Technical Appendix

TECHNICAL APPENDIX

DETAILS OF DATA SOURCES

Tufts Medical Center Cost-Effectiveness Analysis Registry (CEAR) (

Search Terms Used for CEAR Database Search:

GAPPFinder (

Pharmacogenomic Biomarkers on FDA Drug Labels13

CDC Evidence-Based Tier Tables for Clinical Utility 14,15

Top Causes of Mortality

High Expenditure Conditions17

CUA STUDIES INCLUDED IN ANALYSES (N=59)

DETAILS OF DATA SOURCES

Tufts Medical Center Cost-Effectiveness Analysis Registry (CEAR) (

The CEA Registry currently includes 3,067 cost-utility studies with 8,204 cost-effectiveness ratios and 11,355 utility weights from 1976 through 2011 and is regularly updated. Each article is reviewed with the aid of a standard data auditing form.Data from 2011 were the most recent available.

Articles for potential inclusion in CEAR are identified by a Medline search of the keywords “QALYs”, “quality-adjusted” and “cost utility analysis”. Abstracts of these searches are hand screened to identify studies that present original, English language cost utility analyses. Trained reviewers systematically extract data on over 40 variables from articles meeting the inclusion criteria on the study methods, intervention, target population, incremental cost-effectiveness ratios, utility weights, and subjective assessment of the study quality. Every accepted study is assigned a disease classification based on International Classification of Diseases, 10th Revision (ICD-10). 2Reviewers provide a quality score from 1 (lowest quality) to 7 (highest quality). Scores reflect the following considerations (in rough order of importance): 1) whether incremental cost-effectiveness ratios are correctly computed, 2) comprehensive characterization of uncertainty (i.e., either probabilistic or non-probabilistic evaluation of how changes in plausibly important assumptions influence the results, 3) correct treatment and explicit specification of health economic assumptions (discount rate, currency, analysis time horizon, 4) appropriate and explicit estimation of utility weights (the importance of this item depends on the extent to which the intervention influences morbidity vs. mortality).A complete description of the CEA Registry data collection processes is available at

We first used a more inclusive definition to identify all CUAs that examined personalized medicine testing or treatment based on genetic stratification (N=115), then within this sample, we identified CUAs that specifically analyzed the use of personalized medicine testing (N=59). We based this decision on results from our previous work that found that cost-effectiveness analyses examining the method of targeting are more informative than those only examining the targeted therapy; for example, that it is more informative to examine the cost-effectiveness of HER2 testing along with the use of trastuzumab rather than only examine trastuzumab without examining the test that must be used to target it. 3

We used several approaches to validate our search, although it should be recognized that there is no “gold standard” set of studies because there are no standard approaches to searching the literature and various search terms have been used. First, we validated our search by comparing our results against seven prior systematic reviews. 4-10 Second, we compared our results against a search in PubMed.

Because studies are identified for inclusion in the Tufts registry based on PubMed keywords, which search titles and abstracts, studies that do not include the keyword QALYs, quality-adjusted or cost-utility analysis in the title or abstract would be missed. For example, we are aware of one relevant study (Mvundrua et al)that was not included in the CEAR and thus excluded from the present study because none of the relevant keywords were used in the title or abstract11.

For analyses of ratios, we assigned each ratio a statistical weight of 1/n, where n was the number of ratios reported in an article. This approach ensures that no single article disproportionately affects the results by virtue of its reporting a large number of ratios.

Search Terms Used for CEAR Database Search:

General Terms:

biological markers

biomarker

DNA-ploidy

Gene expression profile/GEP

gene expression profiling

gene therapy

genetic markers

genetic test

genetic testing

genomic

genomics

genotype

genotypic

genotyping

hereditary

individualized medicine

personalized genomic

personalized genomics

personalized medicine

pharmacogenetic

pharmacogenetics

pharmacogenomics

phenotype

phenotypic

phenotyping

polymorphism

variant

Specific Markers:

21-gene

5q chromosome

70-gene

ALK

ApoE2

BRAF

BRCA

CCR5

CD 20

CD 30

CD25

CFTR

Cholinesterase

CKit

C-Kit

CYP290

CYP2C19

CYP2C9

CYP2D6

CYP450

Cytochrome P290

Cytochrome P450

DPD

Dysbetalipoproteinemia

E2/E2

EGFR

ER receptor

Factor V LeidenFIP

Fredrickson

G6PD

HER2/HER-2

HLA

HLA-B*1502

HNPCC

IHC

IL28B

KRAS

LDL receptor

Leiden

Micro Satellite Instability

MSI

NAT1

NAT2

PDGFR

Ph Chromosome

PML

RAR

Rh genotype

TPMT

UCD

UGT

VKORC1

GAPPFinder (

GAPP Finder is a searchable database of genetic tests and genomic applications in transition from research to clinical and public health practice sponsored by the Centers for Disease Control and Prevention. In 2010, the GAPP Finder was launched as a continually updated and accessible database on the World Wide Web that tracks the growing number of genetic tests and genomic applications under development or available for use in clinical and public health practice. The GAPP Finder offers a starting point for identifying applications and potential sources of data related to their validity and utility.

GAPPFinder researchers extract relevant genomic applications from horizon scanning alerts and enter them into the GAPP Finder database on a weekly basis. A researcher reviews each initial source for eligibility, decides whether the application will be included in the database, and assigns index terms. When appropriate the GAPP Finder contains links to the Evidence for Genomics Applications journal which contains short summaries of available data on analytic validity, clinical validity, and clinical utility. The GAPP Finder also contains links to the evidence reviews and recommendation statements commissioned and issued by the EGAPP Working Group when available. GAPP Finder utilizes the Unified Medical Language System (UMLS) for indexing to enhance the efficiency of information retrieval. The GAPP Finder accepts user-defined search query that can include disease, genes, target population, and intended use. The resulting list of genomic applications can be further filtered by selected characteristics (disease, gene, drug, test, application, evidence summaries, status, and year).

To be included in the database genomic applications must meet one or more of these criteria:

Under development or in clinical trials
Available for use in clinical or public health practice
Performed in CLIA certified or CAP proficient labs
Licensed by the FDA

During our coding process, duplicate entries for identical tests were removed in order to simplify the analysis.

We considered two other sources of test information in addition to GAPPFinder: GeneTests and the NCBI Genetic Testing Registry. The GeneTests database consists of self-registered research and clinical databases and self-registered tests that are offered by each laboratory. GeneTests specifically includes single gene disorders while excluding pharmacogenetics, HLA allele testing and diagnosis/monitoring of solid tumors, hematologic malignancies and infectious diseases from their database. The Genetic Testing Registry is a new database that provides a central location for voluntary submission of genetic test information by providers. The database contains information found in GeneTests and additional tests for Mendelian disorders, complex tests and arrays, and pharmacogenetic tests, while excluding somatic disorders, research tests or direct-to-consumer tests.

We elected to use the GAPPFinder database for several reasons. A major reason is that only GAPPFinder explicitly allows searches for tests that are clinical available, i.e., on their website they have a search term for “status” that we used to identify tests that are available for clinical use (we considered tests as available if they were coded as either “commercially available” or “available direct to consumer”). Another key reason is that GAPPFinder was developed and is regularly monitored and updated using an objective, evidence-based approach by an impartial organization (CDC). In contrast, both GeneTests and GTR use voluntary submission by laboratories and companies. Additionally, we elected not to use the GeneTests database because it excludes pharmacogenetics, HLA allele testing, hematologic malignancies and infectious diseases, which make up a large portion of our personalized medicine studies included in the manuscript. We elected not to use the GTR as it is a new database that is still being developed and it is not currently accepting registration of tests for somatic disorders, research tests or direct-to-consumer tests.

Pharmacogenomic Biomarkers on FDA Drug Labels13

Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. Drug labels may contain information on genomic biomarkers and can describe:

Drug exposure and clinical response variability
Risk for adverse events
Genotype-specific dosing
Mechanisms of drug action
Polymorphic drug target and disposition genes

The table below lists FDA-approved drugs with pharmacogenomic information in their labels. Some, but not all, of the labels include specific actions to be taken based on genetic information. Relevant sections of the label with such information are noted in the last column of the table. Biomarkers may include gene variants, functional deficiencies, expression changes, chromosomal abnormalities, and others.

Table 1: Food and Drug Administration Table of Pharmacogenomic Biomarkers in Drug Labels.13

Drug / Therapeutic Area / Biomarker / Label Sections
Abacavir / Antivirals / HLA-B*5701 / Boxed Warning, Contraindications, Warnings and Precautions, Patient Counseling Information
Aripiprazole / Psychiatry / CYP2D6 / Clinical Pharmacology, Dosage and Administration
Arsenic Trioxide / Oncology / PML/RARα / Boxed Warning, Clinical Pharmacology, Indications and Usage, Warnings
Atomoxetine / Psychiatry / CYP2D6 / Dosage and Administration, Warnings and Precautions, Drug Interactions, Clinical Pharmacology
Atorvastatin / Metabolic and Endocrinology / LDL receptor / Indications and Usage, Dosage and Administration, Warnings and Precautions, Clinical Pharmacology, Clinical Studies
Azathioprine / Rheumatology / TPMT / Dosage and Administration, Warnings and Precautions, Drug Interactions, Adverse Reactions, Clinical Pharmacology
Boceprevir / Antivirals / IL28B / Clinical Pharmacology
Brentuximab Vedotin / Oncology / CD30 / Indications and Usage, Description, Clinical Pharmacology
Capecitabine / Oncology / DPD / Contraindications, Precautions, Patient Information
Carbamazepine / Neurology / HLA-B*1502 / Boxed Warning, Warnings and Precautions
Carisoprodol / Musculoskeletal / CYP2C19 / Clinical Pharmacology, Special Populations
Carvedilol / Cardiovascular / CYP2D6 / Drug Interactions, Clinical Pharmacology
Celecoxib / Analgesics / CYP2C9 / Dosage and Administration, Drug Interactions, Use in Specific Populations, Clinical Pharmacology
Cetuximab (1) / Oncology / EGFR / Indications and Usage, Warnings and Precautions, Description, Clinical Pharmacology, Clinical Studies
Cetuximab (2) / Oncology / KRAS / Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Clinical Pharmacology, Clinical Studies
Cevimeline / Dermatology and Dental / CYP2D6 / Drug Interactions
Chlordiazepoxide and Amitriptyline / Psychiatry / CYP2D6 / Precautions
Chloroquine / Antiinfectives / G6PD / Precautions
Cisplatin / Oncology / TPMT / Clinical Pharmacology, Warnings, Precautions
Citalopram (1) / Psychiatry / CYP2C19 / Drug Interactions, Warnings
Citalopram (2) / Psychiatry / CYP2D6 / Drug Interactions
Clobazam / Neurology / CYP2C19 / Clinical Pharmacology, Dosage and Administration, Use in Specific Populations
Clomiphene / Reproductive and Urologic / Rh genotype / Precautions
Clomipramine / Psychiatry / CYP2D6 / Drug Interactions
Clopidogrel / Cardiovascular / CYP2C19 / Boxed Warning, Dosage and Administration, Warnings and Precautions, Drug Interactions, Clinical Pharmacology
Clozapine / Psychiatry / CYP2D6 / Drug Interactions, Clinical Pharmacology
Codeine / Analgesics / CYP2D6 / Warnings and Precautions, Use in Specific Populations, Clinical Pharmacology
Crizotinib / Oncology / ALK / Indications and Usage, Warnings and Precautions, Adverse Reactions, Clinical Pharmacology, Clinical Studies
Dapsone / Dermatology and Dental / G6PD / Indications and Usage, Precautions, Adverse Reactions, Patient Counseling Information
Dasatinib / Oncology / Ph Chromosome / Indications and Usage, Clinical Studies, Patient Counseling Information
3Denileukin Diftitox / Oncology / CD25 / Indications and Usage, Warnings and Precautions, Clinical Studies
Desipramine / Psychiatry / CYP2D6 / Drug Interactions
Dexlansoprazole (1) / Gastroenterology / CYP2C19 / Clinical Pharmacology, Drug Interactions
Dexlansoprazole (2) / Gastroenterology / CYP1A2 / Clinical Pharmacology
Dextromethorphan and Quinidine / Neurology / CYP2D6 / Clinical Pharmacology, Warnings and Precautions
Diazepam / Psychiatry / CYP2C19 / Drug Interactions, Clinical Pharmacology
Doxepin / Psychiatry / CYP2D6 / Precautions
Drospirenone and Ethinyl Estradiol / Reproductive / CYP2C19 / Precautions, Drug Interactions
Erlotinib / Oncology / EGFR / Clinical Pharmacology
Esomeprazole / Gastroenterology / CYP2C19 / Drug Interactions, Clinical Pharmacology
Everolimus / Oncology / Her2/neu / Indications and Usage, Boxed Warning, Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies
Exemestane / Oncology / ER &/ PgR receptor / Indications and Usage, Dosage and Administration, Clinical Studies, Clinical Pharmacology
Fluorouracil / Dermatology and Dental / DPD / Contraindications, Warnings
Fluoxetine / Psychiatry / CYP2D6 / Warnings, Precautions, Clinical Pharmacology
Fluoxetine and Olanzapine / Psychiatry / CYP2D6 / Drug Interactions, Clinical Pharmacology
Flurbiprofen / Rheumatology / CYP2C9 / Clinical Pharmacology, Special Populations
Fluvoxamine / Psychiatry / CYP2D6 / Drug Interactions
Fulvestrant / Oncology / ER receptor / Indications and Usage, Patient Counseling Information
Galantamine / Neurology / CYP2D6 / Special Populations
Gefitinib / Oncology / EGFR / Clinical Pharmacology
Iloperidone / Psychiatry / CYP2D6 / Clinical Pharmacology, Dosage and Administration, Drug Interactions, Specific Populations, Warnings and Precautions
Imatinib (1) / Oncology / C-Kit / Indications and Usage, Dosage and Administration Clinical Pharmacology, Clinical Studies
Imatinib (2) / Oncology / Ph Chromosome / Indications and Usage, Dosage and Administration, Clinical Pharmacology, Clinical Studies
Imatinib (3) / Oncology / PDGFR / Indications and Usage, Dosage and Administration, Clincal Studies
Imatinib (4) / Oncology / FIP1L1-PDGFRα / Indications and Usage, Dosage and Administration, Clinical Studies
Imipramine / Psychiatry / CYP2D6 / Drug Interactions
Indacaterol / Pulmonary / UGT1A1 / Clinical Pharmacology
Irinotecan / Oncology / UGT1A1 / Dosage and Administration, Warnings, Clinical Pharmacology
Isosorbide and Hydralazine / Cardiovascular / NAT1; NAT2 / Clinical Pharmacology
Ivacaftor / Pulmonary / CFTR (G551D) / Indications and Usage, Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, Clinical Studies
Lapatinib / Oncology / Her2/neu / Indications and Usage, Clinical Pharmacology, Patient Counseling Information
Lenalidomide / Hematology / Chromosome 5q / Boxed Warning, Indications and Usage, Clinical Studies, Patient Counseling
Letrozole / Oncology / ER &/ PgR receptor / Indications and Usage, Adverse Reactions, Clinical Studies, Clinical Pharmacology
Maraviroc / Antivirals / CCR5 / Indications and Usage, Warnings and Precautions, Clinical Pharmacology, Clinical Studies, Patient Counseling Information
Mercaptopurine / Oncology / TPMT / Dosage and Administration, Contraindications, Precautions, Adverse Reactions, Clinical Pharmacology
Metoprolol / Cardiovascular / CYP2D6 / Precautions, Clinical Pharmacology
Modafinil / Psychiatry / CYP2D6 / Drug Interactions
Nefazodone / Psychiatry / CYP2D6 / Drug Interactions
Nilotinib (1) / Oncology / Ph Chromosome / Indications and Usage, Patient Counseling Information
Nilotinib (2) / Oncology / UGT1A1 / Warnings and Precautions, Clinical Pharmacology
Nortriptyline / Psychiatry / CYP2D6 / Drug Interactions
Omeprazole / Gastroenterology / CYP2C19 / Dosage and Administration, Warnings and Precautions, Drug Interactions
Panitumumab (1) / Oncology / EGFR / Indications and Usage, Warnings and Precautions, Clinical Pharmacology, Clinical Studies
Panitumumab (2) / Oncology / KRAS / Indications and Usage, Clinical Pharmacology, Clinical Studies
Pantoprazole / Gastroenterology / CYP2C19 / Clinical Pharmacology, Drug Interactions, Special Populations
Paroxetine / Psychiatry / CYP2D6 / Clinical Pharmacology, Drug Interactions
Peginterferon alfa-2b / Antivirals / IL28B / Clinical Pharmacology
Perphenazine / Psychiatry / CYP2D6 / Clinical Pharmacology, Drug Interactions
Pertuzumab / Oncology / Her2/neu / Indications and Usage, Warnings and Precautions, Adverse Reactions, Clinical Studies, Clinical Pharmacology
Phenytoin / Neurology / HLA-B*1502 / Warnings
Pimozide / Psychiatry / CYP2D6 / Warnings, Precautions, Contraindications, Dosage and Administration
Prasugrel / Cardiovascular / CYP2C19 / Use in Specific Populations, Clinical Pharmacology, Clinical Studies
Pravastatin / Metabolic and Endocrinology / ApoE2 / Clinical Studies, Use in Specific Populations
Propafenone / Cardiovascular / CYP2D6 / Clinical Pharmacology
Propranolol / Cardiovascular / CYP2D6 / Precautions, Drug Interactions, Clinical Pharmacology
Protriptyline / Psychiatry / CYP2D6 / Precautions
Quinidine / Antiarrhythmics / CYP2D6 / Precautions
Rabeprazole / Gastroenterology / CYP2C19 / Drug Interactions, Clinical Pharmacology
Rasburicase / Oncology / G6PD / Boxed Warning, Contraindications
Rifampin, Isoniazid, and Pyrazinamide / Antiinfectives / NAT1; NAT2 / Adverse Reactions, Clinical Pharmacology
Risperidone / Psychiatry / CYP2D6 / Drug Interactions, Clinical Pharmacology
Sodium Phenylacetate and Sodium Benzoate / Gastroenterology / UCD (NAGS; CPS; ASS; OTC; ASL; ARG) / Indications and Usage, Description, Clinical Pharmacology
Sodium Phenylbutyrate / Gastroenterology / UCD (NAGS; CPS; ASS; OTC; ASL; ARG) / Indications and Usage, Dosage and Administration, Nutritional Management
Tamoxifen / Oncology / ER receptor / Indications and Usage, Precautions, Medication Guide
Telaprevir / Antivirals / IL28B / Clinical Pharmacology
Terbinafine / Antifungals / CYP2D6 / Drug Interactions
Tetrabenazine / Neurology / CYP2D6 / Dosage and Administration, Warnings, Clinical Pharmacology
Thioguanine / Oncology / TPMT / Dosage and Administration, Precautions, Warnings
Thioridazine / Psychiatry / CYP2D6 / Precautions, Warnings, Contraindications
Ticagrelor / Cardiovascular / CYP2C19 / Clinical Studies
Tolterodine / Reproductive and Urologic / CYP2D6 / Clinical Pharmacology, Drug Interactions, Warnings and Precautions
Tositumomab / Oncology / CD20 antigen / Indications and Usage, Clinical Pharmacology
Tramadol and Acetaminophen / Analgesics / CYP2D6 / Clinical Pharmacology
Trastuzumab / Oncology / Her2/neu / Indications and Usage, Precautions, Clinical Pharmacology
Tretinoin / Dermatology and Dental / PML/RARα / Boxed Warning, Dosage and Administration, Precautions
Trimipramine / Psychiatry / CYP2D6 / Drug Interactions
Valproic Acid / Psychiatry / UCD (NAGS; CPS; ASS; OTC; ASL; ARG) / Contraindications, Precautions, Adverse Reactions
Vemurafenib / Oncology / BRAF / Indications and Usage, Warning and Precautions, Clinical Pharmacology, Clinical Studies, Patient Counseling Information
Venlafaxine / Psychiatry / CYP2D6 / Drug Interactions
Voriconazole / Antifungals / CYP2C19 / Clinical Pharmacology, Drug Interactions
Warfarin (1) / Hematology / CYP2C9 / Dosage and Administration, Precautions, Clinical Pharmacology
Warfarin (2) / Hematology / VKORC1 / Dosage and Administration, Precautions, Clinical Pharmacology

CDC Evidence-Based Tier Tables for Clinical Utility 14,15

The CDC Office of Public Health Genomics provides the following list of genomic tests and applications in practice according to three levels of evidence based on the paper by Khoury et al[7]. This list is provided only for informational purposes to researchers, providers, public health programs and others. For the purposes of our study, we did not include newborn screening, use of family history, single gene disorders and chromosomal abnormalities, or Tier 3 applications.

Table 2: Centers for Disease Control and Prevention Genomic Tests by Levels of Evidence. 15

Tier 1genomic and family health history applications are recommended for clinical use by evidence-based panels based on a systematic review of analytic validity, clinical validity and utility for specific clinical scenarios
Test/Application / Scenario / Evidence-based recommendation
Newborn screening panel of 31 core conditions A / Screening all newborns at birth through public health programs / Secretary's Advisory Committee on Heritable Diseases of Newborns and Children(2011)