Thanks to the colleagues at retractionwatch.com, I noticed the recent invited commentary in the prestigious Journal of Clinical Epidemiology, a “confession building on a conversation with David Sackett in 2004” by biostatistician John Ioannidis at Stanford University. Sackett, the pioneer of evidence-based medicine (EBM), has passed last year. While reading Ioannidis’ commentary, it reminded me of obvious attempts of our own “eminent thought-leaders”, in Periodontology, who have recently used (or abused) EBM to promote their strong political agenda. The most striking example is the Perio-Systemic link which resulted in a perplexing question of one of our more independent scientists, “[Does] Perio causes everything?”
Ioannidis explains with some horror that EMB has been hijacked. First,
industry now runs a large share of the most influential randomized trials. They do them very well, they score better on “quality” checklists , and they are more prompt than nonindustry trials to post or publish results . It is just that they often ask the wrong questions with the wrong short-term surrogate outcomes, the wrong analyses, the wrong criteria for success (e.g., large margins for noninferiority), and the wrong inferences [14-16], but who cares about these minor glitches? The industry is also sponsoring a larger number of meta-analyses currently . Again, they get their desirable conclusions . In 1999 at the closing session of the Cochrane Colloquium in Rome, among the prevailing enthusiasm of this benevolent community, I spoiled the mirth with my skepticism. I worried that the Cochrane Collaboration may cause harm by giving credibility to biased studies of vested interests through otherwise respected systematic reviews. […] Now even the logo of the Collaboration, the forest plot for prenatal steroids, has been shown to be partially wrong due to partial reporting  – let alone reviews of trials done with vested interests from their very conception.
The recent supplement of the American Journal of Periodontology on periodontal regeneration had revealed that most authors of systematic reviews had heavily been sponsored by companies marketing the very products they actually reviewed in the most optimistic way, mainly reporting “significant” clinical advantage to standard procedures, be it clinically relevant or (usually) not. Ioannidis continues,
Clinical investigators flock to try to get coauthorship in multicenter trials, meta-analyses, and powerful guidelines to which they contribute little essence. Vested interests dictate preemptively large segments of the research agenda and its evidence-based aura [21,22] which is further propagated in professional societies and larger conferences . Many leaders and members of powerful professional societies and academies and other august bodies grow out of this system. It is sometimes difficult to tell whether a superb CV with a lengthy publication list reflects hard work and brilliant leadership or the composite product of dexterous power game networking, gift authorship , and excellence in the slave trade of younger researchers.
Of course, those who are the most successful in grantmanship include many superb scientists. However, they also include a large share (in many places, the majority) of the most aggressive, take-all, calculating managers. These are all very smart people, and they are also acting in self-defense: trying to protect their research fiefdoms in uncertain times. But often I wonder: what monsters have we generated through selection of the fittest! We are cheering people to learn how to absorb money , how to become more bombastic and least self-critical. These are our science heroes of the 21st century.
The following remarks by Ioannidis may be a strong warning for all advocates of the Perio-Systemic link.
As for epidemiology, risk factors for disease are becoming more dangerous than ever. By this, I mean two things. First, strong risk factors with unquestionable evidence like smoking are killing now globally more people than ever. Second, instead of dealing with these major public health risks, the production of spurious, false-positive, or confounded putative risk factors is more dangerous than ever. Jumping from correlation to causation , data dredging is called causal evidence and fuels guidelines. (Emphasis added.)
The most recent example for promoting a certain agenda may in fact be the tiny association between periodontal disease and incidence of breast cancer reported in the paper by Freudenheim et al. (Cancer Epidemiol Biomarkers Prev 2016; 25: 43-50). The study (Women’s Health Initiative Observational Study, or WHI OS) is huge; 73,737 women, aged between 50 and 79 years, without previous breast cancer had been longitudinally followed up since 1994 and 1998. Invasive breast cancer was associated with periodontal disease with a reported hazard ratio (HR) of 1.11 (95% confidence interval 1.00; 1.23) when the model was adjusted for age, education, race/ethnicity, BMI, age at menarche, age at menopause, parity, age at first birth, hormone use, alcohol consumption, physical activity, NSADs, smoking status and pack-years. This tiny association is reported in Table 4 of the article, and 8 printed pages in a prestigious journal are dedicated to this figure. In Table 5, the authors present further analyses (in a fully adjusted model) as regards smoking status and indeed identified those women who had quit less than 20 years ago to present with a higher HR, 1.36 (1.05; 1.77). Current smoking was similarly risky (HR 1.32), but as few women currently smoked, the confidence interval was wide (0.83; 2.11), and the association not significant. In the abstract, the authors only report these two hazard ratios, not the tiny one (1.11) of the fully adjusted model. They do mention in the abstract that presence of periodontal disease was self-reported. They responded, in a questionnaire, to the query: “Has a dentist or dental hygienist ever told you that you had periodontal or gum disease?” Actually, history of periodontal disease diagnosis was determined at year five of follow-up, so, upon enrollment it wasn’t clear whether periodontitis was present or not. Possible misclassification had been studied in a subsample, and sensitivity, specificity, positive and negative predictive values as regards self-reporting periodontal disease were 56%, 79%, 33% and 91% respectively for clinically determined severe periodontitis (LaMonte et al. 2014), quite low for all parameters. Nevertheless, Freudenheim et al. claim that “misclassification would likely bias results toward the null; it may be that we underestimated [sic] the strength of the association.” What follows is the usual speculation about potential mechanisms for the association (remember, in the fully adjusted model it was extremely weak, just “significant” due to the large number of volunteers in the cohort, with a point estimate of the hazard ration of 1.11). Possible mechanism include, of course, the periodontal microbiome.
It could be that periodontal pathogens directly impact carcinogenesis. bacteria from the oral cavity enter the blood stream following activities including tooth brushing, flossing and chewing, particularly among those with periodontal disease (27). While these circulating oral bacteria are rapidly cleared, there is considerable cumulative exposure to tissues (28). It is known that milk ducts are not sterile, that breast ductal tissues are exposed to bacteria and viruses during lactation and that human milk contains a complex and variable array of microbes (29-31). Furthermore, there is evidence from small studies of the presence of bacteria in breast tissues (32-34) including in breast tumors (34). The origins of microbes in breast tissues and tumors are not known but the oral cavity and gut might contribute (30). Some of the bacteria species identified in breast tissues (33) are also found in the mouth although it is known if they are the same strains. There is some evidence (35-37), although not consistent (38,39), that there is an increase in breast cancer risk associated with antibiotic use. Particular antibiotics might or might not [sic] alter the oral microbiome.
An almost classic example of circular reasoning.
Another potential mechanism is inflammation resulting from the periodontal disease impacting systemic processes including breast carcinogenesis (40). Periodontal disease is associated with chronic systemic inflammation including increased blood C-reactive protein (41, 42), cytokines and chemokines (43), with a potential impact on carcinogenesis (44). Bacterial metabolites produced in the mouth including nitrosamines and acetaldehyde could have a systemic impact on carcinogenesis (45). It could also be that there are common risk factors including smoking, physical activity, or diet as well as etiologic factors such as inflammation, oxidative stress, or shared genetic factors that contribute to host susceptibility to both breast cancer and periodontal disease (26, 46-48). The cytokine receptor of NF-kB (Rank) and its ligand (RANKL) may be important in breast carcinogenesis and metastasis (49-52). Blood and salivary RANKL are increased in periodontal disease, especially among smokers (53, 54).
The entire speculation is based on an estimated HR of 1.11 (1.00; 1.23). Fourteen years ago, Hujoel et al. (2003) had reported small and in part “significant” associations between periodontitis and several types of cancer in the NHANES I Follow-up database which they generally considered spurious, possibly due to incomplete adjustment for smoking. The odds ratio for breast cancer was 1.32 (0.74; 2.38). Freudenberg et al. (2016) quote Hujoel et al. (2003) without mentioning their thoughtful analysis of the NHANES I Follow-up data. They also quote Arora et al. (2010), who found significant positive associations of periodontal disease with incidence of cancer of the digestive tract, colorectal cancer, pancreas cancer, prostate cancer and corpus uteri cancer, but not breast cancer (HR 1.12; 0.75, 1.68) in 15,333 Swedish twins between 1963 and 2004; and Söder et al. (2011), who amazingly found that missing molars in the mandible were associated with breast cancer.
18 March 2016 @ 2:26 pm.
Last modified April 1, 2016.