Contribution of Pharmacogenetic Testing to Modeled Medication Change Recommendations in a Long-Term Care Population with Polypharmacy.

BACKGROUND: Among long-term care facility residents, polypharmacy is common, and often appropriate, given the need to treat multiple, complex, chronic conditions. Polypharmacy has, however, been associated with increased healthcare costs, adverse drug events, and drug interactions. The current study evaluates the potential medication cost savings of adding personalized pharmacogenetic information to traditional medication management strategies. METHODS: One hundred and twelve long-term care residents completed pharmacogenetic testing for targeted variants in the following genes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/CYP3A5, HTR2A, HTR2C, SLC6A4, SLC6A2 COMT, OPRM1, SLCO1B1, VKORC1 and MTHFR. Following reporting of the IDgenetix Polypharmacy® test results, an internal medication management assessment was performed by a licensed clinical pharmacist to identify potential opportunities for regimen optimization through medication changes or discontinuations. The medication cost differences before and after the pharmacogenetic-guided review were assessed. RESULTS: Medication review following pharmacogenetic result reporting identified 54 patients (48.2%) with a total of 132 drug change recommendations (45 reductions; 87 replacements) and an average of 2.4 proposed medication changes (range 1-6) per patient. Medication cost savings related to the identified reduction and replacement opportunities exceeded the cost of testing and are estimated to be US$ 1300 (year 2016 cost) per patient annually assuming full implementation. CONCLUSION: Compared with traditional medication review, pharmacogenetic testing resulted in a 38% increase in the number of patients with current medication change opportunities and also offered valuable genetic information that could be referenced to personalize future prescribing decisions for all patients.

Initial assessment of the benefits of implementing pharmacogenetics into the medical management of patients in a long-term care facility.

The health care costs associated with prescription drugs are enormous, particularly in patients with polypharmacy (taking more than five prescription medications), and they continue to grow annually. The evolution of pharmacogenetics has provided clinicians with a valuable tool that allows for a smarter, more fine-tuned approach to treating patients for a number of clinical conditions. Applying a pharmacogenetics approach to the medical management of patients can provide a significant improvement to their care, result in cost savings by reducing the use of ineffective drugs, and decrease overall health care utilization. AltheaDx has begun a study to look at the benefits associated with incorporating pharmacogenetics into the medical management of patients who are on five or more medications. Applying pharmacogenetic guided PharmD recommendations across this patient population resulted in the elimination and/or replacement of one to three drugs, for 50% of the polypharmacy patient population tested, and an estimated US$621 in annual savings per patient. The initial assessment of this study shows that there is a clear opportunity for concrete health care savings solely from prescription drug management when incorporating pharmacogenetic testing.

Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors.

PURPOSE: To provide practice recommendations for genetic counselors whose clients are considering cystic fibrosis (CF) carrier testing or seeking information regarding CF molecular test results. The goals of these recommendations are to: 1) Provide updated information about the natural history, diagnosis, and treatment of CF and related conditions. 2) Supplement genetic counselors' knowledge and understanding of the available carrier screening and diagnostic testing options. 3) Describe the current state of genotype/phenotype correlations for CFTR mutations and an approach to interpreting both novel and previously described variants. 4) Provide a framework for genetic counselors to assist clients' decision-making regarding CF carrier testing, prenatal diagnosis, and pregnancy management. Disclaimer The practice guidelines of the National Society of Genetic Counselors (NSGC) are developed by members of the NSGC to assist genetic counselors and other health care providers in making decisions about appropriate management of genetic concerns; including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue, and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the NSGC practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are only current as of their publication date, and are subject to change without notice as advances emerge.In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health care provider's best medical judgment based on the clinical circumstances of a particular patient or patient population.Practice guidelines are published by NSGC for educational and informational purposes only, and NSGC does not "approve" or "endorse" any specific methods, practices, or sources of information.

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens.

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

Technical standards and guidelines for spinal muscular atrophy testing.

Spinal muscular atrophy is a common autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. The disease is characterized by progressive symmetrical muscle weakness resulting from the degeneration and loss of anterior horn cells in the spinal cord and brainstem nuclei. The disease is classified on the basis of age of onset and clinical course. Two almost identical SMN genes are present on 5q13: the SMN1 gene, which is the spinal muscular atrophy-determining gene, and the SMN2 gene. The homozygous absence of the SMN1 exon 7 has been observed in the majority of patients and is being used as a reliable and sensitive spinal muscular atrophy diagnostic test. Although SMN2 produces less full-length transcript than SMN1, the number of SMN2 copies has been shown to modulate the clinical phenotype. Carrier detection relies on the accurate determination of the SMN1 gene copies. This document follows the outline format of the general Standards and Guidelines for Clinical Laboratories. It is designed to be a checklist for genetic testing professionals who are already familiar with the disease and methods of analysis.

Cystic fibrosis carrier testing in an ethnically diverse US population.

BACKGROUND: The incidence of cystic fibrosis (CF) and the frequency of specific disease-causing mutations vary among populations. Affected individuals experience a range of serious clinical consequences, notably lung and pancreatic disease, which are only partially dependent on genotype. METHODS: An allele-specific primer-extension reaction, liquid-phase hybridization to a bead array, and subsequent fluorescence detection were used in testing for carriers of 98 CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] mutations among 364 890 referred individuals with no family history of CF. RESULTS: One in 38 individuals carried one of the 98 CFTR mutations included in this panel. Of the 87 different mutations detected, 18 were limited to a single ethnic group. African American, Hispanic, and Asian individuals accounted for 33% of the individuals tested. The mutation frequency distribution of Caucasians was significantly different from that of each of these ethnic groups (P < 1 × 10⁻¹°). CONCLUSIONS: Carrier testing using a broad mutation panel detects differences in the distribution of mutations among ethnic groups in the US.

Carrier testing for spinal muscular atrophy.

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.

Analysis of 3208 cystic fibrosis prenatal diagnoses: impact of carrier screening guidelines on distribution of indications for CFTR mutation and IVS-8 poly(T) analyses.

PURPOSE: To evaluate and quantify indications for CFTR mutation analysis of prenatal specimens, and to determine if a significant portion of tests are performed only for the identification of 5T alleles, we surveyed our laboratory data over a 3-year time period that spanned the issuance of the cystic fibrosis (CF) carrier screening guidelines. METHODS: Referral indications for 3208 prenatal specimens were compared for an 18-month period before (April 2000 to September 2001) and after (October 2001 to April 2003) publication of the ACMG/ACOG statement regarding prenatal and preconception testing for CF. RESULTS: The frequency of cases received for testing when one or both parents were CF mutation carriers did not change significantly after publication of the guidelines. The most frequent indication during the entire 3-year period was fetal ultrasound abnormality, yet in the post-ACMG/ACOG period the percentage decreased significantly due to an increase in the number of prenatal screening cases. Testing indications related to parental 5T status also increased significantly in the post-ACMG/ACOG period and accounted for 2.9% of testing over the 3-year period. A small subset (1.6%) of prenatal specimens were tested for poly(T) even though the parents did not carry 5T allele(s). However, more than 40% of these cases could be attributed to parental R117H mutations. CONCLUSION: These data indicate that although indications for prenatal testing shifted after the issuance of carrier screening guidelines, prenatal testing related to parental 5T alleles comprised < 3% of the total referral indications.

CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations.

PURPOSE: We reviewed CFTR mutation distribution among Hispanic and African American individuals referred for CF carrier screening and compared mutation frequencies to those derived from CF patient samples. METHODS: Results from CFTR mutation analyses received from January 2001 through September 2003, were analyzed for four populations: Hispanic individuals with a CF diagnosis (n = 159) or carrier screening indication (n = 15,333) and African American individuals with a CF diagnosis (n = 108) or carrier screening indication (n = 8,973). All samples were tested for the same 87 mutation panel. RESULTS: In the Hispanic population, 42 mutations were identified: 30 in the patient population (77.5% detection rate) and 33 among carrier screening referrals. Five mutations not included in the ACMG/ACOG carrier screening panel (3876delA, W1089X, R1066C, S549N, 1949del84) accounted for 7.55% detection in patients and 5.58% among carriers. Among African American referrals, 33 different mutations were identified: 21 in the patient population (74.4% detection) and 23 in the carrier screening population. Together, A559T and 711+5G>A were observed at a detection rate of 3.71% in CF patients and 6.38% in carriers. The mutation distribution seen in both the carrier screening populations reflected an increased frequency of mutations with variable expression such as D1152H, R117H, and L206W. CONCLUSIONS: A detailed analysis of CFTR mutation distribution in the Hispanic and African American patient and carrier screening populations demonstrates that a diverse group of mutations is most appropriate for diagnostic and carrier screening in these populations. To best serve the increasingly diverse U.S. population, ethnic-specific mutations should be included in mutation panels.

High allelic heterogeneity between Afro-Brazilians and Euro-Brazilians impacts cystic fibrosis genetic testing.

Cystic fibrosis (CF) is an autosomal recessive disease caused by at least 1,000 different mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). To determine the frequency of 70 common worldwide CFTR mutations in 155 Euro-Brazilian CF patients and in 38 Afro-Brazilian CF patients, we used direct PCR amplification of DNA from a total of 386 chromosomes from CF patients born in three different states of Brazil. The results show that screening for seventy mutations accounts for 81% of the CF alleles in Euro-Brazilians, but only 21% in the Afro-Brazilian group. We found 21 different mutations in Euro-Brazilians and only 7 mutations in Afro-Brazilians. The frequency of mutations and the number of different mutations detected in Euro-Brazilians are different from Northern European and North American populations, but similar to Southern European populations; in Afro-Brazilians, the mix of CF-mutations is different from those reported in Afro-American CF patients. We also found significant differences in detection rates between Euro-Brazilian (75%) and Afro-Brazilian CF patients (21%) living in the same state, Minas Gerais. These results, therefore, have implications for the use of DNA-based tests for risk assessment in heterogeneous populations like the Brazilians. Further studies are needed to identify the remaining CF mutations in the different populations and regions of Brazil.

The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis.

PURPOSE: To determine whether intragenic changes modulate the cystic fibrosis (CF) phenotype in individuals who are positive for the I148T allele. METHODS: The genes from individuals who carried at least one copy of the I148T allele were analyzed for additional changes that may be acting as genetic modifiers. RESULTS: Seven of eight individuals with a known or suspected diagnosis of CF who carried I148T in combination with a severe CF mutation also carried 3199del6. Eight apparently healthy adult individuals who were compound heterozygous for I148T and a severe CF mutation or homozygous for I148T did not carry the deletion ( = 0.0014). The I148T allele occurs on at least three haplotypes: an IVS-8 9T background, a 7T background, or a 9T + 3199del6 background. The 3199del6 allele was not identified in 386 non-CF chromosomes. CONCLUSIONS: It is concluded that I148T occurs on at least three haplotypes and the complex allele I148T + 9T + 3199del6 is associated with a classic CF phenotype.