Cancer Initiation: What is a "Generation Zero" Study?

Thursday, April 27, 2017

What is a "Generation Zero" Study?


  In a previous post, I somewhat arbitrarily ranked scientific epistemological frameworks, or paradigms, based upon the level of technology underlying concept of "proof". In this article, I am going to discuss published studies, that are "level Zero", or do not intend, or incapable of providing any level of "proof" to an underlying natural system. I am going to throw these examples into three categories, case studies, reviews, and pseudo-science.

The "Case Study"

  The case study is important, particularly in medicine because it provides the medical community with an "alert" to a situation which may be in some way novel. A case study does not necessarily state a statistical "proof" of a natural principle, it is merely what we might call "descriptive". Purely descriptive studies have been around since Newton and Galileo, and there is nothing wrong with them, but they do not attempt to use method, control, repetition and statistics to implore the reader as to a causal relationship. A case study may introduce data, but does not necessarily invoke statistics to determine a correlation between factors, or a causal relationship. Non the less, as many factors as possible should be included in the study, in order to hopefully include the correct direction for further study.

A scientific literature "Review"

    A review is an article that typically introduces no new data, but aggregates findings in previous studies into an organized package, typically for educational purposes. A university "Journal Club" may have various literature based groups that meet to discuss current articles. A journal club meeting might typically discuss a topical contribution in the field as well as a "review" article to provide an understanding of the current state of knowledge in a particular field. For example, if researches intend to discuss a paper on treatment of cancer with tumeric, they might first discuss other papers about the medical affects of tumeric, and observations of their known effects on cancer cells.


  Pseudo science in this context  is a published paper which purports to provide additional information on causal  relationships related to a scientific or medical concept, and yet introduces no new data, offers no statistical insight.  This can be thought of an extension to the definition in the field of philosophy that is commonly referenced.  Very often a pseudo-scientific paper may misrepresent known relationships for the purpose of promoting the acceptance of a particular understanding that is beneficial to a related party. This can work many different ways including attempting to provide evidence for a relationship where there is none ( in the case of potential therapeutics ) or providing evidence for NO relationship where a factor is thought to be hazardous.  An interesting quite is from our Stanford philosophy link:
  Some forms of pseudo-science have as their main objective the promotion of a particular theory of their own, whereas others are driven by a desire to fight down some scientific theory or branch of science. The former can be called pseudo-theory promotion and the latter science denial(ism). Pseudo-theory promotion is exemplified by homeopathy, astrology, and ancient astronaut theories. The term “denial” was first used about the pseudo-scientific claim that the Nazi holocaust never took place. The phrase “holocaust denial” was in use already in the early 1980s (Gleberzon 1983). The term “climate change denial” became common around 2005 (e.g. Williams 2005). Other forms of science denial are relativity theory denial, tobacco disease denial, hiv denialism, and vaccination denialism.

Of particular interest in this quote is that "vaccination denialism" is considered a form of pseudo-science by Stanford philosophers. Given that existing framework, it is only interesting to look at current "pro-vaccine" literature using the current epistemological framework of medical science.

  An example of a "Generation Zero" Case study of current interest

 The foundation of current controversy in medical pediatrics is the case study produced by Dr. Andrew Wakefield and a dozen or so colleagues. [1]  Dr. Wakefield is a gastro-interologist, so it is within his field to report on what his group perceives as a group of unusual cases of "Ileal-lymphoid-nodular hyperplasia.  The Ilium is a portion of the intestines or gastro-intestinal tract ( GI ) , which contains lymph nodes ( lymphoid-nodular )  which can become infected or inflamed ( hyperplasia ).
The "pervasive developmental disorder" that Dr. Wakefield was speaking of is more commonly called autism. The findings were presented as follows :
Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration.
The controversy here is the statement "Onset of behavioral symptoms was associated by the parents, with measles, mumps and rubella vaccination in 8 of the 12 children, with measles infection in one child and otitis media in another.". Although Wakefield and associates made no formal statement of correlation or causation,  the words "associated, by the parents" was enough to trigger pseudo-science accusations and retraction retraction.
  A word about probability and statistics here. The probability of throwing a 1 on a 6 face die is 1/6. The probability of throwing two 1's in a row is 1 / ( 6X6 ) or 1/36. At the time ( before 1998 ) autism was fairly rare, it was not the organizing principle of nearly every public schools system. Lets say 1 in 500, Non-specific colitis, or intestinal inflammation at the clinical level was also fairly rare, lets say also 1 in 500. The probability that these two conditions would occur together, by random coincidence would be 0.000004 . The probability that a dozen or so "0.000004" 's would show up to the same GI a the same time is near zero ( assuming one could get much closer to zero ) . Without saying anything else, this is a valid reason for a "case study" or generation zero description of medical observations.

Syndrome Observations

 For obvious statistical reasons then it became  imperative for the pharmaceutical community to shoot down the observation of autism occurring in conjunction with colitis. The observation has held up though. This from the Dan Marino Autism Research Institute

The Marino Autism Research Institute, or MARI, has funded the science behind ViTA DMF, as well as groundbreaking research linking gastrointestinal issues to ASD. MARI also funds the Marino Scholars Program at Vanderbilt University. This program promotes interdisciplinary training in neuroscience for future researchers and clinicians.

The interpretation presented by Wakefield 

The findings, as worded by  Wakefield were :
We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers. [1]
The term "environmental triggers here is meant to mean one or more components of the MMR vaccine or a deficiency in vitamin b12. Elevated urinary methyl-malonic acid was noted an a subset of the children, and this is known to be the strongest marker for vitamin b12 deficiency. I should note here, that in other posts related to autism, auto-immunity and related conditions, I note that vitamin b12 and folate are the necessary inputs that the single carbon metabolism system works on. In other words, Dr. Wakefields wording here is consistent with everything we have observed for the past 20 years.

The Emergence of "Data-Free" "evidence-based" findings

This battle is far from over. in 2017, fully 20 years after the original Wakefield case study, industrial psychologists are still battling over the "environment", meaning non-genetic factors as a cause of autism.  For example, lets look at a "molecular Autism" paper presented by Modabbernia [2].

First of all Modabbernia's title contains the phrase "evidence-based review". The title of the paper itself is a mangling of the difference between a "review" paper and an investigation paper.  The obvious intent is to present itself as an investigation without collecting any data.  A "meta-analysis" is a term that has become popular in politics in the context of a "poll of polls". Unless you have a new method of analyzing existing data, which of course might be interesting, there is no such thing outside of a plain old review.

The "evidence-free" summary of Modabbernai's work is as follows:
Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD.
The reason for providing no evidence is also clearly stated. Its because after 20 years, there in no interest in collecting data that might rock the boat. This is how that is stated.
 Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs.

The above conclusion of "unrelated risk" is based upon a rewording of the study as shown here related to mercury and thimerosal:
 In a meta-analysis of nine studies, Yoshimasu et al. [47] found precise and consistent evidence for lack of association between childhood thimerosal exposure and ASD. The lack of association was consistent in pooled analysis of the adjusted estimates, studies of anti-RhD antibody treatment, and studies of direct thimerosal exposure. In a meta-analysis of three case-control studies, the same authors reported a 60% increase in risk of ASD following higher level of inorganic mercury exposure. Based on their findings, the authors suggested that early life exposure to mercury by vaccination did not increase the risk of ASD, whereas exposure to inorganic mercury in the environment might be associated with an increased risk of ASD (Table 1).

Here the authors are saying that mercury was correlated with autism but not "ethyl-mercury" or thimerosal. There is a presumption ( usually considered false ) that ethyl mercury does not dis-associate into inorganic mercury when it is administered as a vaccine preservative.  That is "yes, but the mercury must have come from somewhere else so  no relationship".

There are other studies that are available that have actual data that do show a relationship between heavy metals ( mercury, lead ) and autism. This from Mohamed [3]
 Results. The mean Levels of mercury, lead, and aluminum in hair of the autistic patients were significantly higher than controls. Mercury, lead, and aluminum levels were positively correlated with maternal fish consumptions, living nearby gasoline stations, and the usage of aluminum pans, respectively. Conclusion. Levels of mercury, lead, and aluminum in the hair of autistic children are higher than controls. Environmental exposure to these toxic heavy metals, at key times in development, may play a causal role in autism. [3]


  Reviews and meta-analysis pseud science are currently being used to pad the literature with reports purporting to be investigations. They consist of lack of relevant data relative to their conclusions, omission of relevant data and misrepresentation of relevant data.


[1] Dr AJ Wakefield, et. al. : , Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and
pervasive developmental disorder in children 
The Lancet, 1998  [Full Text]

[2]  Modabbernia A, Velthorst E, Reichenberg A Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses.  Mol Autism. 2017 Mar 17;8:13. eCollection 2017.[PubMed Central]

[3] Mohamed Fel B, Zaky EA, El-Sayed AB, Elhossieny RM, Zahra SS, Salah Eldin W,
Youssef WY, Khaled RA, Youssef AM.Assessment of Hair Aluminum, Lead, and Mercury in a Sample of Autistic  Egyptian Children: Environmental Risk Factors of Heavy Metals in Autism. Behav Neurol. 2015;2015:545674. [PubMed Central]

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