (SAGE).  At Davos, Melinda Gates chose to speak about the one target that was on track: introduction of new vaccines.

Goats and Soda’s measles story promised to explain “why the world is falling behind,” but did not. Solutions journalism style, however, it covered “new strategies that seem promising” and “other success stories from the front lines.”

By contrast, SAGE explained what had actually gone wrong:

The targets each relate to different vaccines and diseases, but common threads run throughout: failure to extend vaccination services to people who cannot currently access them at all, and failure to strengthen the healthcare system so that all doses of vaccine are reliably provided.

In addition, the total number of unvaccinated children had “basically not changed” and those at greatest risk became more vulnerable: “Looking closer, the number in the lowest bands is getting worse not better,” SAGE reported. However, few or no journalists explored the halt in progress and backslide in immunizing the world's children. How this failure is possible and who is responsible is not a solutions journalism story. Adding to the broken narrative, SAGE wrote: “The habit of missing major vaccination targets undermines global trust in these efforts…” Global trust, however, remains high because no one reads SAGE reports.

In 2000, Gates Foundation mistrust of vaccination efforts led it to create the Gavi Alliance which now runs the world’s child immunization program. Gavi doesn’t keep track of how many children die for lack of vaccination. (This might be like the Department of Labor not counting the number of unemployed.) Instead, Gavi touts “Another record-breaking year in terms of the number of [vaccine] launches,” the same message emphasized by Melinda Gates. 

These introductions, according to Gavi, “made a major contribution to the unprecedented rate of reduction in under five mortality.” Similarly, Melinda Gates said at Davos: “they are getting the vaccines out now very quickly, and that's how we're saving lives.” Readers might conclude that Gavi and the Gates Foundation have been driving down child mortality more quickly than at any time in history. It's a good story, but it isn't true.

The Gates-funded Center for Global Development reported that new vaccine introductions have made no detectable difference in saving lives, finding only “small and statistically insignificant effects for the three high-priced vaccines promoted by Gavi...”

Vaccine coverage, not introductions, is what saves lives. And according to SAGE, immunization coverage has recently shown “no improvement,” leaving the number of unvaccinated children at 22 million. Children that aren’t vaccinated can and do die from preventable disease in large numbers. “1.5 million children die every year of diseases that could be readily prevented by vaccines that already exist,” SAGE reported, based on a 2008 WHO estimate.

Not a problem for solutions journalism.

PBS NewsHour: copying the Gates Foundation's homework

The Gates and MacArthur foundations both support the PBS NewsHour. Although frequently credited together, this is misleading. The two foundations hold very different, indeed opposing worldviews.

Gates grants are, once more, restricted. A $3.6 million grant to the NewsHour in 2008 supported only global health coverage. A current Gates grant directs $320,000 toward stories that “inform the public” about higher education issues. This media spend hits its mark. 

In January, the NewsHour began a new series called “Making the Grade.” The first episode delivered the same messages on higher education as a Gates Foundation video appearing back in November.

The foundation’s video carried forward messages from an earlier blog entry from Bill Gates, who wrote: “The problem is that not enough people are finishing [college]. More than 36 million Americans—a fifth of the working age population—have gone off to college and left without a degree.” The NewsHour segment described the same problem: “nearly 40 percent of those who go to four-year colleges and some 70 percent of students at community college will never earn their degree.”

Given this problem, the question and title of the NewsHour segment was: “Should more kids skip college for workforce training?”

No one from the Gates Foundation appeared in the NewsHour segment. Their parts were taken by people funded by the Gates Foundation. The NewsHour introduced series host, John Tulenko, as a “special correspondent from Education Week.” Education Week’s parent company has received $12.6 million in Gates Foundation funding. Before joining Education Week, Tulenko worked at Learning Matters, recipient of $1 million in Gates grants.

Tulenko interviewed Anthony Carnevale, head of Georgetown’s Center on Education and the Workforce (CEW) and recipient of $9.7 million in Gates grants. CEW’s postsecondary policy appeared as early as 2012 in a Gates-funded report. CEW’s research informs the Gates Foundation’s current postsecondary strategy. It also appeared in Bill Gate’s blog, in the foundation’s video on postsecondary success, and most recently on the Gates-funded PBS NewsHour.

Tulenko also interviewed Michael Petrilli, president of the Fordham Institute, recipient of $7.8 million in Gates funding. Petrilli, Carnevale and the Gates Foundation argue that too many students go to college and amass debt only to drop out. The solution they propose is that students at risk of dropping out receive advice to consider vocational education instead of going to college.

The only person on the show opposed to re-directing students toward job skills programs was Carol Burris. Burris worried that such career advice would be based on stereotypes, especially racial stereotypes. Of the three academics interviewed, Burris was the only one not funded by the Gates Foundation.

For journalism, however, the question is not whether the Gates Foundation’s postsecondary policy should be followed or not. The issue is that the PBS NewsHour ran a story as news that is not distinguishable from the advocacy of a funder.

The Gates Foundation’s role as funder in the story also was not visible to viewers. The credits for the segment stated that principal support came from the Noyce Foundation. The Noyce Foundation is defunct. And although NewsHour spokesperson Nick Masella said “NewsHour's education funders are listed on our education web page,” the Noyce Foundation is not among them.

I asked Masella why the NewsHour used a “special correspondent” rather than a NewsHour correspondent and whether Education Week contributed funding. Masella did not reply. Similarly, Masella would not say whether its Gates Foundation grant supported the segment, only that: “The PBS NewsHour credits the Gates Foundation every night on our broadcast, as we do with other foundations, in accordance with PBS's funding standards.” 

But the NewsHour gives viewers the impression that the Gates Foundation supports all the NewsHour's good work, when actually Gates money funds stories only on education, stories which do not disclose this restricted funding. By contrast, when the NewsHour covers, for example, rail issues, it clearly states that it receives funding from BNSF. 

More in line with the impression PBS gives to viewers, the MacArthur Foundation does support all the NewsHour's good work. MacArthur's  $1.5 million grant is not restricted. Although MacArthur does issue some restricted journalism grants, according to Kathy Im, MacArthur’s Director of Journalism and Media: “When we have a well-established relationship with a grantee and have confidence in their editorial vision and dissemination strategies, we tend to provide unrestricted support in order to provide maximum flexibility to the organization and its leadership.”

Gates Foundation v. the People of the United States

MacArthur supports journalism in the public interest; the Gates Foundation supports journalism in support of its policy interests. The MacArthur Foundation believes in open society principles; Bill Gates believes institutions of civil society are iffy: “The closer you get to it and see how the sausage is made, the more you go, oh my God!” Gates told the Financial Times. He wondered whether in American democracy, “can complex, technocratically deep things – like running a healthcare system properly in the US in terms of impact and cost – can that get done?”

Imagine, continued Gates, “the idea that all these people are going to vote and have an opinion about subjects that are increasingly complex... Do democracies faced with these current problems do these things well?” Perhaps if they are shown how by their betters.

Whether foundations “do” global health better than democracies and the institutions of civil society is a question that is not asked. Instead of holding the Gates Foundation accountable, a number of influential journalists at trusted news organizations write to foundation storylines and pay down their mortgages with foundation funding.

Muckrakers might have called this corruption. At the Gates Foundation, it’s philanthropy.


Article History
14 February: Section with quotations from Economist science editor Geoffrey Carr added

Gavi CEO: Lazard and Gavi Board Chair Positions not a Conflict of Interest

Gavi Board Chair Ngozi Okonjo-Iweala and Gavi CEO Seth Berkley (Photo credits: Gavi, Wikimedia Commons)

"I do not see any conflict of interest." - Seth Berkley

Gavi's new board chair, Ngozi Okonjo-Iweala, simultaneously joined the sovereignty practice at Lazard, an investment bank which Bloomberg has described as "banker to the broke." A number of Gavi-supported countries are Lazard clients. Also, Gavi-eligible countries might consider retaining Lazard to enhance their prospects for Gavi funding. 

[See previous article, "Gavi Board Chair-elect Joins Lazard's Sovereignty Practice the Same Day."]

However, Gavi CEO, Seth Berkley, said: "I do not see any conflict of interest." Continued Berkeley: "Many of our Board members have other jobs and board positions and we are very careful to monitor any potential conflict of interest issues." As a sign of the legitimacy of the arrangement, Berkley said "the announcement of her work with Lazard and Gavi were coordinated by the communication team and announced the same day." Previously, Gavi spokesperson Rob Kelly denied such coordination of the announcement. Kelly also said Gavi had not facilitated Okonjo-Iweala's employment arrangement with Lazard.

As board chair of Gavi, Okonjo-Iweala will oversee and have signing authority on Gavi grants. Gavi recently raised $7.5 billion dollars to fund vaccine grants over the next four years. 

Although Gavi board members do indeed have other jobs, I asked Berkley;

Is it not the case that, as Gavi board chair, Ngozi Okonjo-Iweala will have a hand in distributing several billion dollars to finance ministries while, on  the other hand, as part of Lazard, Okonjo-Iweala will be receiving money from finance ministries?

Berkley did not reply.

The Gavi board, which elected Okonjo-Iweala unanimously, appears to have been unaware of her arrangement with Lazard. According to Berkley, "The Board delegated responsibility for due diligence to the Board-appointed Recruitment Committee." I asked Gavi board member Zulfiqar Buttha if the board knew of the Lazard affiliiation when the board elected Okonjo-Iweala. He wrote back: "No."

None of the Gavi board members I emailed responded regarding whether joint Gavi-Lazard positions represented a conflict of interest. I emailed:

  1. Flavia Bustreo, WHO (Assistant Director-General)
  2. Zulfiqar Buttha, Unaffilliated
  3. Tim Evans, World Bank (Director)
  4. Geeta Rao Gupta, Unicef (Deputy Executive Director)
  5. Orin Levine, Gates Foundation (Director)
  6. Katie Taylor, United States (Deputy , USAID)
Orin Levine, Gates Foundation representative to Gavi (Photo: Gates Foundation)

Gavi originated from a Gates Foundation grant. It is not clear if the foundation had foreknowledge of Okonjo-Iweala's appointment. Neither the foundation nor Seth Berkley answered inquiries on this point.

Okonjo-Iweala's election appears to violate Gavi statutes and bylaws

In addition to conflict of interest problems, the election of Okonjo-Iweala appears to violate Gavi statutes and bylaws. Article 12 says: 

"Board members will select the Chair and a Vice Chair of the Board from among their own voting members..."

The Gavi bylaws appear to reinforce the statutes. Section 2.6 says:

"The Chair and Vice Chair will be selected according to Article 12 of the Statutes from among voting Board Members (not Alternate Board Members)."

Okonjo-Iweala was not a Gavi board member. Perhaps to circumvent Gavi statutes, Okonjo-Iweala was both named to the board and elected board chair at the September 2015 board meeting. By contrast, outgoing board chair, Dagfinn Høybråten, previously served on Gavi's board before becoming chair. 

I asked Seth Berkley if Okonjo-Iweala's election violated Gavi statutes. He did not reply.

Alleged disappearance of Nigerian oil money; Gavi investigation of Nigeria

Okonjo-Iweala is widely known as an anti-corruption crusader. However, the former finance minister of Nigeria has been caught up in allegations that Nigerian oil revenues were improperly diverted. Investigations continue. The newly-elected president of Nigeria, Muhammadu Buhari, recently said, "We have some documents where Nigerian crude oil was lifted illegally and the proceeds were put into some personal accounts instead of the federal government accounts." One estimate put the amount of fraud at $20 billion dollars. A former oil minister is being investigated and others might be named.

In theory, Gavi is still investigating misuse of Gavi funds distributed to Nigeria while Okonjo-Iweala was Finance Minister. A 2014 audit recommended that the Economic and Financial Crimes Commission carry out "a thorough and detailed investigation of the Gavi grants disbursed to Nigeria." In addition, the audit sought "a full-scale audit to cover both select, high-risk expenditures in prior years, and other expenditure from the period 2011-2013" not examined in the course of the 2014 audit.  

It is difficult to see how Gavi could pursue or cooperate fully with any investigation of wrongdoing that might involve its board chair. I emailed Simon Lamb, Gavi's Managing Director, Audit and Investigations, and asked if Gavi was following through on the 2014 audit recommendations. He did not reply.

Correct or Retract Ross et al. Reviews of HER2 as Prognostic in Breast Cancer

Problems with 30 of 107 papers reviewed

Three reviews of HER2 as a prognostic factor in breast cancer have been published by The Oncologist, in 19982003, and 2009.

In the 1998 paper, 10 of the 47 studies were mishandled; correcting the errors overturned the review's conclusion that HER2 is independently prognostic. 

The error rate increased in subsequent reviews. The 2003 update added 34 more papers and 10 new errors. The most recent review, published in 2009, added 26 papers and 10 more new errors. 

All told, in the 2009 review, of the 107 papers reviewed, a total of 30 (28%) are either miscoded or should not have been included:

  • 10 papers coded 'Yes' for multivariate significance should be 'No'
  •  7 papers coded 'Yes' for multivariate significance should be 'NA' 
  • 11 papers should not have been included 
  •  2 papers coded 'No' for multivariate significance should be 'Yes' 

Appendix A below defines what constitutes an error. Appendix A also enumerates and explains the 30 errors contained in the 2009 review.

Stuffing the ballot box

The 11 papers which should not have been included accounted for 7,511 (19%) of the 39,730 patients in the 2009 review. Of the 7,511, the review reported 7,213 supported HER2 as independently prognostic. A single paper, Lal et al. (2005) contributed 3,655 patients to the review, more than twice as many as the next largest study. Like nine of the 11 erroneously included papers, Lal et al. examined the correlation of HER2 with other biomarkers, not HER2 and clinical outcomes.

First author acknowledges possibility of errors, disputes none of them

Jeffrey Ross, the first author on all three reviews, acknowledged the first two might contain errors. Regarding the 1998 review, Ross wrote in email: "It is certainly possible that the studies you have cited were not perfectly listed in my manuscript from so many years ago.” 

With respect to the 2003 review, Ross wrote: "I have no reason to believe that your conclusions are not correct and that there were scattered errors in the meta-analysis of the published literature in our 2003 manuscript."

However, contacted regarding the most recent, 2009 paper, Ross wrote: "Due to time constraints, I am unable at this time to either agree or disagree with your analysis..." In PubMed, the 2009 review is cited 133 times.

No response from The Oncologist

According to the Committee on Publication Ethics (COPE) guidelines, journal editors should consider issuing a correction if "a small portion of an otherwise reliable publication proves to be misleading (especially because of honest error)." 

Three emails documenting possible issues in the Ross et al. reviews, sent to Martin Murphy, executive editor at The Oncologist, have not been answered. The Oncologist is a member of COPE.

Appendix A

Papers counted as representing an error were either miscoded or inappropriately included. Note the 2009 review includes all the papers and errors contained in the 1998 and 2003 reviews.

Miscoding

This examination focuses solely on the reporting of HER2 having independent prognostic value in a multivariate analysis. The reviews misclassified the findings of 19 papers. 

Perhaps most remarkably, seven of the 19 did not report performing a multivariate analysis of HER2 as a prognostic factor. 

Ten papers did perform such an analysis but found HER2 did not predict clinical outcomes although the reviews categorized the 10 as finding HER2 to be independently prognostic. 

Two studies were reported as finding HER2 not prognostic when the papers did find it prognostic. Strangely, one of these false negatives was a paper co-authored by Jeffrey Ross, i.e. he seems to have miscoded one of his own papers.

Inappropriate Inclusion

The three reviews mostly examined papers that included some clinical outcome, such as disease free survival, in HER2 positive and HER2 negative patients. However, particularly in the 2009 review, studies of HER2 were reviewed that did not include any clinical outcome. Of 11 papers that should not have been included, nine correlated HER2 with other biomarkers, not clinical outcomes. 

Inclusion of one the 11 papers, Wright et al., resulted in a double-counting (in Gullick et al.) of a single cohort. 

In the last of the 11, Sandri et al., the paper examined HER2 in serum whereas the other studies in the review were of HER2 overexpression or amplification in tumor cells. The review's conclusions are only for overexpression and/or amplification. 

Enumeration of Errors

Numbers correspond to the study number from Table 1 of the 2009 review.

2. Berger et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: "Correlation of c-erbB-2 Gene Amplification and Protein Expression in Human Breast Carcinoma with Nodal Status and Nuclear Grading."

4. Wright et al.: Yes to Exclude

One of three studies incorporated in Gullick et al. (1991), also in the review. As a result, the same 185 patients are counted twice. 

9. Battifora et al.: Yes to No

The paper reports: "Stepwise Cox Regression: This analysis identified independent prognostic factors of DFS and OS when all variables were considered together. Independent predictors of DFS included stage of disease, histology, and nuclear grade. Nuclear grade and stage were the only significant predictors of OS."

13. Lovekin et al.: Yes to No

The paper reports: “Multivariate analysis (Cox, 1972) was used to identify whether c-erbB-2 was of independent prognostic significance. In the context of the temporal variables, tumour size and lymph node stage, cell membrane staining was found to have independent significance as a prognostic factor but significance was lost when histological grade was included in the analysis."

15. Dykins et al.: Yes to NA

No multivariate analysis

19. Paterson et al.: Yes to No

The paper does not state HER2 is independently prognostic in a multivariate analysis or provide the statistics relevant to such a statement. The authors do suggest possible confounding of prognostic factors: “our study design precluded direct determination of the interrelationships of c-erbB-2 [HER2] amplification with conventional disease parameters.”

21. Molina et al.: Yes to NA

No multivariate analysis

28. Press et al.: Yes to NA

No multivariate analysis

30. Descotes et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: “Correlation study between Her-2/neu amplification and prognostic factors.”

33. Têtu et al.: Yes to No

The paper reports that HER2 was predictive of treatment resistance: “The difference in survival rates between cases was only significant among patients submitted to adjuvant chemotherapy or hormone therapy."

46. Charpin et al.: Yes to NA

No multivariate analysis

54. Scorilas et al.: No to Yes

Tables 2 and 3 show HER2 overexpression prognostic in multivariate analyses of early relapse and overall survival.

59. Agrup et al.: Yes to NA

No multivariate analysis

67. Jukkola et al.: Yes to No

The abstract reports: "In multivariate regression analysis, only tumour size and nodal involvement were risk factors for poor survival when analysed separately together with c-erbB-2 and receptor status..." 

Section 3.2 states: "In multivariate Cox stepwise regression analysis, tumour size and nodal involvement emerged as independent prognostic factors when analysed separately in combination c-erbB-2, indicating a 2.9 (90% CI 1.9-4.4) risk of death in node-positive patients. For patients with tumour sizes T3 or T4 the risk of death was 2.7 (90% CI 1.4-5.1) and 4.8 (90% CI 2.5-9.5), respectively, c-erbB-2 status did not reach significance in this model, nor when analysed in combination with tumour size, nodal involvement and receptors."

69. Rudolph et al.: Yes to No

HER2 only emerges as prognostic if CR is removed: "When all variables that attained statistical significance in the univariate analysis were included in the multivariate model, the CR was the first and most significant independent indicator of both AOS and DFS (P  .0001; Table 3). Next to CR, only PR status was found to be an independent prognostic factor, albeit of borderline significance."

71. Pinto et al.: Yes to No

HER2 is not independently prognostic: "C-erbB-2 is an independent prognostic indicator when evaluated in conjunction with ploidy and SPF." 

73. Horita et al.: Yes to NA

No multivariate analysis

74. Suo et al.: Yes to No

HER2 is only prognostic when combined with EGFR or HER4. See Table 5. 

76. Rosenthal et al.: No to Yes

A paper on which Ross is senior author found "Multivariate analysis of the combined LN+ and LN− lobular and ductal cases revealed that HER-2/neu amplification (P   0.002), pathologic stage (P < 0.0001), and node positivity (P < 0.0001) were all independent predictors of disease-related death."

78. Spizzo et al.: Yes to No

The paper states: "Multivariate analysis for DROS revealed that nodal status, EpCAM overexpression, tumor size and histological grade were significant prognostic factors. Hormone receptor expression and Her-2/neu overexpression were not significant predictors of DROS. For DFS, nodal status, Ep-CAM overexpression, tumor size and progesterone receptor expression were significant prognostic factors. Her-2/neu overexpression, histologic grade and estrogen receptor expression had no prognostic value for disease-free survival (Table III)."

81. Taucher et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes.

84. Lal et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: "Correlation of HER-2 Status With Estrogen and Progesterone Receptors and Histologic Features in 3,655 Invasive Breast Carcinomas"

85. Huang et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: "Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer"

87. Ariga et al.: Yes to Exclude 

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: "Correlation of Her-2/neu Gene Amplification with Other Prognostic and Predictive Factors in Female Breast Carcinoma"

89. Prati et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: "Histopathologic Characteristics Predicting HER-2/neu Amplification in Breast Cancer"

90. Tanner et al.:Yes to NA

The study does not include a multivariate analysis of HER2 as an independent prognostic factor. In the paper's only multivariate analysis, all the patients were HER2+: 

91. Diallo et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes.

99. Sandri et al. Yes to Exclude

Examines HER2 in serum, as the title suggests: "Serum EGFR and serum HER-2/neu are useful predictive and prognostic markers in metastatic breast cancer patients treated with metronomic chemotherapy"

101. Sunami et al.: Yes to Exclude

Correlates HER2 with other biomarkers not clinical outcomes, as the title suggests: "Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors"

106. Ludovini et al.: Yes to No

Found HER2 by IHC and FISH significant in univariate analysis. But only serum HER2 was found prognostic in the multivariate analysis. (See table 5.) 

More Review Errors Shrink Evidence Base for HER2 Prognostic Role

HER2 is widely, even universally recognized as prognostic of adverse clinical outcomes in breast cancer. However, two review papers supporting this belief contain a remarkable number of errors, raising the question of what evidence now supports a prognostic role for HER2.

Correcting the errors in a 1998 review of 47 studies by Jeffrey Ross and Jonathan Fletcher overturns the review's conclusion that HER2 is independently prognostic. Ross did not dispute the corrections.

The 47 papers and the errors of the 1998 review are included in a 2003 update from Ross et al. The 2003 edition adds 34 more papers and introduces 10 new errors. All told, the 2003 review examined 81 papers and erred on 20. 

I previously documented the mistakes of the 1998 review. There were nine coding errors and two papers that should not have been included in the review. (One of the two papers was also miscoded, but I only count the paper mistaken once, making for 10 total errors rather than 11.)

The 2003 review adds the following 10 new errors:

  • 5 papers coded 'Yes' for multivariate significance should be 'No'
  • 2 papers coded 'Yes' for multivariate significance should be 'NA' 
  • 1 paper should not have been included 
  • 2 papers coded 'No' for multivariate significance should be 'Yes' 

The basis for these conclusions are found in Appendix I below.

Contacted regarding these errors, first author Jeffrey Ross replied that because he was traveling, he didn't "have complete access to review your findings." But, continued Ross: "I have no reason to believe that your conclusions are not correct and that there were scattered errors in the meta-analysis of the published literature in our 2003 manuscript."

The scope and scale of the errors might make both papers candidates for correction or retraction. The Oncologist published both. Executive Editor Martin Murphy did not reply to an email regarding problems with the 1998 review.

------------------

Appendix I

5 papers coded 'Yes' for multivariate significance should be 'No'

1) Jukkola et al. (2001)

The abstract reports: "In multivariate regression analysis, only tumour size and nodal involvement were risk factors for poor survival when analysed separately together with c-erbB-2 and receptor status..." 

Section 3.2 states: "In multivariate Cox stepwise regression analsis, tumour size and nodal involvement emerged as independent prognostic factors when analysed separately in combination c-erbB-2, indicating a 2.9 (90% CI 1.9-4.4) risk of death in node-positive patients. For patients with tumour sizes T3 or T4 the risk of death was 2.7 (90% CI 1.4-5.1) and 4.8 (90% CI 2.5-9.5), respectively, c-erbB-2 status did not reach significance in this model, nor when analysed in combination with tumour size, nodal involvement and receptors."

2) Rudolph et al. (2001)

HER2 only emerges as prognostic if CR is removed: "When all variables that attained statistical significance in the univariate analysis were included in the multivariate model, the CR was the first and most significant independent indicator of both AOS and DFS (P  .0001; Table 3). Next to CR, only PR status was found to be an independent prognostic factor, albeit of borderline significance."

3) Pinto et al. (2001)

HER2 is not independently prognostic: "C-erbB-2 is an independent prognostic indicator when evaluated in conjunction with ploidy and SPF." 

4) Suo et al. (2002)

HER2 is only prognostic when combined with EGFR or HER4. See Table 5. 

5) Spizzo et al. (2002)

The paper states: "Multivariate analysis for DROS revealed that nodal status, EpCAM overexpression, tumor size and histological grade were significant prognostic factors. Hormone receptor expression and Her-2/neu overexpression were not significant predictors of DROS. For DFS, nodal status, Ep-CAM overexpression, tumor size and progesterone receptor expression were significant prognostic factors. Her-2/neu overexpression, histologic grade and estrogen receptor expression had no prognostic value for disease-free survival (Table III)."

2 papers coded 'Yes' for multivariate significance should be 'NA' 

1) Agrup et al. (2000)

No multivariate analysis

2) Horita et al. (2001)

No multivariate analysis

1 paper should not have been included 

Wright et al. (1989) is one of three studies incorporated in Gullick et al. (1991) with the result that the same 185 patients are counted twice. 

2 papers coded 'No' for multivariate significance should be 'Yes' 

1) Scorilas et al. (1999) 

Tables 2 and 3 show HER2 overexpression prognostic in multivariate analyses of early relapse and overall survival.

2) Rosenthal et al. (2002) 

A paper on which Ross is senior author found "Multivariate analysis of the combined LN+ and LN− lobular and ductal cases revealed that HER-2/neu amplification (P   0.002), pathologic stage (P < 0.0001), and node positivity (P < 0.0001) were all independent predictors of disease-related death."

Gavi Board Chair-elect Joins Lazard's Sovereignty Practice the Same Day

Ngozi Okonjo-Iweala, Chair-elect of the Gavi Board (Photo credit: Gavi)

Gavi, the public-private partnership in charge of global immunization efforts, recently announced the unanimous approval of Ngozi Okonjo-Iweala as board chair-elect. The same day, Lazard announced that Okonjo-Iweala, the former finance minister of Nigeria, had joined its sovereignty practice. Recent Lazard clients have included countries receiving Gavi funding, potentially creating a conflict of interest. 

In January, Gavi raised $7.5 billion to be disbursed to developing countries from 2016 through 2020.

Gavi knew of Okonjo-Iweala's Lazard appointment and believes it will not pose a problem. According to Gavi spokesperson, Rob Kelly: "Financial oversight of programmes [is] the responsibility of the Gavi CEO and is managed on a day-to-day basis through teams within the Gavi Secretariat." Potential conflicts of interest, Kelly argues, won't compromise decisions about money because of how Gavi is structured. However, the CEO reports to the board which has ultimate financial oversight of Gavi. The board chaired by Okonjo-Iweala is Gavi's "supreme governing body," according to its statutes.

Lazard’s sovereignty clients include Gavi grant recipients such as the Democratic Republic of Congo, Mauritania, Nicaragua and Ukraine, according to recent regulatory filings. Retaining Lazard, so-called “Banker to the Broke,” might be seen by all Gavi-eligible countries as a way to, for example, win larger grants. Also, Gavi eligibility and criteria for graduating from Gavi support have less obvious but still significant financial implications for many countries in the world. A country paying Lazard might lead directly or indirectly to a financial benefit to Okonjo-Iweala who, at least according to Gavi statutes, exerts considerable influence on Gavi decisions having financial consequences for countries seeking or receiving Gavi support.

In addition, Nigeria was found by Gavi to have misused vaccine grant money while Okonjo-Iweala was finance minister. After a 2014 audit, Gavi demanded repayment of $2.2 million, a figure which may understate the extent of fraud. As much as 87% of the amount audited might have been skimmed off. Okonjo-Iweala's signature, along with that of the health minister, is on Nigeria's status reports to Gavi for 2011, 2012 and 2013, the years examined by the Gavi audit. Gavi has announced a more far-reaching audit and requested that Nigeria conduct a criminal investigation. Okonjo-Iweala might play multiple, conflicting roles in these investigations.

Okonjo-Iweala is also embroiled in an alleged missing $20 billion in missing Nigerian oil revenue. According to Rob Kelly, Gavi was aware of the matter and Okonjo-Iweala "was selected following an intensive and competitive search, which included a thorough due diligence process." Okonjo-Iweala has a reputation as an anti-corruption crusader. In 2012, she published a book on her experience entitled "Reforming the Unreformable: Lessons from Nigeria."

Nigeria has one of the worst immunization systems in the world which Kelly said "didn’t play a role" in Okonjo-Iweala's selection to Gavi board chair. Nigeria's system is so weak that it is difficult to ascertain immunization rates. According to Gavi, Nigeria reported 70% coverage for 2014, but a 2013 house-to-house survey found only 38% of children immunized. 

Prior to the founding of Gavi in 2000, WHO and UNICEF ran global immunization. Gavi originated partly in reaction to the perception that WHO had been debilitated by politically and financially motivated appointments and staffing decisions. In contrast to WHO processes, the most recent selection of Gavi's CEO and board chairs have been tightly controlled. 

The current CEO, Seth Berkeley, won unanimous approval from the board on March 8, 2011. His nomination by the Governance Committee came earlier the same day, again unanimously. Board minutes record one member mentioning that this “short turnaround time” meant there was little opportunity to consult with board constituencies. Both meetings were by teleconference.

Berkeley's selection was actually the work of a four-person subcommittee. Donor nations, who provide most Gavi funding, were placed in a "reference group" outside the four-person subcommittee with actual authority to choose a CEO. The countries Gavi is supposed to serve appear to have had no involvement in selecting the CEO: “Developing country voices need to be part of this process," noted Gavi meeting minutes, "however no volunteers from this constituency emerged." And although Gavi has board seats for developing countries, Gavi chooses who will "represent" those countries. WHO and UNICEF get only 2/3 of a seat each, squeezing in with the World Bank to share two seats total, the same number held by the vaccine industry.

Selection of the last two Gavi board chairs followed a ramrod process similar to the 2010 CEO decision. The Governance Committee appointed a smaller subcommittee. In both 2010 and 2015, this group was chaired by George Wellde Jr., a former partner at Goldman Sachs, and one of nine "unaffiliated individuals" on Gavi's 28-member board. Wellde's subcommittee proposed Ngozi Okonjo-Iwealaa as nominee to the Governance Committee which approved the choice on September 17. The board unanimously approved her selection the next day, September 18th, according to Gavi's Rob Kelly.

The simultaneous announcements about Okonjo-Iweala raises the question of whether Lazard and Gavi coordinated their timing. Gavi has not yet said if the coordination extended to helping facilitate Okonjo-Iweala's joining Lazard. [Update 10/20/2015: Gavi's Rob Kelly says Gavi did not coordinate announcement timing with Lazard nor did Gavi facilitate Okonjo-Iweala's position at Lazard.] 

The Gates Foundation, which started Gavi, and the US representative to Gavi, USAID's Katie Taylor, had not responded to requests for comment by publication time.  

Prognostic Findings for HER2 in Breast Cancer not Reproducible

That HER2 is prognostic of outcome in breast cancer is unquestioned. As Jeffrey Ross at Albany Medical College put it: “Today, no one I know doubts in any way that, in the absence of anti-HER2 therapy, HER2+ breast cancer is an unfavorable subtype and HER2+ status by IHC or FISH is a significant and independent prognostic factor.”

Ross helped shape HER2’s reputation as a particularly aggressive form of breast cancer. In 1998, Ross and co-author Jonathan Fletcher published a review of 47 studies of HER2. Each study was checked for an “impact” on prognosis, either univariate or multivariate. (Appendix C lists the 47 studies.)

Univariate findings can be misleading, often losing significance when multiple factors are taken into account. Regarding the more robust multivariate analyses, Ross and Fletcher reported that 28 (60%) of 47 studies found multivariate impact. The remaining 40% of studies either found no multivariate impact or didn’t conduct a multivariate analysis.

Counted by cases, 10,142 (67%) patients out of 15,248 were in studies found by Ross and Fletcher to have a multivariate impact. Their review concludes: “The preponderance of evidence indicates that HER- 2/neu gene amplification and protein overexpression are associated with an adverse outcome in breast cancer.”

However, the review’s conclusion depends on miscategorizing 9 of the 47 papers examined. Correctly categorizing these 9 studies to reflect their actual findings overturns the conclusion that HER2 is prognostic. The preponderance of evidence is inverted and points to no adverse outcome from HER2 (Table 1). Similarly, the number of cases supporting a prognostic value for HER2 fall from two thirds to less than half (Table 2).

Table 1: Number of studies finding HER2 independently prognostic in multivariate analysis

Table 2: Number of cases in studies finding HER2 independently prognostic in multivariate analysis

Appendix A lists the 9 studies and justification for each recoding.

Ross did not dispute the recodings. Provided with the information in Appendix A and asked if he agreed with the recoding, Ross replied: “I am traveling in Europe and have limited time to review. It is certainly possible that the studies you have cited were not perfectly listed in my manuscript from so many years ago.”

Ross and Fletcher’s review suffers from multiple shortcomings. (Appendix B enumerates important but secondary flaws.) However, the miscoding of papers in Ross and Fletcher’s review is sufficient to overturn the paper’s conclusion.

Conflicts of interest

Investigations of HER2 as a prognostic factor produced contradictory findings and argument—resolved by Ross and Fletcher. Of note, commercial interests played a role in several of the studies they reviewed and the review itself.

Among the 47 papers examined, four [4, 10, 29, 48] list at least one author with a corporate rather than academic affiliation. One abstract [49] includes an author who was then a director of diagnostics at Oncor, maker of a HER2 test. All five studies reported HER2 as prognostic.

In their review, Ross and Fletcher report being consultants for Oncor. However, according to Bloomberg, Ross was Medical Director at Oncor beginning in late 1995 and later Chief Medical Officer when his review with Fletcher was published in 1998. Ross confirmed the accuracy of Bloomberg’s information. The FDA rejected Oncor’s test in 1995 but, as reported in the New York Times, Oncor won approval in 1998.

Conclusion

It is likely true, as Ross stated, that today no one questions that HER2 is prognostic in breast cancer. However, this supreme confidence needs to be recalibrated.

Appendix A: Recoded papers

Of the 47 studies, the nine below were recoded:

[11] (Battifora et al.): Yes to No

The paper reports: "Stepwise Cox Regression: This analysis identified independent prognostic factors of DFS and OS when all variables were considered together. Independent predictors of DFS included stage of disease, histology, and nuclear grade. Nuclear grade and stage were the only significant predictors of OS."

[14] (Lovekin et al.): Yes to No

The paper reports: “Multivariate analysis (Cox, 1972) was used to identify whether c-erbB-2 was of independent prognostic significance. In the context of the temporal variables, tumour size and lymph node stage, cell membrane staining was found to have independent significance as a prognostic factor but significance was lost when histological grade was included in the analysis."

[16] (Dykins et al.): Yes to NA

No multivariate analysis

[20] (Paterson et al.): Yes to No

The paper does not state HER2 is independently prognostic in a multivariate analysis or provide the statistics relevant to such a statement. The authors do suggest possible confounding of prognostic factors: “our study design precluded direct determination of the interrelationships of c-erbB-2 [HER2] amplification with conventional disease parameters.”

[22] (Molina et al.): Yes to NA

No multivariate analysis

[29] (Press et al.): Yes to NA

No multivariate analysis

[31] (Descotes et al.): Yes to NA

As its title states, the paper is a “correlation study between Her-2/neu amplification and prognostic factors.” No disease outcome data are included in the paper.

[34] (Têtu et al.): Yes to No

The paper reports that HER2 was predictive of treatment resistance, not prognostic: “The difference in survival rates between cases was only significant among patients submitted to adjuvant chemotherapy or hormone therapy."

[47] (Charpin et al.): Yes to NA

No multivariate analysis

Appendix B: Additional methodology issues

Inclusion criteria

How the 47 papers reviewed by Ross and Fletcher were selected is not described. In email, Ross wrote that “if you just limit the publications cited to those finding HER2 positive rates between 10 and 30% the prognostic impact of HER2+ status in the pre-anti-HER2 targeted therapy era was profound.”

However the review includes Dittadi et al. [44] which describes a “high risk” group comprising 44% of all cases, well above 30%. Ross and Fletcher count the study as supporting the independent, multivariate prognostic impact of HER2.

Berger et al. [5] and Descotes et al. [31] only examine correlations between biomarkers not with disease outcomes and should not have been included.

Ross and Fletcher included two studies [42, 49] for which there are only abstracts. More generally, the studies included were not graded for quality.

An unknown number of papers were omitted, potentially introducing a selection bias. An omitted paper from Zhou et al. (1989), for example, found no prognostic value for HER2. On the other hand, Wright et al.  (1989) also was not included but found HER2 independently prognostic. Other possible biases in the literature, against publishing, for example, are not examined.

Reviews frequently require a minimum number of cases for a study to be included. Indeed, a number of the papers reviewed by Ross and Fletcher attribute the conflicting results in HER2 studies in part to studies with small numbers of cases.

One study [43] had 37 cases. Ross and Fletcher record it as finding HER2 prognostic in univariate analysis but the paper contains no p values, perhaps because n is so small. O’Malley et al. [41] does not state the number of HER2 positive cases that provided the basis for the conclusion that HER2 was prognostic in multivariate regressions. (The corresponding author did not reply to an email inquiry.)

A 2002 review of prognostic factors in node-negative breast cancer specified inclusion criteria and set a minimum number of cases (200). The paper concluded HER2 is not prognostic.

No quantification of prognostic influence

Ross and Fletcher do not provide summary statistics based on a pooling of results. Heterogeneity of the study designs perhaps made this difficult or impossible. However, if heterogeneity prevented statistical summarization, that would be an important finding to report.

The review includes a table of 18 prognostic factors in breast cancer but makes no comparison of their relative strength and clinical value. The prognostic value of HER2 varied widely. In [18], the p value rested at precisely 0.05. Nodal status and tumor size were vastly more prognostic: p < 0.0001 and p = 0.003 respectively. Quénel et al. [39] found HER2 weakly prognostic: "in our hands, c-erbB2 [HER2] had a poor prognostic value in comparison with the classical prognostic variables…” However, whether such weak prognostic value is general among the papers finding HER2 prognostic is not examined by Ross and Fletcher.

Differences in treatment of cases occur within and between studies but the paper does not control for confounding of prognosis with predicting resistance to treatment.

HER2 positive undefined

Different studies used different definitions of HER2 positive. Even today, the definition of HER2 positive and the search for the best HER2 assay continue to be active areas of study. Ross and Fletcher identify the different assays used in HER2 determination (e.g. IHC, FISH) but cut points are not extracted.

Three studies [4, 20, 30] found amplification of HER2 prognostic. But each used a different cut off for gene copy number: six, three, and seven respectively. A single threshold would likely change the findings of these studies and affect the count of studies finding HER2 prognostic.

Some papers determined cutoffs and comparison groups based on achieving statistical significance. One study [44] found HER2 prognostic by creating a “high risk” group that combined cases with the lowest and the highest expression of p185. The low expression group had the worst outcome. Dittadi et al. go on to conclude p185 was independently prognostic in a multivariate analysis. Slamon et al. [4] simply dropped 23 cases with 2-5 copies of HER2. This remarkably unscientific omission enabled comparing a group with one copy of HER2 to those with six or more, providing the basis for the claim HER2 was independently prognostic in a multivariate analysis.

Negative findings not counted, contradictory findings are

Studies with even a single positive finding were counted by Ross and Fletcher as evidence supporting HER2 as a prognostic factor. The number of negative findings is not reported. For example, O’Reilly et al. [19] found HER2 prognostic for relapse-free survival but not overall survival in node-positive disease. Ross and Fletcher count [19] as one of 28 papers supporting the finding that HER2 is prognostic.

Quénel et al. [39], conducted multivariate analyses for three clinical outcomes for three groups. Among the nine tests in total, HER2 showed prognostic value in two and no prognostic value in seven. Ross and Fletcher count [39] among the papers showing that HER2 is prognostic.

Ross and Fletcher’s design also allows studies with opposing findings to be counted as finding HER2 prognostic.  For example Gusterson et al.  [27] found HER2 prognostic in node-positive but not node-negatives patients. However, Giai et al. [32] found the opposite. The papers contradict each other but both are counted as showing HER2 is prognostic by Ross and Fletcher.

Appendix C: Citations for the 47 studies reviewed by Ross and Fletcher

Footnote numbers are those used by Ross and Fletcher. The same numbers are used throughout this article.

4 Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the Her-2/neu oncogene. Science 1987;235:177-182.

5 Berger MS, Locher GW, Saurer S et al. Correlation of c-erb B2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res 1988;48:1238-1243.

6 van de Vivjer MJ, Peterse JL, Mooi WJ et al. Neu-protein overexpression in breast cancer. N Engl J Med 1988;319:1239-1245.

7 Heintz NH, Leslie KO, Rogers LA et al. Amplification of the c-erb B-2 oncogene in prognosis of breast adenocarcinoma. Arch Pathol Lab Med 1990;114:160-163.

8 Tsuda H, Hirohashi S, Shimosato Y et al. Correlation between histologic grade of malignancy and copy number of c-erbB-2 gene in breast carcinoma. A retrospective analysis of 176 cases. Cancer 1990; 65:1794-1800.

9 Borg A, Tandon AK, Sigurdsson H et al. HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res 1990;50:4332-4337.

10 Paik S, Hazan R, Fisher ER et al. Pathologic findings from the nations’ surgical adjuvant breast and bowel project: prognostic significance of erb B2 protein overexpression in primary breast cancer. J Clin Oncol 1990;8:103-112.

11 Battifora H, Gaffey M, Esteban J et al. Immunohistochemical assay of neu/c-erb B-2 oncogene product in paraffin-embedded tissues in early breast cancer: Retrospective follow-up study of 245 stage I and II cases. Modern Pathol 1991;4:466-474.

12 Kallioniemi OP, Holli K, Visakorpi T et al. Association of Cerb B2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 1991;49:650-655.

13 Clark GM, McGuire WL. Follow-up study of HER-2/neu amplification in primary breast cancer. Cancer Res 1991;51:944-948.

14 Lovekin C, Ellis IO, Locker A et al. C-erb B2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer 1991;63:439-443.

15 McCann AH, DeDervan TA, O’Regan M et al. Prognostic significance of C-erb B2 and estrogen receptor status in human breast cancer. Cancer Res 1991;51:3296-3303.

16 Dykins R, Corbett IP, Henry J et al. Long term survival in breast cancer related to overexpression of the C-erb B2 oncoprotein: an immunohistochemical study using monoclonal antibody NCL-CB11. J Pathol 1991;163:105-110.

17 Rilke F, Colnaghi MI, Cascinelli N et al. Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer 1991;49:44-49.

18 Winstanley J, Cooke T, Murray GD et al. The long term prognostic significance of C-erb B2 in primary breast cancer. Br J Cancer 1991;63:447-450.

19 O’Reilly SM, Barnes DM, Camplejohn RS et al. The relationship between C-erb B2 expression, and s-phase fraction in prognosis in breast cancer. Br J Cancer 1991;63:444-446.

20 Paterson MC, Dietrich KD, Danyluk J et al. Correlation between C-erb B2 amplification and risk of recurrent disease in node-negative breast cancer. Cancer Res 1991;51:556-567.

21 Toikkanen S, Helin H, Isola J et al. Prognostic significance of Her-2 oncoprotein expression in breast cancer: a 30-year follow up. J Clin Oncol 1992;10:1044-1048.

22 Molina R, Ciocca DR, Candon AK et al. Expression of HER-2/neu oncoprotein in breast cancer: a comparison of immunohistochemical and western blot techniques. Anticancer Res 1992;12:1965-1991.

23 Noguchi M, Koyasaki M, Ohta N et al. c-erb B-2 oncoprotein expression versus internal mammary lymph node metastases as additional prognostic factors in patients with axillary lymph node-positive breast cancer. Cancer 1992;69:2953-2960.

24 Allred DC, Clark GM, Tandon AK et al. HER-2/neu nodenegative breast cancer: prognostic significance of overexpression influenced by the presence of in-situ carcinoma. J Clin Oncol 1992;10:599-605.

25 Babiak J, Hugh J, Poppeme S. Significance of c-erb B-2 amplification in DNA aneuploidy. Analysis in 78 patients with node-negative breast cancer. Cancer 1992;70:770-776.

26 Tiwari RK, Borgen PI, Wong GY et al. HER-2/neu amplification and overexpression in primary human breast cancer is associated with early metastasis. Anticancer Res 1992;12:419-426.

27 Gusterson BA, Gelber RD, Goldhirsch A et al. Prognostic importance of C-erb B2 expression in breast cancer. J Clin Oncol 1992;10:1049-1056.

28 Bianchi S, Paglierani M, Zampi G et al. Prognostic significance of C-erb B2 expression in node negative breast cancer. Br J Cancer 1993;67:625-629.

29 Press MF, Pike MC, Chazin VR et al. Her-2/neu expression in node-negative breast cancer: direct tissue quantification by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res 1993;53:4960-4970.

30 Seshadri R, Firgaira FA, Horsfall DJ et al. Clinical significance of Her-2/neu oncogene amplification in primary breast cancer. J Clin Oncol 1993;11:1936-1942.

31 Descotes F, Pavy J-J, Adessi GL. Human breast cancer: correlation study between Her-2/neu amplification and prognostic factors in an unselected population. Anticancer Res 1993;13:119-124.

32 Giai M, Roagna R, Ponzone R et al. Prognostic and predictive relevance of C-erb B2 and ras expression in node-positive and negative breast cancer. Anticancer Res 1994;14:1441-1450.

33 Muss HB, Thor AD, Berry DA et al. Cerb-B2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994;330:1260-1266.

34 Têtu B, Brisson J. Prognostic significance of Her-2/neu oncogene expression in node-positive breast cancer. The influence of the pattern of immunostaining and adjuvant therapy. Cancer 1994;73:2359-2365.

35 Hartmann LC, Ingle JN, Wold LE et al. Prognostic value of CerbB2 overexpression in axillary lymph node-positive breast cancer. Results from a randomized adjuvant treatment protocol. Cancer 1994;74:2956-2963.

36 Jacquemier J, Penault-Llorca P, Viens P et al. Breast cancer response to adjuvant chemotherapy in correlation with erb B2 and p53 expression. Anticancer Res 1994;14:2773-2778.

37 Marks JR, Humphrey PA, Wu K at al. Overexpression of p53 and Her-2/neu proteins as prognostic markers in early stage breast cancer. Ann Surg 1994;219:332-341.

38 Rosen PP, Lesser ML, Arroyo CD et al. Immunohistochemical detection of Her-2/neu expression in patients with axillary lymph node-negative breast carcinoma. A study of epidemiologic risk factors, histologic features and prognosis. Cancer 1995;75:1320-1326.

39 Quénel N, Wafflart J, Bonichon F et al. The prognostic value of c-erbB2 in primary breast carcinomas: a study on 942 cases. Breast Cancer Res Treat 1995;35:283-291.

40 Sundblad AS, Pellicer EM, Ricci L. Carcinoembryonic expression in stages I and II breast cancer; its relationship with clinicopathologic factors. Hum Pathol 1996;27:297-300.

41 O’Malley FP, Saad Z, Kerkvliet N et al. The predictive power of semiquantitative immunohistochemical assessment of p53 and C-erbB2 in lymph node-negative breast cancer. Hum Pathol 1996;27:955-963.

42 Hieken TJ, Mehta RR, Shilkaitis A et al. Her-2/neu and p53 expression in breast cancer: valid prognostic markers when assessed by direct immunoassay, but not by immunochemistry. Proc Annu Meet Am Soc Clin Oncol 1996;15:113a.

43 Xing W-R, Gilchrist KW, Harris CP et al. FISH detection of HER-2/neu oncogene amplification in early onset breast cancer. Breast Cancer Res Treat 1996;39:203-212.

44 Dittadi R, Brazzale A, Pappagallo G et al. ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method. Anticancer Res 1997;17:1245-1247.

45 Fernandez-Acenero MJ, Farina Gonzalez J, Arangoncillo Ballesteros P. Immunohistochemical expression of p53 and c-erbB-2 in breast carcinoma: relation with epidemiologic factors, histologic features and prognosis. Gen Diagn Pathol 1997;142:289-296.

46 Eissa S, Khalifa A, el-Gharib A et al. Multivariate analysis of DNA ploidy, p53, c-erbB-2 proteins, EGFR, and steroid hormone receptors for short-term prognosis in breast cancer. Anticancer Res 1997;17:3091-3097.

47 Charpin C, Garcia S, Bouvier C et al. c-erbB-2 oncoprotein detected by automated quantitative immunocytochemistry in breast carcinomas correlates with patients’ overall and disease-free survival. Br J Cancer 1997;75:1667-1673.

48 Press MJ, Bernstein L, Thomas PA et al. Her-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol 1997;15:2894-2904.

49 Ross JS, Muraca PJ, Jaffe D et al. Multivariate analysis of prognostic factors in lymph node negative breast cancer. Mod Pathol 1998;11:26a.

50 Depowski PL, Brien TP, Sheehan CE et al. Prognostic significance of p34cdc2 cyclin dependent kinase and MIB1 overexpression, and HER-2/neu gene amplification detected by fluorescence in-situ hybridization in breast cancer. Mod Pathol 1998;11:18A. 

Academia and advocacy conflict on economics of malaria eradication

[Please see the clarification at the end of this article.]

Don’t ask where the numbers came from, but beating malaria is a great way to make $4 trillion dollars.

In July, the Rollback Malaria initiative rolled out its “exceptional case” for investment in eliminating malaria, a plan promising a 40:1 return on investment (ROI), rising to 60:1 in sub-Saharan Africa.  Malaria elimination will purportedly bring a multi-trillion dollar windfall: $700 billion within a few short years (by 2020), growing to an impressive $4.1 trillion by 2030.

(Source: Rollback Malaria, Action and Investment to defeat Malaria 2016-2030)

However previous research, also conducted by advocates for malaria elimination, found insufficient basis for using financial benefits to justify the costs of fighting malaria.

Rollback Malaria (RBM) would not explain how it arrived at its inviting rates of return, declining to provide a spreadsheet. “The Excel sheet has data from all countries that was modelled up to give the global costs so it isn’t terribly helpful,” said Helen Prytherch of the University of Basel. Prytherch would not send the spreadsheet and suggested talking with the lead economist instead.

The process of peer review prevented bringing forth the details of the estimate. “We are working on your request,” said Prytherch, who continued:

“Several scientists from different institutions worked over a two-year period to establish the new malaria targets, cost them and then to establish and implement a cost benefit analysis. They are now preparing scientific papers to get the work into the public domain. They should be ready for submission by end September.”

However, in 2010, a consortium of pro-elimination researchers concluded that "policy makers should not view the generation of substantial short-term or medium-term cost-savings as a rationale for elimination until more robust evidence is available to suggest otherwise."

Investigators at the University California at San Francisco (UCSF) subsequently sought but did not find robust evidence of cost saving. Findings from ten case studies “do not change the conclusion” that cost should not be viewed as rationale for elimination, according UCSF’s Rima Shretta. Shretta said “malaria elimination should not be pursued merely on the grounds of cost-savings as these often fail to capture all the externalities garnered by disease elimination.”

Of RBM’s plan, Shretta says “it is an advocacy document rather than an academic analysis.” RBM’s macroeconomic analysis “was done using published data rather than an empirical analysis.” In the reinterpretation of existing results, RBM “used a full-income approach which produced larger benefits than some other approaches.” Several previous studies “have not been able to do this using short term projections,” according to Shretta.

Either malaria advocacy is going to depart from established academic research, or the academic consensus might be about to change. “I think if an academic analysis supports elimination – great,” said Shretta. Rather than argue against such an analysis, Shretta seems to have adapted to its inevitability: “the benefits are often underestimated so [elimination] should not ONLY be based on an economic argument but ALSO a social, development and moral perspective.”

On the present trajectory, science will soon give its blessing to malaria eradication being wildly profitable in addition to its other virtues.

Clarification

Posted August 26, 2015

Since publication of this article, Rima Shretta disclosed to me her membership in the task force for Action and Investment to defeat Malaria (AIM). AIM produced the estimate of $4.1 trillion of economic benefits to be gained from malaria elimination examined in my article. Shretta would not explain why she did not inform me of this critical fact. However, it is the responsibility of the journalist to establish the independence of an observer and I regret that I failed in this regard.

Shretta disputes multiple aspects of the article. Prior to disclosing her involvement in AIM, Shretta requested a correction to the article:

I believe my opinion has been mis-represented. I do not dispute the analysis in AIM. I also have not adapted to its inevitability. The statement below is incorrect:

"Rather than argue against such an analysis, Shretta seems to have adapted to its inevitability"

We strongly believe in the case for elimination and its returns - financial and otherwise. In my opinion often the analysis does not make the case strong enough because of the other factors that cannot be measured well.

I responded in part:

I asked Richard Feachem if there was new evidence on the matter of costs and benefits. He referred me to you. You stated there was no new evidence to change the conclusion of the 2010 [Lancet] paper.

So something has to give. There is a $4 trillion discrepancy. 

Shretta, now stating she was on the AIM task force, then requested multiple changes to the article, including re-working or deleting all quotations except one. She wrote in email: “I am fine with the statement that ‘malaria elimination should not be pursued merely on the grounds of cost-savings as these often fail to capture all the externalities garnered by disease elimination.’ “ However, “the rest of the quotes are out of context…”

Shretta did not reply to a question regarding her involvement with AIM. However, I withdraw the statement that Shretta adapted to the inevitability of the AIM document.

Post-publication, regarding the key question of reconciling the Lancet paper with AIM, Shretta wrote: “The Lancet paper warned on rationalizing elimination based on a financial argument alone.” Arguably, this is a considerable misinterpretation. The Lancet paper warned that short- and medium- term economic benefits cannot be part of an argument for elimination, whether alone or in conjunction with any other arguments.

Shretta’s penultimate communication states:

The AIM is based on country level data on malaria disease and a transmission model that forecasts the disease over time. This was then costed out. The analysis on the benefits is from published data. We at UCSF do not dispute the findings of AIM.

One less apocalypse: Questioning the spread of drug-resistant malaria

Drug resistance has twice started in Southeast Asia, both times leading to massive epidemics of untreatable malaria in Africa. Only the introduction of artemisinin combination therapy earlier this century beat back the most recent wave of drug resistance. Now artemisinin is buckling, leading to understandable worry about yet another resistance apocalypse. But current scientific evidence contradicts the narrative of doom voiced by journalists (including me) and much of the malaria research community.

Artemisinin resistance has barely spread but instead popped up on its own, evolving independently in areas scattered across Southeast Asia. The effort to “contain” resistance by wiping out malaria in the region will not prevent independent emergence in Sub-Saharan Africa where home-grown resistance could develop undetected by today’s weak surveillance system.

Artemisinin resistant malaria results from changes to a complicated genetic network that will be difficult to infiltrate into other parasite populations without it coming apart. However, elimination efforts Southeast Asia both strengthen resistance and streamline its genetics for easier transmission abroad, fomenting the very apocalypse it supposedly seeks to avoid.

Not spreading even in Southeast Asia

Drug resistant malaria is scarcely spreading at all in Southeast Asia, even within national borders. The most comprehensive survey found only three instances of spread out of 112 samples from across the region. Parasites thought to have originated in Cambodia were found in people tested near the border with Vietnam. “All other mutations appear to have arisen independently,” scientists concluded. Other researchers concur that resistance “is primarily due to the proliferation of newly emerging mutations…” Rather than spreading, most instances of resistance “appear to be localized to a relatively small geographical area…”

A paper on resistance in Myanmar includes the word “spread” in its title but adduces little evidence and no claims for it. Scientists found “strong evidence” of resistance in Myanmar “including regions close to the Indian border in the northwest,” a worry because past drug resistance is thought to have spread first to India before leaping to Africa. However, resistance is not spreading, according to the authors, rather it “extends” across Myanmar. Seven individual mutations appear “to have arisen independently” more than once, pointing not to spread but de novo emergence.

Resistance has not spread to Myanmar: “Contrary to the widely assumed scenario,” concluded another research group, “we found no evidence of westward spread of artemisinin resistance from Cambodia to Myanmar.” So far in Laos and Bangladesh, mutations associated with resistance are “absent or found at much lower frequency,” additional evidence against regional spread.

Sizable population movements within and between countries seemingly ought to create an equivalent dispersion of resistance. Why that hasn’t happened is “a very good question,” said Philippe Guyant, co-author of a paper on malaria and migrant workers in Cambodia. “I don’t think there is a definitive answer to it given the current state of knowledge.”

But the domino theory of spreading resistance, although widely-discussed and deeply worrisome, is not supported by current scientific evidence which shows that drug-resistant malaria is scarcely spreading even within Southeast Asia.

Genetic complexity militates against spread

Conclusive evidence of artemisinin resistance emerged in 2008, but the complexity of the underlying genetics frustrated efforts to find a molecular marker until 2014 when mutations in a gene called Kelch 13 (K13) were finally implicated.

K13 mutations appear necessary but not sufficient for resistance; supporting mutations appear to be needed. Scientists inserted resistance-associated K13 mutations into parasites susceptible to artemisinin. Modified parasites originally from Cambodia showed a greater increase in resistance than other genetically altered lines, “suggesting a role for additional parasite factors in augmenting K13-mediated resistance…” Four other genes have been connected with resistance in Southeast Asia. In two African samples, scientists found the supporting mutations “were rare or absent… suggesting that they are the product of evolutionary selection within Southeast Asia.” In Southeast Asia, the K13 mutations appeared only after the supporting cast was in place.

Right now, artemisinin resistance in Southeast Asia is tightly bound to an interconnected set of genetic changes particular to its evolutionary history, a history that differs greatly from much of Africa—although not all.

For artemisinin resistance to spread to Africa it will have to overrun incumbent populations. However, the delicate architecture of resistance—multiple mutations riding several different chromosomes—is likely to be pulled apart by the sexual recombination of malaria parasites. Years ago, malaria dragged down the combination drug sulfadoxine-pyrimethamine by incrementally accumulating changes. By contrast, a mutation to K13 seems to need simultaneous changes elsewhere in the genome to balance fitness costs, compete with other parasites or both.

According to Olivo Miotto, co-author of a paper on the genetic architecture of artemisinin-resistance:

“The fact that the main Kelch 13 mutations emerge only on a certain genetic background suggests that there is something special about those parasites. Perhaps it is this ‘something special’ (associated with the genetic background we have identified) that needs to spread in Africa before Kelch 13… I’m pretty sure that Kelch 13 mutations alone will not be enough.”

Another obstacle to the spread of resistance to Africa is far lower drug pressure there. Malaria in Southeast Asia is less intense, so people generally do not acquire immunity and fall ill when infected. The sick seek and receive treatment at very high rates, piling on drug pressure. By contrast, “Right now, only a portion of African parasites get exposure to the drug,” observed Miotto. In much of Sub-Saharan Africa, more intense malaria means greater natural immunity, leading to a greater number of infections that cause no sickness. The unsick seek no treatment. If parasites aren’t exposed to the drug, resistance to artemisinin confers no fitness advantage and will be swept from the genome.

Unknown unknowns

However, much remains unknown and possible parallels with the past are cause for concern. Although artemisinin resistance appears to rely on more than K13 mutations, according to Miotto, chloroquine resistance, early in its development, also might have needed more than one mutation. For chloroquine, “the key marker was identified, but the story may still be incomplete—don’t confuse that with it being simple… We could only study the aftermath,” which pointed to a mutation in one gene. According to Miotto, malaria could yet produce a single K13 mutation that prevails against artemisinin.

Chris Plowe at the University Maryland concurred: “What is happening now with artemisinin resistance may not be all that different from what happened with chloroquine, sulfadoxine and pyrimethamine resistance in the past. We are just witnessing it in real time with a lot more data.”

Continuing research might find more evidence for spread. According to Shannon Takala-Harrison at the University of Maryland, with increasing numbers of samples, “we are seeing additional evidence for spread as well as independent emergence of mutations.” She looked forward to discussing “more concrete results and conclusions as they become available.”

At this particular time, however, there is astonishingly little evidence of spread and sizable genetic and environmental obstacles working against it.

Policy discomfited by evidence

The current policy of elimination fits somewhat awkwardly with current evidence. If artemisinin resistance mostly emerges independently, increased surveillance in Africa rather than containment in Southeast Asia might be more sensible. But according to Patrick Kachur, head of the malaria branch at the Centers for Disease Control (CDC), eliminating all malaria in Southeast Asia makes good sense: “I think the threat of artemisinin-resistance spreading to Africa is a compelling reason why global malaria advocates should be interested in eliminating malaria in Southeast Asia.” Also, countries in the region have their own, additional reasons for wanting to be completely free of malaria, according to Kachur.

Elimination has been “a moderately effective advocacy message,” Kachur said. It is one the malaria research community seems loathe to change even though science does not clearly support it. Neither Kachur nor Plowe responded to emails asking them to contradict the hypothesis that drug-resistant malaria is not actually spreading. Emails to the Gates Foundation also received no answer.

The narrative of doom obscures an all-too rare bright spot in malaria and global health: the pipeline for new antimalarial drugs is incredibly robust. Although grim headlines say, for example, “No 'plan C' drugs available,” multiple new candidate drugs and entire new drug classes have been discovered largely under the umbrella of the Medicines for Malaria Venture, a public-private partnership started by the Gates Foundation.

However, Bill Gates adds his voice to the apocalypse chorus. In a YouTube video, Gates described the possible spread of resistance as “the biggest disaster for control ever.”

Next Gates says: “We’re trying to figure out if we can do local eradications.” But if resistance, rather than eradication, were the primary concern, elimination is no longer automatically the right strategy.

“Drug resistance is driven by drugs,” as Olivo Miotto put it. Elimination maximizes drug resistance, making it stronger and more heritable as drug pressure reshapes and streamlines the initially complex genetics of resistance. This is “the core question” for Miotto. “Drug resistance doesn’t come from heaven; we create it, we encourage it.” He called for better models “to predict the outcome of intervention as we move forward,” saying “responsible approaches to deploying drugs are key.”

Nonetheless, CDC’s Kachur said “enthusiasm is high among global and subregional malaria subject matter experts” for elimination.  Chris Plowe argues that “What the independent emergences tell us is that containment is not likely to work, so by eliminating we can at least try to prevent the most fit, viable and dangerous forms from spreading.” However, elimination propels greater fitness, viability and more dangerous forms that are more likely to spread.  Per the title of a 2009 paper about eliminating artemisinin-resistant malaria in Cambodia, “The last man standing is the most resistant.”

Mathematical models show elimination is unlikely to work. Gates Foundation-funded researchers found that extinguishing malaria was not possible in many places, including in Southeast Asia: “Prospects for elimination in Myanmar and southern Thailand do not appear to be favorable.” Myanmar, recently announced the goal of eliminating malaria.

In another study, “An optimal control strategy to reduce the spread of malaria resistance,” even models using both mass drug administration and insecticide measures fail to completely get rid of drug-resistant malaria. “We think from our models that it is true it is not possible to eliminate drug resistant malaria just using mass drug administration and insecticide,” confirmed co-author Fatmawati Armawi of the Universitas Airlangga.

With elimination exacerbating resistance, evidence-driven policy would seem to suggest reducing drug pressure in Southeast Asia and intensifying surveillance in Africa. The edges of the malaria belt in Africa have low transmission like Southeast Asia. In addition, countries that have advanced toward malaria elimination also have low transmission coupled at times with high drug pressure. According to Miotto, “These should probably be our ‘sentinels’ ” for artemisinin resistance in Africa.

At present, however, malaria science and malaria advocacy appear to have separated.