Matched, equal, equipoise

I’m often asked to talk to orthodontic audiences about what works and what doesn’t. I oblige and express my opinions on why some things work the way they do, and why other things yield less impressive results despite similar mechanotherapies. Variations in clinical studies are the norm. Even separate randomized clinical trials exploring identical queries report different results. Something must be missing.

We know that some of our clinical studies actually could not discover much. All we can do is to write the discussion section of the article to explain why we think we got the results we did. Observational studies are easier because there are no truly innovative hypotheses to be tested. The results of observational or exploratory studies have been easier to publish. After all, who could argue with what was observed? Indeed, observational studies could argue that the earth is flat or the sun goes around the earth; it is obvious that the earth is flat as far as the eye can see, isn’t it? Anyone who watches the sky all day and witnesses the trajectory of the sun from east to west can only conclude that the sun goes around the earth. Arguing the opposite or differently is difficult. Perhaps the abundance of identical reports in our literature is a warning for the paucity of (1) true advances or (2) proper tools of science to cause paradigm shifts. The rest of health sciences is no different.

Also true, many published reports of novel ideas have been irreproducible. This is not unique to orthodontics; all life sciences suffer from the harm of ill-conceived, poorly conducted, and poorly interpreted reports in the same manner. Irreproducible clinical research is very costly. For example, in nutrition, at first fat intake was vilified; now, fat is fine, and sugar is the new bogeyman. Such logically impossible swings remind us of orthodontists’ confusion over extraction, nonextraction, belief in growth modification, or “treating patients twice is better than just once” arguments, not to mention the utility of occlusal equilibration.

Confusion happens. It is because not all evidence is equal. Observational evidence, for example, proves that the earth is flat or the sun goes around the earth. The design of observational studies can be problematic, however innocently committed. Any large clinical study population also comes with a host of potentially confounding variables. Take studies of clinical effectives when there are control and treatment (or experimental) groups separated by age, sex, and defined parameters of the problem to be treated. These are ineffective selection criteria, yet the investigator must ignore the potential that the 2 groups might be “genetically” heterogeneous. In fact, there is an overwhelming possibility that heterogeneity is built in. And once the data are collected and the numbers crunched, differences between the groups end up being minimal because the subjects were not matched, and there was questionable equipoise. Analyses of collected data average the treatment effects across all participants, missing distinct effects in subsets of patients. In the end, observational studies often “fish” for results. One must be careful that the “fish” does not smell. A 3,000% increase in the risk of lung cancer from smoking, for example, is certainly genuine, but a 38% increased risk for breast cancer from occupational exposure of electromagnetic fields may be completely bogus. Unequal and ill-matched groups do not induce equipoise.

Distinguishing a “smaller thing” from a “bigger thing” is not always easy. Furthermore, given our conventional methods to separate subjects without attention to the heterogeneity of the groups, it can be hard to distinguish the “smaller thing” from nothing at all. What is the fix? It has to be profiling. In January, a $215 million Precision Medicine Initiative was announced to fund the National Institutes of Health and the Food and Drug Administration to develop and evaluate targeted therapies. Orthodontics could use a similar approach to unveil the genome of individual patients to test the feasibility of novel treatment modalities in much cleaner study designs. Of course, as biomarkers become more complex and numerous, the so-called experimental and control groups end up populated by mutant orphans. The Craniofacial Growth Legacy Collections Project funded by American Association of Orthodontists Foundation could be exceedingly helpful in sorting out matters of this nature.

Historically, orthodontic research in craniofacial growth or growth modification has been underwhelming for the reasons stated above. In contrast, there have been some successes in studying tooth movement. Unfortunately, the puzzle of child and adult patient response differences to applied mechanics and stimuli still remains. Recent data have shown that young people age differently. Orthodontists knew this all along but could not control or account for it. It might now be time to incorporate the effect of “aging” on tooth movement and not limit the investigations to only the patient’s genetic makeup. It has long been known that youthful collagen is more compliant in tooth movement. With age, compliance characteristics are altered. Reports of longevity offer hope for age reversal in collagen production via separate rather than genetic (ie, pharmacologic) mechanisms. It would be a significant advance when the orthodontist can induce age reversal in the periodontal tissues. People age differently. Not all same-aged people are equally old. The process of age reversal in periodontal tissue collagen production might be within reach of the orthodontist. Meanwhile, these advanced therapeutic operations of combined genetic profiling and induction of age reversal ought to be performed “only” by the orthodontic specialist.

There are many models to study tooth movement. The one that suffers the most from incorrect assumptions is the finite element analysis model. It assumes that a singular value input for the periodontium will do, when there are many types of fibers in different regions, designed for different functions, and all possessing different biomechanical properties. Nonetheless, the investigators are not to be blamed because they are fooled by the textbook illustrations of the periodontal ligament (PDL). Typically, the PDL is depicted by a series of lines drawn to extend from root surface to the bone. The illustration resembles a centipede more than the actual and functional anatomy of the PDL. In other textbooks, however, it is possible to see that PDLs are classified as oblique, horizontal, apical, and the like. But there is no mention of the behavior of these discrete fiber bundles while functioning. Moreover, there is no accounting for their biomechanical characteristics, potentially modified by stages of formation, maturity, fiber density, hydration level within the PDL space, vascular supply, or oxidative state. Tooth movement queries need to take into account the patient’s genetic profile and tissue biology with equal importance.

The motto of the Royal Society of London, the oldest scientific society in the modern world, is “ nullius in verba .” This phrase is translated as “on the word of no one” or “take no one’s word for it” and suggests that scientific knowledge should be based not on authority, rhetoric, or mere words, but on objective evidence. It follows, therefore, that imagination is not enough to predict the future. The next big paradigm shift in orthodontics ought to be simultaneously in the unlocking of genetic secrets and the manipulation of the tissue behavior of tooth movement.

These newly discovered methods of biologic manipulation may be accompanied by technical advances such as the use of robots in the clinic. They can replace the orthodontic assistant. Combined with robotic assistance, methods of using tissue biology will promote the specialty to a level so that no other clinician can play orthodontist. It is a future where orthodontics is, once again, separated from dentistry, as it was in the beginning. It’ll be a good day when orthodontists hear again the words “you really are not a dentist.” The future is most exciting. The orthodontist who is writing this editorial at the tail end of his career might not last long enough to take part in the celebration. But he wishes this future of orthodontics will arrive soon.

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Apr 6, 2017 | Posted by in Orthodontics | Comments Off on Matched, equal, equipoise
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