Fundamentals of Precision Medicine

Kimon Divaris, DDS, PhD

Imagine a world where clinicians make accurate diagnoses and provide targeted therapies to their patients according to well-defined, biologically informed disease subtypes, accounting for individual differences in genetic makeup, behaviors, cultures, lifestyles, and environment. This idea is not as utopic as it may seem. Relatively recent advances in science and technology have led to an explosion of new information on what underlies health and what constitutes disease. These novel insights emanate from studies of the human genome and microbiome, their associated transcriptomes, proteomes, and metabolomes, and epigenomics and exposomics—such “omics” data can now be generated at unprecedented depth and scale, and at rapidly decreasing cost. Integrating these fundamental information domains to transform healthcare and improve health remains a challenge but is an ambitious, laudable, and potentially high-yield goal.

The Precision Medicine Initiative

The 2015 initiative on precision medicine^1-3 articulated a concerted effort of governmental, academic, and professional stakeholders to accelerate the translation of the new, deeper understanding of human health to better care. The initiative entails three broad directions of anticipated impact:

1) to optimize and improve healthcare: “an innovative approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles”

2) to help understand/discover mechanisms underlying health and disease: “precision medicine gives clinicians tools to better understand the complex mechanisms underlying a patient’s health, disease, or condition”

3) to enable clinicians to select and apply effective therapies: “to better predict which treatments will be most effective”

An example of how the precision medicine approach can improve outcomes and people’s lives is offered by Insel and Cuthbert for the mental health domain.⁴ In their model, patients presenting with a range of mood disorders (eg, an overlapping symptom-based category with diverse underlying etiologies) undergo several tests and data-generating processes; the integration of genomics, brain function, physiologic, behavioral, and life experience data can guide the definition of biologically and mechanistically homogeneous clusters of patients and thus help optimize their management.

Six Pillars of Precision Medicine

Six important building blocks, or pillars, need to be in place for the precision medicine initiative to succeed and realize its full potential. First and foremost is the creation of a new taxonomy of human disease.⁵ The importance of biologically, molecularly, or genetically defined disease subtypes for otherwise clinically similar conditions cannot be overemphasized—the cornerstone of precision medicine is the ability to make precise diagnoses, based on a mechanistically informed taxonomy. Disease subtyping is becoming commonplace in cancer treatment, and one can anticipate that subtyping will follow for other chronic diseases. Redefining disease will require substantial efforts from multiple stakeholders and will be a slow process, but a necessary one.

Second, precise care requires the discovery, validation, and application of health and disease biomarkers—biologic variables that reliably and validly represent and discriminate between health statuses. In the not-too-distant future, biomarkers that can be measured with fidelity in a noninvasive, remote, or “live” manner will be tracked using biosensors. This will facilitate a more precise, remote monitoring and tailoring of disease management strategies and will aid self-management.

Third, it follows that these new information structures that include deep (ie, multiple “omics” layers per person) and wide (ie, health outcomes of thousands or millions of people) data require new approaches for generating, storing, analyzing, and sharing them. In this domain, advances in bioinformatics, scalable or cloud computing, and clinical decision support systems (eg, dashboards) are necessary to support precision medicine pipelines.

The fourth pillar: At a time when molecular and genomics applications are in the spotlight, there is no better opportunity to increase understanding and operationalize the consideration of the social determinants of health in precision medicine. Advanced, personalized, or precision approaches may be futile in their implementation unless social and behavioral sciences are intentionally and explicitly integrated in the precision medicine context. Molecular approaches can elevate the argument for upstream action and precision public health⁶ because they can illuminate the biologic mechanisms that operate between social disadvantage and health outcomes.

Training “precision-minded” healthcare providers is the fifth, fundamental pillar—it could arguably be the first one. Substantial investments in resources will be required to prepare, train, and continuously update the next generation of healthcare providers. They will be faced with a sea of “omics” and biomarker data that will need appreciation and interpretation. With an aim to increase providers’ genomics and precision medicine literacy, equal emphasis must be placed on the humanistic aspects of healthcare—precision medicine is explicit in its consideration of individual differences, wherever they may have originated.

Finally, for precision healthcare to succeed, government, academic, corporate, and professional stakeholders must take initiatives to prepare and educate the public for this new era. Genomics and other molecular tests can affect people’s lives above and beyond the realm of seeking a diagnosis or getting treatment. It is imperative that partnerships are formed with community stakeholders and representatives to prevent or address ethics and genomics literacy issues. Meaningful community engagement will also help ensure that precision medicine brings about the intended positive health outcomes, for all people.

The Vision for Precision Oral Healthcare

The information in this article was first presented at the University of North Carolina (UNC) Perio 2017 Expo, a 2-day course organized in celebration of 50 years of the UNC-Chapel Hill Periodontology Residency Program and 20 years of the Center for Oral and Systemic Disease. The program showcased the current concepts in periodontics and implantology, including disease diagnosis, treatment, and management. To provide a more focused perspective for the status of dentistry, a brief overview is in order regarding the progress of precision medicine (or precision dentistry) in the oral health domain.

Overall, precision medicine in the oral health domain is in its infancy. The absence of robust or consensus disease taxonomies and the lack of sizeable cohorts with well-measured clinical and “omics” data are two major reasons for this lag in comparison to other fields. It is encouraging that biologically informed disease subtypes⁷ and precise disease taxonomies⁸ have recently been proposed for periodontal disease; however, redefining dental caries as a person-level disease, in a precise manner and in biologic terms, remains to be done.^9,10 Nevertheless, the importance of genomics and other “omics” structures^10-13 has been acknowledged as a major opportunity for the health community to improve health outcomes. Precision medicine has been discussed within the realms of periodontology,^7,8 pediatrics,¹² orthodontics,¹⁴ and oral-maxillofacial surgery.¹⁵

On a positive note, there is enormous opportunity and potential for dentistry to realize and benefit from the fundamentals of precision medicine. In fact, oral health professionals have relatively easy and noninvasive access to important biomarkers drawn from saliva and the oral microbiome (ie, the beginning of the gut microbiome) that could enable chairside, remote, or even live (eg, via biosensors) precision medicine applications. The inherent periodicity of routine dental visits adds to the practicality and value of employing the oral healthcare domain as a possible vehicle for the realization of precision medicine.

References

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3. Ashley EA. Towards precision medicine. Nat Rev Genet. 2016;17(9):507-522.

4. Insel TR, Cuthbert BN. Medicine. Brain disorders? Precisely. Science. 2015;348(6234): 499-500.

5. National Research Council. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. Washington, DC: National Academies Press; 2011.

6. Khoury MJ, Iademarco MF, Riley WT. Precision public health for the era of precision medicine. Am J Prev Med. 2016;50(3):398-401.

7. Offenbacher S, Divaris K, Barros SP, et al. Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease. Hum Mol Genet. 2016;25(10):2113-2129.

8. Morelli T, Moss KL, Beck J, et al. Derivation and validation of the periodontal and tooth profile classification system for patient stratification. J Periodontol. 2017;88(2):153-165.

9. Köhler S, Vasilevsky NA, Engelstad M, et al. The Human Phenotype Ontology in 2017. Nucleic Acids Res. 2017;45(D1):D865-D876.

10. Divaris K. Predicting dental caries outcomes in children: a “risky” concept. J Dent Res. 2016;95(3):248-254.

11. Slavkin HC. From phenotype to genotype: enter genomics and transformation of primary health care around the world. J Dent Res. 2014;93(7 suppl):3S-6S.

12. Divaris K. Precision dentistry in early childhood: the central role of genomics. Dent Clin North Am. 2017 Jul;61(3):619-625.

13. Kornman KS. Traditional and emerging diagnostic strategies for identifying risk. Compend Contin Educ Dent. 2014;35(3 suppl):12-15.

14. Hupp JR. Precision medicine--implications for oral-maxillofacial surgery. J Oral Maxillofac Surg. 2015;73(5):795-796.

15. Iwasaki LR, Covell DA Jr, Frazier-Bowers SA, et al. Personalized and precision orthodontic therapy. Orthod Craniofac Res. 2015;18(suppl 1):1-7.