Monday, 17 July 2017

#TeachSpeak: reverse causation

Are you a knee-jerker or a deep-thinker? #TeachSpeak #MSBlog

Yesterday's post on B-cells and breast cancer has generated a lot of debate, some justified and some not. Before joining the debate you need to know how the mind works. There is a rapid, or fast, intuitive decision making system called system 1 and a slow more rational decision making system called system 2. If you are interested in reading about the way we think I would suggest you read 'Thinking, Fast and Slow', the best-selling book by Nobel laureate Daniel Kahneman. Just reading the introductory chapter of the book will be enough to give you the gist of system 1 and system 2 thinking. 

Based on Kahnerman's theory a system 1 (knee-jerk) response to my post is that B-cells prevent breast cancer hence ocrelizumab causes breast cancer. A system 2 response, the slower more rational response, would lead to a more nuanced interpretation. Firstly, you need to be aware that greater than 50% of oncology research findings can't be reproduced. In other words this paper's finding are likely to be a false positive based on pure statistics. 

Then there is 'reverse causation', which is likely to be the best explanation. In other words benign breast lesions that don't recruit B-cells are different biologically to those that do and are more likely to become malignant. The B-cells may simply be innocent bystanders and their presence or absence makes no difference in the long-term. Despite this there is the possibility that the findings are causal, i.e. B-cells are involved in preventing breast cancer. 

So what needs to be done? Other groups need to try and replicate the Mayo clinic study's findings and additional studies need to be done to explore the role of B-cells in breast cancer pathogenesis. We also need to set-up and monitor breast cancer incidence in relation to B-cell depletion therapies to assess whether or not the signal in the ocrelizumab trial programme is real or not. As with most DMTs the trial programme is too small and too short to give a definitive answer. All I would suggest is that pwMS considering ocrelizumab are made aware of the uncertainty and let them make up their own mind about the potential risk. You also have to remember that breast cancer can be detected early with increased vigilance and that the prognosis of breast cancer in 2017 is very good most patients with breast cancer are cured. All pwMS, women and men, need to be made aware about the possibility of secondary malignancies on immunosuppressive  therapies and taught how to monitor for possible malignancies. This message is not unique to ocrelizumab and applies to all most all of the DMTs. 

Another example of reverse causation in MS is low vitamin D levels in pwMS that have been linked to MS disease activity. Because of this observation everyone has interpreted the results that vD supplementation is essential to control MS disease activity. In reality almost every inflammatory disease studied has shown low vD levels that are linked to the degree of inflammation. The most likely explanation is a consumptive hypovitaminosis  D; i.e. inflammatory cells consume vD as part of their biology. Giving vD is unlikely to make any difference to their functioning or the outcome of the diseases concerned. We did a meta-analysis of the trials of vD supplementation that had been done to date and found no indication of vD being a DMT. Please note this comment does not apply to vD supplementation and MS prevention. Based on the literature and epidemiological studies vD plays a role in MS risk and there is an overwhelming case for doing vD prevention studies. 

Baker & Dolgin. Cancer reproducibility project releases first results. Nature 18 January 2017.


..... The Reproducibility Project: Cancer Biology launched in 2013 as an ambitious effort to scrutinize key findings in 50 cancer papers published in Nature, Science, Cell and other high-impact journals. It aims to determine what fraction of influential cancer biology studies are probably sound — a pressing question for the field. In 2012, researchers at the biotechnology firm Amgen in Thousand Oaks, California, announced that they had failed to replicate 47 of 53 landmark cancer papers. That was widely reported, but Amgen has not identified the studies involved.

..... The reproducibility project, by contrast, makes all its findings open — hence Ruoslahti’s discomfort. Two years in, the project downsized to 29 papers, citing budget constraints among other factors: the Laura and John Arnold Foundation in Houston, Texas, which funds the ­project, has committed close to US$2 million for it. Full results should appear by the end of the year. But seven of the replication studies are now complete, and eLife is publishing five fully analysed efforts on 19 January.

...... These five paint a muddy picture (see ‘Muddy waters’). Although the attempt to replicate Ruoslahti’s results failed, two of the other attempts “substantially reproduced” research findings — although not all experiments met thresholds of statistical significance, says Sean Morrison, a senior editor at eLife. The remaining two yielded “uninterpretable results”, he says: because of problems with these efforts, no clear comparison can be made with the original work.

CoI: multiple


  1. 2 very relevant questions:

    1) How about your running advice to take 5,000 IU of D3 daily?

    2) why is the anti-CD20 confined to breast cancers only? How about other cancers?

    1. Re vD

      Advice about being vD replete is based on long-term bone health and MS prevention. There is on class 1 evidence that it is a DMT. The dose I recommend is based on the Vitamin D Council recommendations.

    2. Vit D and MS prevention: what about MS patients?

      Breast cancer - what about the rest of the cancer family?

    3. Re: "How about other cancers?"

      We will need to wait for the post-marketing surveillance studies. It will take many thousands of patients and many years to answer this question.

    4. "You also have to remember that breast cancer can be detected early with increased vigilance and that the prognosis of breast cancer in 2017 is very good most patients with breast cancer are cured."

      "(2015)approximately 40,290 US women are expected to die from breast cancer. Only lung cancer accounts for more cancer deaths in women."

      ..out of 290,000 diagnosed cases..most are cured..but
      40,000 are not.

    5. "Breast cancer - what about the rest of the cancer family?"

      Other Malignancies in MS trials
      "Other than breast cancer, the malignancies were generally isolated cases and it is not possible to
      draw a conclusion between ocrelizumab exposure and a specific type of these malignancies,
      although a role for ocrelizumab cannot be ruled out."

  2. There was an occurrence of breast cancer in a Japanese man in the rheumatoid arthritis trial.

    See page 292 of the FDA medical review:

    The background annual incidence of breast cancer in Japanese men is two in a million.

  3. "The most likely explanation is a consumptive hypovitaminosis D; i.e. inflammatory cells consume vD as part of their biology. Giving vD is unlikely to make any difference to their functioning or the outcome of the diseases concerned." You appear to be saying that although vitamin d has a function in the immune system, a lack of vitamin d will not change how the immune system functions, which does not make sense. If the cells are using vitamin d to function then a shortage must have some effect on how they function.

    1. Re; "If the cells are using vitamin d to function then a shortage must have some effect on how they function."

      Possibly, which is why we need trials. The data to date of vD as a DMT is not that convincing, which is why we need properly designed and powered studies.

    2. What is really needed is a basic biochemical understanding of what the immune system is using the vitamin d for, then we would understand why it depletes. More badly designed trials will not really help, and without knowing what is going on they are likely to be badly designed. The past few years are scattered with badly designed under powered trials, as researchers bandwagoned.

  4. Whether one engages in system 1 or system 2 thinking, the ocrelizumab and cancer issue won't be put to rest for at least several years, as data is collected from the use of the drug in real-world clinical settings.

    I consider my neurologist a very rational man (and an aggressive MS treatment advocate), and he is not prescribing ocrelizumab to his patients due to the cancer signal. He's especially concerned with the seven additional cancers that occurred in the third year of treatment (two in the PPMS trial, and five in the RRMS trials, none of which were reported in the original trial data, since the state only included the initial two years that the studies were designed to cover).

    He is, however, continuing to prescribe Rituxamab to his patients, as the safety record of this drug in his own clinic as well as in several longitudinal studies is more to his satisfaction. Whether this is a correct decision or not will only be borne out in the coming years.

    However, as I mentioned in a comment on a previous post, it may be that the differences in mechanism of action between Ocrevus and Rituxan can account for differences in efficacy and safety profile. We saw the Ocrevus RA trials halted because of opportunistic infections and patient deaths, whereas Rituxan has been used successfully in this setting, with a relatively robust safety profile, for the last 11 years. This would seem to indicate a difference in how the body reacts to the two antibodies.

    Hoping that Dr. G sees this comment, as I'd like to reiterate my invitation to conduct an interview with him, the transcript of which would appear on my blog, Wheelchair Kamikaze. I very much like to discuss Dr. G's thoughts on therapeutic lag, the role of viruses in MS, and the big Pharma alternative initiative, as well as any other topics he deems important. I've posted interviews with several other prominent neurologists/researchers, all of which have been widely read and received very positive response. If you're interested, please contact me at


    1. WK your neurologist is making the same mistake I, and many others, make when considering the cancer risk with ocrelizumab. I suggest you read the classic, and one of the most influential papers, in psychology by Tversky and Kahneman on the 'belief in small numbers'. The problem with the human brain is that we believe is small numbers. What we really need is slow thinking and large numbers, for that we will have to wait for some time.

      AMOS TVERSKY and DANIEL KAHNEMAN. BELIEF IN THE LAW OF SMALL NUMBERS. Psychological Bulletin, 1971, Vol. 76, No. 2. 105-110.


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