The investigators are concerned with patient safety and ADRs as these areas of clinical
practice represent significant causes of death, ahead of many of the better recognized
acute and chronic causes of mortality. While prescribing medicines can have life-altering
benefits, a more precise way of choosing among the options on a formulary continues to
lag behind existing technologies. A person's drug response can vary by means of drug-drug
or drug-food interactions, as well as by sex, age, and disease status. Large
interpersonal variabilities of up to 1000-fold exist in response to the same dose of a
given medication. Genetic polymorphisms help define pharmacokinetic and pharmacodynamic
profiles, but these insights have not yet been consistently incorporated into clinical
practice and standards of care. Several medication management programs have appeared in
recent years, but these are mainly geared toward adherence, with only limited
incorporation of pharmacogenomics-based medication management. Precision medicine
advocates that one size does not fit all medical care. How might the provision of care
get closer to the bullseye in polychronic disease management, and the management of
polypharmacy?

There exists a polypharmacy crisis in the United States that is large in scope,
especially among the older populations who often have diminishing renal and hepatic
functions. The prevalence of potential hepatic cytochrome enzyme-mediated drug-drug
interactions was estimated to be as high as 80% in one study with elder adults considered
to be more susceptible to problematic drug interactions. Conventionally, polypharmacy
refers to taking five or more medications concurrently. An estimated 15 million patients
65 or older have been identified as facing the challenge. Polypharmacy patients often
have at least two comorbid chronic diseases, and nearly 50% of older adults are using at
least one medication that is not necessary. Hospitalized patients average five to eight
medications, and the number surpasses nine in 40% of nursing home residents. In a study
of patients with cognitive decline or mild Alzheimer's disease, 88% of these patients met
polypharmacy criteria, with anticholinergic cognitive burden, drug-drug interactions, and
drug-gene interactions all prevalent issues in these populations. In an increasing number
of extreme cases, polypharmacy can approximate 20 drugs posing risks for adverse drug
outcomes that equal nearly 100%. The greater the number of medications in a regimen, the
higher the risk to patient safety and compromised clinical outcomes. One in twenty
polypharmacy outpatients seek medical care for ADRs. Polypharmacy has also been
associated with hospitalizations among the elderly. Polypharmacy is associated with
decreased medication adherence, nutrition, urinary incontinence, reduced activities of
daily living, and loss of physical and cognitive functions. Increased falls occur along
with accompanying morbidity and mortality. Financially, the impact of polypharmacy has
been associated with a 30% increase in health care expenditures, and a major factor in
ultrahigh healthcare utilizers. Analysis of the Observational Health Data Sciences and
Informatics data set showed that 10% of diabetes patients, 24% of hypertension patients,
and 11% of depression patients followed a treatment pathway that was unique among a
population of 250 million cases, illustrating the need for electronic decision support to
flag drug interactions resulting from patient specific care plans and implement
corrective measures.

Electronic health records continue to fall short regarding their level of
interoperability, with significant deficiencies enabling a care plan and medication
management that can draw data and decision support from across the provider continuum.
This is a suboptimal situation in the provision and refinement of precision and
personalized medical care. The clinical burden of polypharmacy and medication
reconciliation often impacts primary care clinicians who may not have the necessary data
at the point of service, a nidus for polypharmacy management problems. Innovative
approaches to managing the polypharmacy challenge include the creation of medical
management clinics with focused efforts on mitigating the cost and healthcare burden of
polypharmacy and to systematically evaluate the incremental clinical changes that
accompany medication alterations, modification or discontinuation where indicated.

Utilizing an interprofessional care team that includes physicians, pharmacists, nurses,
case coordinators, along with telemedicine and digital tools, the investigators can
engage patients and garner information such as phenotypic, functional, and social
determinants of disease profiles. These data can be entered as computable actionable data
prior to a visit in order to better track what happens in- between visits (adherence to
the care plan, or lack thereof). The investigators posit that this information is as
important as what happens at an appointment, and this is especially true in clinical
cases of polypharmacy. In the end, this information can become more readily available to
both patient and provider utilizing the Interprofessional Pharmacogenomics (IPGx) care
model.

The investigators are developing a care decision support protocol and pharmacogenomic/
pharmacokinetic dashboards that augment the capacity for primary care clinicians to
manage medication more precisely for individual cases and that is minimally disruptive.
Additionally, interoperability between electronic medical records, clinical decision
support (CDS) and genomic test data formats remains a barrier for reuse of PGx tests and
implementation of whole genome and whole exome sequencing across time and different
healthcare providers. These efforts will inform the feasibility of using whole genome
sequencing (research use only under this study protocol) across the informatics platforms
used in the IPGx care model.

The dashboards will be useful to providers and patients, helping to identify clinical
cases where there might be benefit from proactive medication management to identify those
who may not respond and those at heightened risk of ADRs. The dashboards would be
informed by a growing library of clinical cases with a clinical data warehouse. The
dashboard would generate and iteratively refine novel care decision trees (algorithms)
centered on medication management. The data structure and care protocol are designed to
enable concomitant and longitudinal observation (research) of the clinical activities
toward validation of the ActX CDS and dashboards as a useful tool for patient-centric
clinical research. The ideal databank will include drug blood levels (not relevant to
this PILOT), drug list and other relevant modifier data that may impact medication use
and effectiveness. This approach would also provide a means to learn more about drug
adherence and help to systematically identify patients who may be candidates for a
pharmacogenomic evaluation and longer-term participation in a medication management
program.

Specific questions that this GENERALIZED approach might inform:

Does a drug level near zero mean non-adherence, or is the patient metabolizing a drug
extensively such that blood or urine levels become undetectable after administration? The
phenotypic questionnaire coupled with drug blood or urine level measurements will answer
that question.

Is a protocol needed to determine when to order a pharmacogenomic test? The
investigator's data platform, powered by the ActX platform, can validate the clinical and
cost-effectiveness of those decisions.

What is the best use pharmacogenomic data? If a patient has had a pharmacogenomic test,
blood or urine drug levels might help refine knowledge about the metabolic activity for
pertinent enzymatic pathways and help craft key questions to identify what constitutes an
overloaded CYP P450 pathway in the setting of polypharmacy.

ADRs might be preventable in the psychotropic domain by applying the knowledge derived
from a medication management consultation. For instance, in the case of antidepressants,
weeks may go by before a clinical response can be evaluated after initiating medication
based on standard dosing and trial and error. In a precision medication management
scenario, the provider would know at the outset if the patient were an ultra-rapid
metabolizer for a relevant CYP P450 enzymatic pathway and be better equipped to identify
the drug of choice and to optimize dose titration. If the clinical dashboard reveals a
patient that is receiving several medications competing for a common pathway, proper
medication adjustments can also be made, as needed.

The ActX to be used here is a clinical decision support system containing millions of
interrelated variant-drug concepts that arc with each other to create a knowledge
network. As data is entered, weighted arcs are used to build clinical decision support
and differential diagnoses. This provides a potentially strong environment for a
pharmacogenomic profile to create a precision drug and dosing regimen tool while taking
advantage of clinical workflows currently in practice. The pharmacogenomic dashboard is
contained within the ActX platform.

Compare and contrast WGS and Genotyping

The ActX test is a genotyping test conducted in a CAP/CLIA-compliant laboratory for
complex lab-developed tests (LDTs) to ensure that results can be used for clinical
decision-making within the LDT regulatory framework. This type of test examines a limited
number of features in the human genome, specifically just under 400 known genetic
variants with clinical significance. The results from the ActX test will be returned to
the provider and discussed with patients. Whole Genome Sequencing (WGS) provides a
complete comprehensive inventory of the entire human genome, which consists of
approximately 4 billion base pairs. While WGS can be performed under CAP/CLIA regulations
for clinical decision-making, the testing laboratory we will be using will conduct a
Research Use Only (RUO) test and WILL NOT be an LDT. As a result, WGS results will not be
provided to healthcare providers or patients.