Implementing Precision Medicine in Best Practices of Chronic Airway Diseases

EUFOREA.

Part I

The Concept of Precision Medicine and Precision Health

Outline

Chapter 1 The Audacious Goal of Precision Medicine

Chapter 2 Critical Entry Points—Genetics and Epigenetics

Chapter 3 Critical Entry Points—Microbiome

Chapter 4 Factors Modulating the Disease Endotype

Chapter 5 Revised Disease Nomenclature Including Disease Endotypes

Chapter 1

The Audacious Goal of Precision Medicine

Ioana Agache¹ and Peter W. Hellings²,³,⁴,    ¹Faculty of Medicine, Transylvania University, Brasov, Romania,    ²Department of Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium,    ³Laboratory of Experimental Immunology, University Hospitals Leuven, Leuven, Belgium,    ⁴Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The Netherlands

Abstract

Before the precision medicine approach is broadly advocated, there is an urgent need to show robust data on its value by continuously measuring and documenting its benefit. Improved understanding and common usage of the endotype-driven approach at the point of care combined with real-time full patient monitoring and feedback using novel digital technology are key steps to advance the implementation of the precision medicine concept.

Keywords

Phenotypes; endotypes; biomarkers; point of care; pathway-specific diagnostic tests; data-driven policies; precision medicine; cost-effectiveness

Precision medicine is an ambitious concept integrating the endeavors of research, daily clinical practice, and healthcare. Tailoring prevention, diagnostics, and therapeutics to individual patients, while reinforcing the participation of the patient in the decision-making process is at the heart of precision medicine. The goal of precision medicine is simple—offer individual patients exactly the right medical care at the right time, taking their genes, lifestyle, and environment into account. The creative and energetic involvement of many is required to achieve the ambitious goal of precision medicine, from biologists, physicians, and technology developers to data scientists, patient groups, governments, and many more. Global, multidiscipline partnerships, innovative health, IT, and rethinking healthcare are important prerequisites to move the field forward. Both science and policy priorities need to be defined, agreed, and implemented upon.

Precision medicine is impacting healthcare in several domains, from pharmacogenomics, better selection of treatment responders, risk prediction, and design of disease-modifying strategies to ethics and patient-centered care models.

Improved understanding and common usage of disease phenotypes, endotypes and biomarkers at the point of care, validation, qualification of biomarkers and their translation into pathway-specific diagnostic tests, full patient monitoring using novel biomarkers digital technology and a revised disease taxonomy based on disease endotypes—are all key steps to bring precision medicine to the clinic. Learning how healthcare professionals engage with and use precision-medicine care pathways and what resources are needed to promote high-quality care of patients will serve to orient the dynamic governance that includes all stakeholders and is designed to remain agile and responsive to emerging opportunities and experience.

Implementing precision medicine in a clinical setting requires seamless integration of data from clinical evaluations and biomedical investigations with genomics and other endotyping profiling to characterize an individual patient’s disease progression followed by mainstreaming of all these data back to the point of care in a format that is ready and easy to use by the clinician. Designing methods for streaming data capture, real-time data aggregation, machine learning, predictive analytics, and visualization solutions to integrate wellness or health monitoring data elements with the electronic medical records maintained by healthcare providers permits better resource utilization. Establishing data-driven policies to balance privacy and security concerns with participant and public interests in the sharing of data for research, remains a major challenge.

There is limited evidence that precision medicine care pathways improve clinical outcomes and increase cost-effectiveness and affordability leading to a better quality of care. Reconciling concerns about rising costs, accessibility, and affordability of the precision medicine approach is central to the debate over implementing precision medicine at a larger scale. We need to encourage valuable innovation and enterprises willing to assume the risk in developing precision medicine approaches, while continuously measuring and documenting the benefit.

Before the precision medicine approach is broadly advocated, there is an urgent need to show robust data on its value. An agreement between all stakeholders on a flexible framework balancing the use of randomized control trials (the golden standard for evidence at present) against big data and observational analysis, while including health–economic impact analysis (encompassing cost-effectiveness and long-term savings) for regulatory and payer approval, are essential steps to move the field forward.

Further Reading

1. Bahk CY, Goshgarian M, Donahue K, et al. Increasing patient engagement in pharmacovigilance through online community outreach and mobile reporting applications: an analysis of adverse event reporting for the essure device in the US. Pharmaceut Med. 2015;29(6):331–340.

2. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–795.

3. Dzau VJ, Ginsburg GS, Van Nuys KD, et al. Aligning incentives to fulfill the promise of personalised medicine. Lancet. 2015;385(9982):2118–2119.

4. Gibson CJ, Dixon BE, Abrams K. Convergent evolution of health information management and health informatics: a perspective on the future of information professionals in health care. Appl Clin Inform. 2015;6(1):163–184.

5. Goldman D, Gupta C, Vasudeva EK, et al. The value of diagnostic testing in personalized medicine. Forum Health Econ Policy. 2013;16(2):121–133.

6. Greene SM, Tuzzio L, Cherkin D. A framework for making patient-centered care front and center. Perm J. 2012;16(3):49–53.

7. Holeman I, Cookson TP, Pagliari C. Digital technology for health sector governance in low and middle income countries: a scoping review. J Glob Health. 2016;6(2):020408.

8. Manyazewal T, Oosthuizen MJ, Matlakala MC. Proposing evidence-based strategies to strengthen implementation of healthcare reform in resource-limited settings: a summative analysis. BMJ Open. 2016;6(9):e012582.

Chapter 2

Critical Entry Points—Genetics and Epigenetics

Leandra Mfuna Endam¹, Eve Sedillot¹,² and Martin Desrosiers¹,²,    ¹Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada,    ²Division of Otolaryngology-Head & Neck Surgery, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC, Canada

Abstract

Precision medicine’s approach to the diagnosis and treatment of chronic rhinosinusitis (CRS) will depend on the identification of individual genetic traits conferring susceptibility to CRS, evolution of disease, or response to medical or surgical treatment. In this review, the authors review the current knowledge of the role of genetics and epigenetics in CRS and describe current practical applications. While the interaction of genetic factors with environmental influences such as bacteria complicate direct transposition of genetic results to the clinic, there is nevertheless enough evidence to support that identification of genotypes conferring susceptibility will find a role in the precision medicine’s efforts of the future.

Keywords

Sinusitis; chronic rhinosinusitis; genetics; population association genetics; single nucleotide polymorphisms; genome-wide association study; epigenetics; Staphylococcus aureus

Critical Entry Points—Genetics and Epigenetics

Personalized or predictive medicine is based on use of biomarkers or phenotypic traits allowing for advance selection of optimal effective therapy or else to minimize undesirable side effects. Given that in other disease areas, genetic traits have already been identified which allow administration of appropriate therapy while minimizing side effects, it is certainly intriguing to explore what role genetic variations may play in diagnosis and therapy of chronic rhinosinusitis (CRS).

CRS is a complex disease in which combinations of genetics factors, environmental factors, immunologic responses, and barrier dysfunction interact to produce the disease phenotype seen in CRS. Current therapy is nonspecific, with antibiotics and immunomodulatory agents administered in different forms and combinations. Recent improvements in outcomes have been attained not so much via novel therapies but rather by integrating surgery with continued medical therapy and improved adherence to management strategies. There nevertheless remains a need for improvement as suboptimal outcomes are seen in up to 40% of subjects by 6 months following endoscopic sinus surgery (ESS). A better understanding of CRS at the basic level and targeted therapies promise to improve on the current state. A better appreciation of the role of genetic variation offers the potential for a novel understanding of CRS and possible improvements in therapy.

Genetics: An Overview

The term Genetics encompasses transmissible gene variations causing or predisposing to development of disease or phenotype in question. Transmissible variations in gene function may also be induced by exposure to outside agents in a process termed epigenetic regulation or epigenetics. In a newer challenge, previously ignored short sequences of the genome called microRNAs have been found to play important roles in regulation of gene function, and transmission of de-novo genetic material via bacterial viruses termed bacteriophages may also modulate genetics activity.

The identification of a genetic basis to a disease may be difficult. Sinus physiology is a complex system, with multiple steps involved in even a single process such as pathogen recognition and initiation of initial defensive responses. Variations in function of a number of different genes or regulatory elements may lead to dysfunction within this system, ultimately yielding the same common disease phenotype. In addition, different genetic variations within a same gene may produce variable degrees of dysfunction.

The earliest-identified genetic disorders were discovered because they showed a clear pattern of heritability, with well-defined disease phenotype or by using phenotypic markers such as the sweat chloride test used in cystic fibrosis (CF). These well-characterized genetic disorders implicated single genes with a high penetrance and strong effects, which made the search for the genetic underpinnings of the disease much simpler. In contrast, most chronic disease such as asthma and CRS are considered complex diseases, where multiple genes are believed to participate in disease development, with each genetic factor having weak effects and thereby making only a partial contribution. In addition, the genetic basis may not be immediately obvious. For example, while it may seem obvious that an immune deficiency may predispose to chronic infection with bacteria, a defect in a gene involved of the epithelial barrier may lead to poor epithelial regeneration following viral insult, thereby facilitating bacterial subepithelially and thereby yielding the same result.

Despite the considerable difficulties posed by the multiplicity of factors implicated in CRS pathogenesis, strong evidence nevertheless supports that there is a hereditary component to CRS. A classic example is cystic fibrosis (CF), in which homozygous mutations in the CFTR gene lead to defects in chloride transport and yield the clinical manifestations of the disease. Chronic sinusitis, preferentially affecting the maxillary sinuses, is a consistent feature of CF. Other examples of well-characterized genetic diseases, which include CRS in their phenotype include the forms of ciliary dyskinesia, which can be coded for by at least 31 different genes implicated in coding a different portion of the structural arm of the cilia. (Zariwala MA, Knowles Mr, Leigh MW. Primary Ciliary Dyskinesia. 2007 Jan 24 [Updated 2015 Sep 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1122/)

More recent work by Orlandi assesses the heritability of CRSwNP and CRSsNP in a more general population. In a study of 1638 patients with CRSwNP and 24,200 patients with CRSsNP, they identified that first-degree family members of affected subjects are 4.1 times more likely to develop CRSwNP and 2.4 times more likely to develop CRSsNP. However, despite the demonstration of a heritable component, they still suggest an environmental factor, as spouses of an affected patient are also 2.0 times more likely to develop CRSsNP as well. (Oakley G, Curtin K, Orb Q, Schaefer C, Orlandi R, Alt J. International Forum of Allergy & Rhinology. Volume 5, Issue 4, pages 276–282, April 2015)

Techniques used to identify the genetic basis of disease involve comparisons between two or more groups, usually separated according to the element under study. For CRS, comparisons can either be made for CRS versus undiseased groups, CRSwNP versus CRSsNP, or for disease markers in CRS (IgE level, culture positive for Staphylococcus aureus) or outcome of therapy (success or failure following endoscopic sinus surgery). Markers of genetic variation (microsatellites or single nucleotide polymorphisms (SNP))—single genes or multiple genes of a pathway are compared to identify differences in frequency of identified traits. More productive techniques will assess either multiple elements of implicated pathways or else interrogate the entire genome in a hypothesis-free fashion in order to identify new mechanisms and targets using high-throughput chips congaing 1,000,000 or more SNPs (Genome-wide association study (GWAS)). More recently, whole-genome sequencing has been used; however, bioinformatic analysis of results remains a rate-limiting step. For validation, findings must be validated via replication in a second population and/or associated with genotype-specific variation in a biologic mechanism or in outcome. For a number of genetic findings, biological plausibility may not be evident as the role these genes play in normal function may not yet be described.

Identified genetic variations may be directly responsible for changes in the amino acid composition of the proteins they code for, leading to a change in structure and/or function. However, their role is often less obvious, as they may be in an intronic area, where they are believed to play regulatory roles, or else they may influence function of other genes either situated nearby (cis-regulation) or even on adjacent chromosomes (trans-regulation).

Genetics of CRS

Despite these challenges, genetic assessments of CRS are suggesting links with exiting concepts of pathophysiology and extending the tantalizing promise of future results down the road.

Assessment of published validated SNPs identifies that these group loosely into regulation of immune function, barrier function, and a wide variety of SNPs in genes whose functions are unknown or difficult to integrate into our current vision of CRS pathophysiology (Table 2.1). Note that the high percentages of identified genes related to immune function may reflect a selection bias of candidate genes studied rather than their actual level of implication. The limited number of studies in CRS performed with agnostic or hypothesis-free approach has suggested potential novel pathways implicating the epithelial barrier or, at a more basic level, regulation of cellular function.

Table 2.1