Assessing the published literature

Though well-grounded in molecular and clinical data, the conclusions offered by Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis. researchers are sometimes met with skepticism by clinicians and fellow researchers. Some wonder how the MP science could be valid, given the existence of any of the seemingly contradicting evidence.

Researchers who work with Autoimmunity Research FoundationNon-profit foundation dedicated to exploring a pathogenesis and therapy for chronic disease. (ARF) take no special pride in arguing that the nature of chronic disease is different than most clinicians and researchers have imagined. In fact, it makes matters more difficult: the less familiar a conclusion is, the harder it is to persuade someone of its validity.

Using statistical inferences, John P. A. Ioannidis concluded in the prestigious journal PLoS Medicine that half of published research must be wrong.¹ In grappling with a confusing study or even a field of study, it's seriously worth considering how Ioannidis could be right.

The pervasive influence of the market can and has compromised doctors' judgment.

What assumptions do researchers routinely make that prevent them from embracing the science behind the MP? The following is a list of hypotheses about medical research that explains some of the hurdles that some have had to overcome thus far in accepting the MP.

1. Despite ambitious efforts, there is limited evidence that defective genes cause most human diseases.
2. The idea of permanent spontaneous remission of chronic disease is a myth.
3. Diseases and symptoms of disease share a common pathology and are part of a single disorder. Although patients who become infected with the Th1 pathogens are given a variety of diagnoses, there are often no clear-cut distinctions between one disease and the next. Rather, symptoms frequently overlap, creating a spectrum of illness in which diseases are more connected to one another than mutually exclusive disease states. One significant piece of evidence for this is the high rate of familial aggregation.
4. The era of specialization has reduced the level of interdisciplinary cooperation and consequently the ability for clinicians to appreciate the underlying connection among diseases.
5. The concept of the “blood-brain barrier” has lost meaning in today's world of molecular genomics.²
6. Animal models do not always accurately represent human biology. In fact, murine (mouse) models are particularly problematic as the murine Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. is not analogous to the human Vitamin D Receptor in some very key respects.
7. Only certain bacteria grow in an in vitro environment. Many fastidious forms of bacteria can only grow in the conditions offered by the human body.
8. Koch's postulates, the theory that a single species of pathogen causes a single disease is plainly wrong and continues to be embraced, despite strong evidence to the contrary.
9. In silico studies are a valid way to model the interactions between molecules and nuclear receptorsIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affect transcription..
10. Studies touting a therapy against chronic bacterial infections which doesn't demonstrate some manner of immunopathology, or bacterial die-off, are not demonstrating that recovery is possible.

The process by which studies are designed and research is interpreted and shared has a number of liabilities.

1. One of the basic assumptions underlying many genome-wide association studies has been that the genetic makeup of all an individuals’ cells is essentially the same. In the vast majority of genetic studies to date, researchers have assumed that in sequencing DNA isolated from blood would reveal the genetic makeup of diseased tissues as well. This supposition was convenient: except for cancer, samples of diseased tissue are difficult or even impossible to take from living patients.³ However, recent evidence has emerged that the genes of at least some cells from the blood and tissue do not match genetically,⁴ meaning that ambitious and expensive genome-wide association studies may prove to have been essentially flawed from the outset.
2. Science is often not objective.⁵ The choice of research questions, the methods to collect and analyze data, and the interpretation of results all reflect the worldview of the investigator.⁶ Investigators often overemphasize the importance of their findings and the quality of their work and choose interpretations that will enhance chances of success of obtaining funds from granting bodies.
3. Other serious conflicts of interest arise when for-profit organizations, such as device, biotechnology, and pharmaceutical companies, provide funds for conducting research, consulting, and attending scientific meetings. In the past 20 years, there has been an 8-fold increase in the number of trials for which authors declare industry affiliation.⁷ For example, one of the chief vitamin D researchers also sells a product containing vitamin D. Investigators accepting funds risk conflicts of interest. Even more problematic, they may cede their right to directly supervise data collection, participate in or supervise data analysis, and write the research reports to which their name is attached.^{8 9 10}
4. Observational epidemiological studies are compromised by bias inherent to the design of the studies themselves. It is arguably impossible to sufficiently control the socioeconomic factors, which drive a person to participate in a therapy or take a supplement. Patients who take drugs or supplements, as recommended by experts, are more likely to have better education, better access to health care, etc.
5. Publication or reporting bias, or the tendency not to publish negative results, increases the likelihood that the literature's descriptions of a therapy's efficacy are erroneous and decreases the likelihood that adverse effects are fully reported.¹¹
6. Smaller-sized studies are often published without the necessary statistical power to prove the validity of an observation or therapy. For example, an article in 1994 reported that a variant of the Vitamin D Receptor gene explains most of the population's risk for having low bone-mineral density.¹² The finding made the cover page of Nature, heralding the “osteoporosis gene.” Other subsequent studies showed an opposite effect, with the same variant predisposing to stronger bones. A large-scale analysis, of 100-fold more participants than the original Nature study, showed that there is no effect at all.¹³
7. In some fields, the reverence for experts and expert opinion has fostered mistaken consensus, even while successful cures for chronic disease remain elusive.
8. Peer review has had the effect of validating popular theories to the detriment of novel and/or contradictory theories.
9. Therapeutic interventions, for which there is a short-term benefit but long-term harm, are not accurately represented in studies over shorter time windows. Insufficient follow-up is particularly problematic in studies looking at vitamin D and other immunosuppressants. Successful treatments must be curative, not palliative.
10. Many of the articles that appear in scientific journals, under the bylines of prominent academics, are actually written by ghostwriters, who are paid by drug companies.¹⁴ These seemingly objective articles, which doctors around the world use to guide their care of patients, are often part of a marketing campaign by companies to promote a product or play up the condition it treats. One recent and prominent example relates to the way studies supporting HRT were written by ghostwriters.

Spielmans and Parry offer a robust critique of the series of assumptions upon which evidence-based medicine is based in their 2010 Bioethical Inquiry paper available here.