Cystic Fibrosis Carrier Testing Research Articles

Newborn screening for cystic fibrosis: Role of primary care providers in caring for infants with positive screening results.

To explore primary care providers' (PCPs') preferred roles and confidence in caring for infants receiving a positive cystic fibrosis (CF) newborn screening (NBS) result, as well as management of CF family planning issues, given that expanded NBS has resulted in an increase in positive results. Mailed questionnaire. Ontario. Ontario FPs, pediatricians, and midwives identified by Newborn Screening Ontario as having had an infant with a positive CF NBS result in their practice in the previous 6 months. Primary care providers' preferred roles in providing well-baby care for infants with positive CF screening results. Overall, 321 of 628 (51%) completed surveys (208 FPs, 68 pediatricians, 45 midwives). For well-baby care for infants confirmed to have CF, 77% of PCPs indicated they would not provide total care (ie, 68% would share care with other specialists and 9% would refer to specialists completely); for infants with an inconclusive CF diagnosis, 50% of PCPs would provide total care, 45% would provide shared care, and 5% would refer to a specialist; for CF carriers, 89% of PCPs would provide total care, 9% would provide shared care, and 2% would refer. Half (54%) of PCPs were extremely or very confident in providing reassurance about CF carriers' health. Only 25% knew how to order parents' CF carrier testing; 67% knew how to refer for prenatal diagnosis. Confidence in reassuring parents about the health of CF carrier children was associated with providing total well-baby care for CF carriers (risk ratio of 1.50; 95% CI 1.14 to 1.97) and infants with an inconclusive diagnosis (risk ratio of 3.30; 95% CI 1.34 to 8.16). Most PCPs indicated willingness to treat infants with a range of CF NBS results in some capacity. It is concerning that some indicated CF carriers should have specialist involvement and only half were extremely or very confident about reassuring families about carrier status. This raises issues about possible medicalization of those with carrier status, prompting the need for PCP education about genetic disorders and the meaning of genetic test results.

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges.

Identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis, research and treatment of cystic fibrosis (CF). The current and future challenges of molecular diagnosis of CF and CFTR-related disorders and of genetic counseling are here reviewed. Technological advances have enabled to make a diagnosis of CF with a sensitivity of 99% by using next generation sequencing in a single step. The detection of heretofore unidentified variants and ethnic-specific variants remains challenging, especially for newborn screening (NBS), CF carrier testing and genotype-guided therapy. Among the criteria for assessing the impact of variants, population genetics data are insufficiently taken into account and the penetrance of CF associated with CFTR variants remains poorly known. The huge diversity of diagnostic and genetic counseling indications for CFTR studies makes assessment of variant disease-liability critical. This is especially discussed in the perspective of wide genome analyses for NBS and CF carrier screening in the general population, as future challenges.

Creating genetic reports that are understood by nonspecialists: a case study

PurposeGuidelines recommend that genetic reports should be clear to nonspecialists, including patients. We investigated the feasibility of creating reports for cystic fibrosis carrier testing through a rapid user-centered design process that built on a previously developed generic template. We evaluated the new reports’ communication efficacy and effects on comprehension against comparable reports used in current clinical practice. MethodsThirty participants took part in three rounds of interviews. Usability problems were identified and rectified in each round. One hundred ninety-three participants took part in an evaluation of the resulting reports measuring subjective comprehension, risk probability comprehension, perceived communication efficacy, and other factors, as compared with standard reports. ResultsParticipants viewing the user-centered reports rated them as clearer, easier to understand, and more effective at communicating key information than standard reports. Both groups ended up with equivalent knowledge of risk probabilities, although we observed differences in how those probabilities were perceived. ConclusionOur findings demonstrate that by starting with a patient-friendly generic report template and modifying it for specific scenarios with a rapid user-centered design process, reports can be produced that are more effective at communicating key information. The resulting reports are now being implemented into clinical care.

Exploring approaches to facilitate family communication of genetic risk information after cystic fibrosis population carrier screening.

Population carrier screening for cystic fibrosis (CF) enables individuals with no known family history of the condition to ascertain their risk of having a child with CF. When an individual is identified as a carrier of CF, a life-shortening condition, they are encouraged to inform their relatives who are at increased risk of being a carrier. Research suggests that the uptake of CF carrier testing amongst relatives of carriers or people with CF is low. This study aimed to explore approaches to facilitate the process of family communication of genetic information after an individual is identified as a carrier of CF through population screening. Five key informants were interviewed to inform the development of a telephone survey which was administered to 21 individuals identified as carriers of CF through population carrier screening at Victorian Clinical Genetics Services. This study suggests that providing carriers with additional information and follow-up support would be appreciated by carriers and could result in more accurate information being disseminated more widely within families, which could lead to more at-risk relatives accessing testing. Suggested strategies to enhance current practice include mailing a fact sheet to carriers and a follow-up telephone call provided by a genetic counsellor to carriers to offer further support in communicating this information to their relatives.

VP103 Health Technology Assessment Of Genetic Tests For Cystic Fibrosis Carrier Screening In Italy

INTRODUCTION:Cystic Fibrosis (CF) is a genetic disorder caused by mutations in CFTR gene. In Italy, reported prevalence is approximately .70 per 10,000 inhabitants (1). The practice and recommendations for Cystic Fibrosis carrier screening are very heterogeneous in Europe. A proposal of a carrier genetic test in the general population raises many questions. Health Technology Assessment (HTA) could offer a sound methodological basis for this evaluation. The aim of this work was to summarize the available evidence, using the HTA approach, on the genetic tests for Cystic Fibrosis carrier screening.METHODS:A systematic literature search was used to find the best available international and national evidence on genetics test for CF carrier screening. In this report, we specifically addressed the health problem of disease, description and technical characteristics of tests – its analytic and clinical validity, and clinical utility. Economic evaluation of different scenarios was synthesized from the literature. Ethical, organizational, and social aspects of CF and genetic screening were also considered.RESULTS:Several screening strategies have been evaluated in the literature and screening options can be characterized by different timing, model and place of screening (2). The reported cost of a screening test ranged from EUR25 to EUR212 (3). Estimated life time cost of care for CF patients ranged from EUR291,048 to EUR1,105,452. Ethical analysis emphasized that the use of these tests is an advantage in terms of the acquisition of knowledge and of responsible management of choices, but at the same time raises many ethical questions. Social considerations reported among patients and their families an overall positive attitude toward population CF carrier screening.CONCLUSIONS:The advances in the molecular genetics technology have made CF carrier testing reliable and affordable. The multidisciplinary approach of this HTA provided an evidence-based evaluation of genetic tests and offers a firm scientific background for the decision-makers to consider the implementation of a screening for Cystic Fibrosis carriers into the Italian health care system.

Revisión sistemática de estudios de costo-efectividad del test de portadores para fibrosis quística

Introducción. La fibrosis quística es considerada la enfermedad autosómica con afecciones multisistémicas más común en población blanca no hispánica.Objetivo. Revisar la evidencia disponible sobre costo-efectividad del test de portador para fibrosis quística en comparación con la no intervención.Materiales y métodos. Se realizó una revisión sistemática de evaluación de costo-efectividad del test genético para portadores de fibrosis quística a través de las base de datos MEDLINE, Embase, NHS, EBM Reviews - Cochrane Database of Systematic Reviews, LILACS, Health Technology Assessment, Genetests.org, Genetsickkids.org y Web of Science. Fueron incluidos estudios de costo-efectividad sin restricción de lenguaje ni fecha de publicación.Resultados. Solo 13 estudios fueron relevantes para su revisión completa. Se encontraron estrategias de tamizaje prenatal, preconcepcional y mixto. La perspectiva en salud fue la más usada; la tasa de descuento aplicada fue heterogénea entre 3.5% y 5%; la unidad de análisis principal fue el costo por pareja portadora detectada seguida de costo por nacimiento evitado con fibrosis quística. Se evidenció que la estrategia más costoefectiva fue la del tamizaje preconcepcional asociada al test prenatal.Conclusiones. Se encontró marcada heterogeneidad en la metodología aplicada, lo que llevo a que los resultados no fueran comparables y se concluyera que existen diferentes enfoques de este test genético.

Expanded carrier screening panels-does bigger mean better?

Prenatal carrier screening is offered for some inherited conditions based on recommendations of the American Congress of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG). Currently, ACOG and ACMG recommend that cystic fibrosis carrier screening be offered to all women of reproductive age and that fragile X syndrome (FXS) carrier screening be offered to women with a family history suggestive of FXS or who ask to have testing following genetic counseling (Committee Opinion 469 2010; Committee Opinion 486 2011). For individuals of Eastern European Jewish descent, ACOG recommends carrier screening for Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia (Committee Opinion 442 2009) stating that further testing should be permitted with appropriate counseling if the patient inquires about other conditions that occur more commonly in their ethnic group. ACMG recommends general population screening for spinal muscular atrophy, though this is unsupported by ACOG (Committee Opinion 432 2009; Prior 2008). All of these conditions are inherited in an autosomal recessive fashion except for fragile X syndrome, which is X-linked. People have two copies of each autosomal gene, one inherited from each parent. Recessive conditions manifest when both copies of the same gene have a mutation or do not function normally. Carriers have one abnormal gene copy, as well as one normal copy and are asymptomatic individuals. A 25 % risk for an affected child exists when both parents are carriers, as that poses a one in four risk for a child to receive a gene mutation from both parents. It is estimated that each individual is a carrier of between zero and seven severe childhood recessive conditions, with an average of 2.8 found in one study (Bell et al. 2011). As the first condition for which ethnicity based carrier screening was offered, cystic fibrosis (CF) is the most common lifelimiting autosomal recessive condition in non-Hispanic Caucasians. The debate over general population carrier screening began in 1990 following the discovery of the gene associated with cystic fibrosis (Karem et al. 1989; Beaudet 1990; Caskey et al. 1990; Tatsugawa et al. 1994). The discovery of the gene and the subsequent development of a genetic test were considered breakthroughs in science that would presumably lead to a cure. Questions of when and to who to offer the test presented a new ethical quandary at that time. The first report regarding routine CF carrier screening recommended against offering it to pregnant women stating that it should not yet be considered standard of care (Caskey et al. 1990). With the main benefit being to provide information for reproductive decision making, the potential limitations include anxiety over residual risk, anxiety associated with carrier status, and the cost of testing a large volume of people with very little financial benefit (Beaudet 1990). This debate was largely resolved over the next 10 years by an improvement in testing that increased detection rate, thereby reducing residual risk after negative CF carrier testing. By 2001, prenatal and preconception carrier screening for CF was S. Wienke : C. Strange Division of Pulmonary & Critical Care, Medical University of South Carolina, Charleston, SC, USA

Molecular Testing for Cystic Fibrosis Carrier Status Practice Guidelines: Recommendations of the National Society of Genetic Counselors

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.

CFTR2: How will it help care?

The Clinical and Functional Translation of CFTR (CFTR2) project presents a novel approach to clinical and functional annotation of mutations identified in disease-causing genes. Phenotype and genotype information on approximately 40,000 cystic fibrosis (CF) patients were collected from registries and large clinics. The disease-liability of the 160 most frequently reported mutations was evaluated by means of a multistage process which involved clinical (sweat chloride average), functional (expression in cell-based systems) and epidemiological (mutation analysis in obligate heterozygotes) steps. The results of this analysis can be consulted in a dedicated website. Data originated by CFTR2 may be valuable in several facets of CF care, including diagnosis, newborn screening, carrier testing, genotype/phenotype correlation and mutation-specific therapeutics.

Verification of Performance Specifications of a Molecular Test: Cystic Fibrosis Carrier Testing Using the Luminex Liquid Bead Array

The number of clinical laboratories introducing various molecular tests to their existing test menu is continuously increasing. Prior to offering a US Food and Drug Administration-approved test, it is necessary that performance characteristics of the test, as claimed by the company, are verified before the assay is implemented in a clinical laboratory. To provide an example of the verification of a specific qualitative in vitro diagnostic test: cystic fibrosis carrier testing using the Luminex liquid bead array (Luminex Molecular Diagnostics, Inc, Toronto, Ontario). The approach used by an individual laboratory for verification of a US Food and Drug Administration-approved assay is described. Specific verification data are provided to highlight the stepwise verification approach undertaken by a clinical diagnostic laboratory. Protocols for verification of in vitro diagnostic assays may vary between laboratories. However, all laboratories must verify several specific performance specifications prior to implementation of such assays for clinical use. We provide an example of an approach used for verifying performance of an assay for cystic fibrosis carrier screening.

An Interactive Computer Program Can Effectively Educate Potential Users of Cystic Fibrosis Carrier Tests

The demand for cystic fibrosis (CF) carrier testing is steadily growing, not only from individuals with raised a priori carrier risk, but also from the general population. This trend will likely exceed the availability of genetic counselors, making it impossible to provide standard face-to-face genetic counseling to all those asking for the test. In order to reduce the time needed to educate individuals on the basics of the disease, its genetic transmission, and carrier testing peculiarities, we developed an educational method based on an interactive computer program (IC). To assess the effectiveness of this program and to compare it to a classical genetic counseling session, we conducted a comparative trial. In a population setting of people undergoing assisted reproduction, 44 individuals were randomly assigned to either receiving standard one-on-one genetic counseling or education by the IC program. We measured pre- and post-intervention knowledge about CF genetic transmission and carrier testing. Starting from an equivalent baseline of correct answers to a specially designed multiple-choice questionnaire (47% in the counselor group and 45% in the computer group) both groups showed a highly significant and similar increase (reaching 84% in the counselor group and 85% in the computer group). The computer program under evaluation can successfully educate individuals considering genetic testing for CF. © 2011 Wiley-Liss, Inc.

Cystic Fibrosis Carrier Testing in an Ethnically Diverse US Population

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. 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. 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 × 10⁻¹⁰). Carrier testing using a broad mutation panel detects differences in the distribution of mutations among ethnic groups in the US.

An interactive computer program can effectively educate potential users of cystic fibrosis carrier tests

The demand for cystic fibrosis (CF) carrier testing is steadily growing, not only from individuals with raised a priori carrier risk, but also from the general population. This trend will likely exceed the availability of genetic counselors, making it impossible to provide standard face-to-face genetic counseling to all those asking for the test. In order to reduce the time needed to educate individuals on the basics of the disease, its genetic transmission, and carrier testing peculiarities, we developed an educational method based on an interactive computer program (IC). To assess the effectiveness of this program and to compare it to a classical genetic counseling session, we conducted a comparative trial. In a population setting of people undergoing assisted reproduction, 44 individuals were randomly assigned to either receiving standard one-on-one genetic counseling or education by the IC program. We measured pre- and post-intervention knowledge about CF genetic transmission and carrier testing. Starting from an equivalent baseline of correct answers to a specially designed multiple-choice questionnaire (47% in the counselor group and 45% in the computer group) both groups showed a highly significant and similar increase (reaching 84% in the counselor group and 85% in the computer group). The computer program under evaluation can successfully educate individuals considering genetic testing for CF.

A case for cystic fibrosis carrier testing in the general population

A case for cystic fibrosis carrier testing in the general population

Ethical considerations in choosing a model for population‐based cystic fibrosis carrier screening

Cystic fibrosis (CF) carrier testing can be used to inform reproductive decision making, allowing carriers to avoid having a child with CF. A government-funded, population-based CF carrier screening program would allow greater equity of access to this test. The setting in which CF carrier screening is offered significantly affects the extent to which participants make well informed, voluntary decisions to accept or decline testing. Screening offered before pregnancy and in non-clinical environments better promotes participant autonomy than screening offered in the prenatal consultation.

Uptake of carrier testing in families after cystic fibrosis diagnosis through newborn screening

Newborn screening (NBS) for cystic fibrosis (CF) provides the opportunity for cascade carrier testing of relatives. Uptake of testing by adult non-parent relatives of children diagnosed with CF through NBS has not been previously described, and this study describes uptake by both parents and adult non-parent relatives in Victoria, Australia. Pedigrees were taken from parents of children who were born in 2000-2004 and diagnosed with CF. A total of 40 families were eligible for the study and 30 (75%) were recruited. In all, 716 non-parent relatives were identified from the pedigrees as eligible for carrier testing, and 82 (adjusted uptake percentage: 11.8%; 95% confidence interval 8.0-15.7) have had carrier testing by March 2009. On average, 2.7 non-parent relatives per family had CF carrier testing after diagnosis through NBS. The odds of being tested were greater for females than males (adjusted odds ratio 1.61; 95% confidence interval 1.11-2.33; P=0.01) and greater for those more closely related to the child with CF (adjusted odds ratio 5.17; 95% confidence interval 2.38-11.24; P<0.001). Most relatives who undergo testing are tested immediately after the baby's diagnosis; however, some testing is undertaken up to 8 years later. These results indicate that in a clinical setting, the diagnosis of a baby with CF by NBS does not lead to carrier testing for the majority of the baby's non-parent relatives. We suggest re-contact with parents to offer cascade carrier testing.

Outcomes of a cystic fibrosis carrier testing clinic for couples

Outcomes of a cystic fibrosis carrier testing clinic for couples

Outcomes of a cystic fibrosis carrier testing clinic for couples

Outcomes of a cystic fibrosis carrier testing clinic for couples

Outcomes of a cystic fibrosis carrier testing clinic for couples

To review the outcomes of offering carrier testing for cystic fibrosis (CF) to couples considering pregnancy, and to women in early pregnancy and their partners. An after-hours clinic was established in Newcastle for discussion of issues related to prenatal testing. Couples were offered CF carrier testing by extracting DNA from a mouthwash sample. An expanded one-step model was used with both partners being tested initially for the p.F508del cystic fibrosis transmembrane conductance regulator gene (CFTR) mutation. If one partner was a p.F508del carrier, the other partner was tested for an additional 28 CFTR mutations. Of 1000 individuals who were offered CF carrier testing, none declined. No re-collections of mouthwash samples were required, and results were available within 14 days. There were 730 individuals who had no family history of CF (73%); 27 were carriers (4%; 95% CI, 2.4%-5.3%), and there were two high-risk couples where both partners were carriers of p.F508del. There were 270 individuals who had an affected family member with CF or a child identified as a CF carrier through newborn screening; 126 were carriers (46%; 95% CI, 40.6%-52.8%), and there were two high-risk couples - one couple where both partners were carriers of p.F508del, and another couple where the woman was homozygous for p.F508del and the man was a p.F508del carrier. The information on carrier status led the four high-risk couples to change their reproductive decisions to avoid having a child with CF. CF carrier testing for couples using an expanded one-step model will detect about 80% of high-risk couples and enables various reproductive choices. We believe that all couples considering pregnancy, and women in early pregnancy and their partners, should be offered CF carrier testing.

Pregnancy as Foreground in Cystic Fibrosis Carrier Testing Decisions in Primary Care

Cystic fibrosis carrier testing (CFCT) is among the first of the DNA tests offered prenatally in primary care settings. This paper from a descriptive qualitative study describes the influence of pregnancy in CFCT decisions by women receiving community-based prenatal care. Twenty-seven women receiving prenatal care in Midwestern U.S. primary care clinics completed semistructured interviews. Audiotaped interviews were analyzed using content analysis. Participants described decision-making influences and strategies from the perspective of "being pregnant." Patterns of attitudes and beliefs include (1) dealing with emotions, (2) pregnancy is natural, and (3) thinking about the baby. Strategies in the decision-making process included (1) reducing stress, (2) choosing what is relevant, (3) doing everything right, (4) wanting to be prepared, (5) delaying information, and (6) trusting God. While other factors were mentioned by some women, major themes reflect the influence of currently being pregnant on the decision-making process. These findings suggest that pregnancy is a powerful influence on the decision-making process and may not be the optimal time to make fully informed decisions regarding genetic carrier testing. Further understanding of factors influencing the genetic testing decision-making process is needed. Offering CFCT prior to conception is advocated.