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Tuesday, July 23, 2013

AllTrials vs PhRMA

The AllTrials campaign asks for all trials to be registered and their results published. Ben Goldacre says we need the evidence to make informed decisions about medicines. John Castellani says mandatory disclosure could affect patient privacy, stifle discovery, and allow competitors or unscrupulous actors to use the information.
There is a very interesting battle taking place between AllTrials and  PhRMA.

PhRMA Mission Statement:

PhRMA's mission is to conduct effective advocacy for public policies that encourage discovery of important new medicines for patients by pharmaceutical and biotechnology research companies. To accomplish this mission, PhRMA is dedicated to achieving these goals in Washington, the states and the world:

  • Broad patient access to safe and effective medicines through a free market, without price controls;
  • Strong intellectual property incentives;
  • And transparent, effective regulation and a free flow of information to patients.

It's time all clinical trial results are reported.
Patients, researchers, pharmacists, doctors and regulators everywhere will benefit from publication of clinical trial results. Wherever you are in the world please sign the petition:
Thousands of clinical trials have not reported their results; some have not even been registered.
Information on what was done and what was found in these trials could be lost forever to doctors and researchers, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated.
All trials past and present should be registered, and the full methods and the results reported.
We call on governments, regulators and research bodies to implement measures to achieve this.

AllTrials logo
The Cargo Cult Scientist is pretty transparent with opinions on the honesty of the pharmaceutical industry. I think we need help being honest. It's not that we're bad people, just that we are in bad situations. Specific outcomes make or break our careers. We have an incentive to highlight the good and hide the bad. In science however, we have to leave our hopes and dreams at the door. What we perceive as good and bad should not effect our judgement. The problem is that we are all human beings. The solution is transparency. 
If you've made up your mind to test a theory, or you want to explain some idea, you should always decide to publish it whichever way it comes out. If we only publish results of a certain kind, we can make the argument look good. We must publish both kinds of results. - R. Feynman 

Thursday, July 18, 2013

There's No Business Like Science Business

It didn't work. I only got four hits in a day. Perhaps the words Trayvon Martin and George Zimmerman are saturated on the internet. It was just a test.

I mentioned The Bonfire of the Vanities. A real life tragic human situation became became useful to powerful people. The whole story becomes a screenplay to the powerful people. They, like Hollywood producers and directors, began to rewrite and tweak the script to fit their careers. Al Sharpton, for example, turned the Trayvon Martin Story into yet another case that requires one of his world famous protest marches. Lesser players, wanting to brand themselves as the next Al Sharpton, took the script and wrote themselves in as the civil rights leader in the scenes following the verdict.

The case is not unlike the world of science. Leaders often go astray for years but find new hope in a new screenplay. How many old scientists became RNAi experts? A producer or director in Hollywood becomes successful by making movies that make money. It's "Show Business". The same goes for science. It's "Science Business". The RNAi story, real or not, was a script that anyone could sell.

When selecting a screenplay to produce and direct, a scientist must look at the ones that will get published by the best journals. Here is what the journal Science has to say about what they will publish:

Science's Mission: Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit the recognition by the scientific community and general public provided by publication in Science, beyond that provided by specialty journals.

Ones adherence to the truth, and the ability for others to reproduce your work, is not mentioned in Science's Mission. Your screenplay need only influence, be novel, seem important and merit recognition. The skill of the new scientist is to select the topic of their career. In most cases however, the scientist does not get to select his/her topic. It is given to them by the person with the money. That person has already selected the topic/screenplay. The new PhD is then brought in as an expert witness. What happens next is very creative. The simple FACS data, western blots and ELISAs come to life and tell the story. 

Great science and art begins where our hopes and dreams leave off. The hopes and dreams of the journal Science is that all of their articles are influential, novel and will advance scientific understanding. It is thus, up to the current editors to select that caliber of screenplay. It is a scary job to tackle. Lets see what can go wrong.

Vitaly Komar and Alexander Melamid were two artists who took a scientific approach to creating the best painting ever. They began with an extensive poll of peoples art preferences. Subjects were asked if they preferred interior or landscape scenes, what kind of animals they liked, favorite colors, what kinds of people and so forth. Taking the aggregate results, the artists produced this painting.

Hilarious. The painting is called America's Most Wanted. This is what the people wanted, according to the survey.

What the journal "Science" (and the others) want, is like this. The journal tells you in advance what they expect. You take their expectations and write your story. You pitch the story, first, in your own mind. What kind of experiments and results do they want from me? How about some Resverotrol making old mice appear more youthful! Maybe RNAi knocking out TNF alpha! You design experiments to provide results like the elements in this painting. George Washington, pretty kids, deer, a nice lake, some mountains... You put them all together and you have provided the customer with what they asked for. You have written the screenplay that people want. It is Science Business 101.

What people outside of science do not know is that most of what gets published is to science what America's Most Wanted is to art. But science is abstract. It is complicated and complex. It is not easy to separate the good from the bad, especially when you are dealing with an accomplished writer. They know what the "best story" is, and exactly where to place it on their canvas.

In the end, our leaders do not have much of an impact on the real world. Al Sharpton will not change racial attitudes. David Sinclair will not make Resveratrol into the fountain of youth in a pill. They will however, remain at the top of their game until a better story comes along.

Sunday, July 14, 2013

George Zimmerman and Trayvon Martin

It is clear that certain topics elicit a massive amount of reads and comments. The Huffington Post kept the George Zimmerman / Trayvon Martin verdict as their headliner for over 12 hours. I may be wrong but I think they set a record for the most comments from this story. There were close to 100,000 comments last time I checked. Everyone has something to say about George Zimmerman and Trayvon Martin.

My only goal for this post is to see how many people click on my blog. I will add this link to homicides in Los Angeles, Jan 1, 2007 to July 10, 2013. It is disturbing.

What we are witnessing is a story that was told in The Bonfire of the Vanities.

Friday, July 12, 2013

Scientific Myth

But it's not clear that a direct effort to "build community" will work in the absence of common ideals or values for which individuals are willing to sacrifice. Athenian citizens, for example, had to swear an oath to uphold "the ideals and sacred things of the city." The most common use of the word "sacred" in our public life is in relation to "cow." For the most part, we treat each other not as citizens but as consumers. 
John Stuart Mill said something about happiness that applies to this notion of building community. He said that happiness is the test of all rules of conduct and the end of life; but he also said that this end--happiness--is only attained by not making it the direct end. The same can be said of community. Community is not a direct end, but arises as a kind of by-product when people are working for common ideals that are larger than themselves--such as "the ideals and sacred things of the city. 
- Betty Sue Flowers - The American Dream and the Economic Myth
The same can be said of the scientific community. A cure or a new paradigm for improving health is not a direct end but arises as a by-product when scientists pursue the truth. I want to highlight a few concepts from this essay, as they pertain to Cargo Cult Science.

Direct End Research - Quest For The Cargo

Here is an example of the problems one encounters when seeking a "direct end".  "The Death of a Drug Class Shows Difficulty of Using Gene Data to Design Drugs"The "direct end" is diabetes. Scientists found a correlation between mutations on the PPAR gamma gene and an increased risk for diabetes. An intervention on PPAR activity was designed with the hopes and dreams of altering the "direct end". They took a shot and exacerbated the direct end!

Why call it quits? Is there nothing to be learned from all of this "science"? Wouldn't it be interesting to be put on a project to explain how this drug target brought about an opposite direct end? The current view is that there is no money in explaining what happened. Yet a by-product of this project could be a greater understanding of cardiovascular health. It could lead to a greater understanding of gene "mutations" and their consequences.

How Tall Is Your Building?
The mythologist Joseph Campbell used to say that you could always tell what the dominant myth of a culture was by looking at its tallest buildings. In medieval times, the tallest buildings in any city were the cathedrals; later, princely palaces and government buildings dominated the landscape; now the tallest buildings are commercial, reflecting the economic myth within which we now live.
I once went in for a job interview at the now defunct Targeted Genetics, a gene therapy company. 1100 Olive Way, Suite 100 downtown Seattle. I got to the building and looked up at the towering structure surrounded in glass. The men entering the building were dressed in suits and ties, the women in dresses looking fine. "Finally," I thought, "a work space worthy of a scientist." I went inside, "Targeted Genetics 17th floor. "Wait a minute, suite 100? This can't be." I went back outside. There to the west was an old one story building with the number 1100 above the door. People dressed in jeans and t-shirts were coming and going. Alas, the laboratories were here. The people on the 17th story of 1110 (not 1100) Olive Way had a different function. They handled the money, the narrative, the legal issues and investor relations.

The Economic Myth / Good Science = Good Money
American culture knows the price of everything and the value of nothing.
The economic myth honors quantity over quality.
If you were a Martian who speaks English and you came to this planet to study our understanding of the life forms that exist on planet earth, you may wonder why earthlings have placed a financial value on science. Publicly traded companies see their stock price going up and down based upon stories. Sometimes a patient will die during a clinical trial. Sometimes the CEO will be sent to jail for insider trading. The real value of a science based company, to a Martian, may be in their grasp of what is true and what is false. Each company boasts of their techology. Alnylam, for example, "is focused on developing a new class of innovative medicines with the potential to revolutionize the treatment of human disease by harnessing a powerful and natural biological mechanism known as RNA interference." Yet laying off the scientific staff boosts the stock price. Leaving only a product, and not an ongoing harnessing of RNAi potential increases the company value. 

The real value of a biotech/pharma company is in the lead product/s and the ability of key players to get approval, make sales, and not get caught cheating. The quality of the science and technology (the community of scientists and their rules of conduct) that produced the product takes a back seat the the potential quantity of money involved in future sales.  

The Loss of Self Worth to Scientists
In addition to a loss of the values embodied in our earlier myths, there is a danger for the society dominated by the economic myth that its citizens can lose their sense of a larger significance--or even of significance on an individual level. 
The thousands and thousands of highly educated people have gone through the system of scientific employment at biotech/pharma companies. When people lose their jobs we all think, in the back of our minds, that we/they were not good enough. We were hired to fill up the pipelines, yet they are drying up. The direct end, the reason we were hired, is often not accomplished. We are hired to fill up the journals with new exciting avenues for ourselves and others to pursue. Yet we are a community that lives in fear of job loss. We live in fear that the results from our experiments will not match up to the hoped for direct end. Our self worth is tied to understanding the things in nature that make others wealthy.

Our community is deteriorating. Those Athenian citizens, who swore an oath to uphold "the ideals and sacred things of the city" were different than us. We don't slow it down and talk much about our ideals and sacred things. We have deadlines and money to make. So much that much of what passes for science is purely mythological story telling. How do we tell science from Cargo Cult Science in this age of increasing deception? Start a conversation. Here is a good one. 

Our journals offer up depictions of scientific work. But do they speak for the entire community of scientists? Do they protect the truth in nature as "our ideals and sacred things"?

Tuesday, July 09, 2013


The number one argument in favor of working towards reproducible science is the "The Drunk Under the Streetlamp". "The Drunk Under the Streetlamp"looks for his keys where the lighting is good. His friends threw his keys in the ditch far from the light so he wouldn't find them and drive home drunk. His mind is not clear so instead of hailing a cab he looks for the keys under a streetlamp. Non-reproducible narratives work in this manner. Non-reproducible narratives will never get the job done. Why do we allow them to predominate the journals? Because they are easier to work with, just as it is easier to see under a streetlamp. Just ask Diederik Stapel! But they are not science. Science works. Science is powerful. When you work on non-reproducible narratives, "the best story", you are not conducting science. We know the current system of publication does not involve the scientific method. The scientific method is too hard. It would be too expensive to bring about reproducible work. Lets take a look a few arguments in favor of the current system.

The first set of arguments comes from yesterdays Retraction Watch comment section. The article was about creating a reproducibility index (RI).
Rather than rate journals on how often their articles are cited by other researchers, let’s grade them on how well those papers stand the most important test of science: namely, does the work stand up to scrutiny?
Seems reasonable. Hold the journals feet to the fire and let them know that we are going to test the research on which they are putting their stamp of approval.  They judge the scientists without using the scientific method. Why not judge them? Not for spite but as a professional courtesy to other researchers trying to use their journal to do work. The first argument against RI:
Reproducibility would take years to achieve, depending on the discipline. It could be one measure to enforce quality control, but it wouldn’t work accross the board. For example, it would be rare to find any group who would be willing to repeat 3-5 season/year agronomic experiments. - Jaime A. Teixeira da Silva
It would take too long. True, those who are the fastest get the rewards. But how is that working out for us? The drunk under the streetlamp, looking for his keys that he knows he lost in the darkened ditch, because the lighting is better, also feels he has a limited amount of time.

Discounting the huge resources necessary to establish a ranking system for which bits of data matter, and which conclusions do not, the whole issue of reproducibility is a hot potato that no publisher’s legal division will want to touch. I foresee litigation in which an author sues a journal for defamation because they down-ranked a paper based on inability to reproduce, when actually the experiment was perfectly sound and the “reproducers” were just not paying attention to experimental details. - Paul Brookes
I will first discount the "huge resources" because we already spend huge resources conducting mostly non-reproducible science. The solution to legal issues is a simple waiver. You waive the right to sue based on the (RI) which is not dictated over by the journal. It is an index that rates reproducibility. If you are trying to publish bad science, you should expect a low rating. If you think the (RI) will hurt your career, be very careful in what you put out into the world. People are watching. You can't just sue a journal because no one else can reproduce your work. But let the lawyers work out those details on protecting journals.
...the idea that journals will somehow willingly accept manuscripts that conflict with established results or confirm what is already known is laughable. 
That is the current situation that people are trying to change. Conflicting with "established results" is what sets science apart from other human endeavors. That is how we "self correct". And yes, even scientists have to fight against "established results" that are not true. In time, the truth will prevail. Think of the (RI) as an index that will make the journals less resistant towards challenging things we know, that aren't so.

Of course the biggest road block here is curating such an index because it’d probably require a lot of reading (or a genius to write an accurate text reading algorithm…key word being accurate).
Again, it's too hard. Too hard because it would require a lot of reading? Why not read a lot? Why not work towards a world where "a lot of reading" is done and reproducibility of what is read is part of what scientists do? It would actually create more work for scientists. Perhaps reproducibility studies could one day employ the minds that would otherwise go to waste looking for jobs at Pfizer running the HPLC department.

In our current system we have plenty of proverbial drunks looking for their keys under a streetlamp. You can spend all night looking. You can put on your glasses and break out a metal detector, but you are not going to find the keys. They are in the ditch where the lighting is not so good. The amount of people defending this foolish system, this system of taking the easy route, maintaining the status quo, works against future generations of scientists. But in 100 years there will be a different system. The truth has a way of making itself known whenever real science is lurking. I can see it now. Real science is making people think about the problems with reproducibility in the year 2013. The current leadership doesn't want a change but real science is lurking. A change is coming, like it or not. You may laugh at those who are fighting for the change but put yourself in historical context. Change does not come easily. If you think reproducibility is not worth fighting for, you are standing in the way. You are now the Nattering Nabob of Negativity. Get out of the way and let this experiment begin.

Stewart Lyman made his arguments against The Reproducibility Initiative back in 2012. Why won't it work? Money, Ego, Time and Science. His argument on Science begins:

Some types of data are easy to replicate, whereas others are much more difficult to reproduce. Cutting-edge experiments may be harder to replicate than “average” data, because, as one of my profs used to tell me “if it was easy, someone else would have already done it”. If you’ve worked in a lab for any length of time, you know that when trying to reproduce someone else’s results, the devil is in the details. 

Science can be hard. The devil is in the details. That is why the Reproducibility Initiative and Index, PloS ONE, and all of the other efforts to clean up this mess, should be considered scientific pursuits. If it was easy, someone else would have already done it. The lack of money and time are the weapons of egotistical scientists who always seem to have more money. They always seem to get results faster than others. They are winning but real science is lurking in the background. Real science is hard. It takes time and plenty of money. But it's worth it. Bad science is not worth fighting for.

Friday, July 05, 2013

Diederik Stapel Lessons in Honesty

Stapel did not deny that his deceit was driven by ambition. But it was more complicated than that, he told me. He insisted that he loved social psychology but had been frustrated by the messiness of experimental data, which rarely led to clear conclusions. His lifelong obsession with elegance and order, he said, led him to concoct sexy results that journals found attractive. “It was a quest for aesthetics, for beauty — instead of the truth,” he said. 
If you agree with Diederik Stapel that you will someday have to make the choice between beauty or the truth, you may be a Cargo Cult Scientist. Diederik, the former Tilburg University psychology professor is also a former PhD. He voluntarily gave up the PhD. He also retracted 53 papers because he fabricated the data. He'll do some community service and give up some government support as punishment. He's also lost his career. We don't feel bad about that. We like his counter-human; R. Feynman.
In physics the truth is rarely perfectly clear, and that is certainly universally the case in human affairs. Hence, what is not surrounded by uncertainty cannot be the truth.
The truth is beautiful. Take this question. Sally gets a degree in "Female Studies" from Oberlin U. She marries her girlfriend and sets out to start her professional life. What is more likely? A) She becomes a banker. B) She becomes a banker and an advocate for gay marriage? The answer is A because B is A with an additional condition. Sally becoming an advocate for gay marriage is more likely than her becoming a banker, but that is not the question. The truth is beautiful here. Once you hear the logic you start to think. It doesn't matter who Sally is or what she does for a living. She could have been a Young Republican who became a advocate for gay marriage and then a banker. You can change the words but you can't change the logic. That is what draws some people to science.

I have asked this question to friends and family. Not all agree with the answer. The arguments against B being the answer, are not beautiful. The individuals who make the arguments often times get tripped up in faulty logic. They use more words than those used to describe the simple truth. It gets ugly.

Once again let's revisit the Amgen study:

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies. 
"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."
See any similarities between Diederik Stapel and the scientist who got away with his crime of telling "the best story"? A true scientists keeps looking for the truth and the beauty. Diederik and the lead scientist from The Amgen Story decided on what they consider to be more beautiful. Notice how few benefit from their dishonesty. Notice that those who do benefit always benefit from the status quo and beautiful stories. Those with the power over publication, be it in an oncology journal or a social psychology journal, prefer pretty stories. They do not see beauty and the truth co-existing.

Imagine stripping away the words to the point where you are just looking at the logic. There is the beauty. A is more likely than A plus B. Boil down your biases and see the truth as beauty.

Monday, July 01, 2013

GSKs Honesty Tour Rolls Into China

I mentioned here that GSK has a history of dishonesty. They obscured safety data on Avandia that put their patients at risk. They produce an antidepressant that spawns a book called "Side Effect", A Prosecutor, A Whistleblower, and A Best Selling Antidepressant on Trial. They pay three billion dollar fines from sales and marketing practices from the asthma drug Advair and other drugs. In this post I asked the question, "What kind of an evil organization are we dealing with here?"

China Probes Staff of GlaxoSmithKline After Corruption Claims Aired 
Corruption is rampant in China’s health system, according to industry insiders. Public hospital budgets depend on commissions from the sale of medicines and doctors’ low salaries are supplemented by payments from patients and kickbacks from equipment and drug suppliers.  
Corruption is rampant in GSKs sales and marketing department. We've established that fact with the $3 billion fine. Some things never change.

The whistleblower’s allegations, according to The Wall Street Journal, which broke the story, included claims about fees paid to doctors, both in kind and cash, and all-expense trips. The quid pro quo was prescription of Glaxo-supplied drugs. 
Who are the men and women behind the curtains that make The Great Wizard of GSK such a dishonest entity? While I think it would be a good idea to put them in jail and air their names so the consumers know who the bad guys are, I fear that the rest of the industry giants will end up standing at the prison gates when these guys get out of jail. They'll shuffle them off in limousines to corner offices in tall buildings throughout the world to seek new grifts.