Publications

OBJECTIVE

We investigated genetic variants predictive of muscular side effects in patients treated with statins. We utilized a physiogenomic approach to prototype a multi-gene panel correlated with statin-induced myalgia.

BACKGROUND

Statin-induced myalgia occurs in ∼10% of lipid clinic outpatients. Its clinical manifestation may depend in part upon gene variation from patient to patient.

METHODS

We genotyped 793 patients (377 with myalgia and 416 without) undergoing statin therapy at four U.S. outpatient clinic sites to evaluate 31 candidate genes from the literature for their association with statin-induced common myalgia.

RESULTS

Three previously hypothesized candidate genes were validated: COQ2 (rs4693570) encoding para-hydroxybenzoate-polyprenyltransferase, which participates in the biosynthesis of coenzyme Q10 (p<0.000041); ATP2B1 (rs17381194) which encodes a calcium transporting ATPase involved in calcium homeostasis (p<0.00079); and DMPK (rs672348) which encodes a protein kinase implicated in myotonic dystrophy (p<0.0016).

CONCLUSIONS

The candidate genes COQ2, ATP2B1, and DMPK, representing pathways involved in myocellular energy transfer, calcium homeostasis, and myotonic dystonia, respectively, were validated as markers for the common myalgia observed in patients receiving statin therapy. The three genes integrated into a physiogenomic predictive system could be relevant to myalgia diagnosis and prognosis in clinical practice.

BACKGROUND

Language barriers present a substantial communication challenge in the hospital setting.

OBJECTIVE

To describe how clinicians with various levels of Spanish language proficiency work with interpreters or their own Spanish skills in common clinical scenarios.

DESIGN & PARTICIPANTS

Survey of physicians and nurses who report ever speaking Spanish with patients on a general medicine hospital floor.

MEASUREMENTS

Spanish proficiency rated on a 5-point scale, self-reported use of specific strategies (own Spanish skills, professional or ad-hoc interpreters) to overcome the language barrier.

RESULTS

Sixty-eight physicians and 65 nurses participated. Physicians with low-level Spanish proficiency reported frequent use of ad-hoc interpreters for all information-based scenarios, except pre-rounding in the morning when most reported using their own Spanish skills. For difficult conversations and procedural consent, most used professional interpreters. Comparatively, physicians with medium proficiency reported higher rates of using their own Spanish skills for information-based scenarios, lower rates of professional interpreter use, and little use of ad-hoc interpreters. They rarely used their own Spanish skills or ad-hoc interpreters for difficult conversations. Physicians with high-level Spanish proficiency almost uniformly reported using their own Spanish skills. The majority (82%) of nurses had low-level Spanish proficiency, and frequently worked with professional interpreters for educating patients, but more often used ad hoc interpreters and their own Spanish skills for information-based scenarios, including medication administration.

CONCLUSIONS

Physicians and nurses with limited Spanish proficiency use these skills, even in important clinical circumstances in the hospital. Health-care organizations should evaluate clinicians' non-English language proficiency and set policies about use of language skills in clinical care.

BACKGROUND

Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine.

OBJECTIVE

To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives.

DESIGN

Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.

DATA SOURCES

Published literature.

TARGET POPULATION

All persons with newly diagnosed colorectal cancer and their relatives.

TIME HORIZON

Lifetime.

PERSPECTIVE

Third-party payer.

INTERVENTION

Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.

OUTCOME MEASURES

Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.

RESULTS OF BASE-CASE ANALYSIS

The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36,200 per life-year gained.

RESULTS OF SENSITIVITY ANALYSIS

The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years.

LIMITATION

Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.

CONCLUSION

Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.

PRIMARY FUNDING SOURCE

National Institutes of Health.