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1.  Perception, Experience, and Response to Genetic Discrimination in Huntington Disease: The International RESPOND-HD Study 
Genetic discrimination—defined as the denial of rights, privileges, or opportunities or other adverse treatment based solely on genetic information (including family history)—is an important concern to patients, healthcare professionals, lawmakers, and family members at risk for carrying a deleterious gene. Data from the United States, Canada, and Australia were collected from 433 individuals at risk for Huntington disease (HD) who have tested either positive or negative for the gene that causes HD and family members of affected individuals who have a 50% risk for developing the disorder but remain untested. Across all three countries, a total of 46.2% of respondents report genetic discrimination or stigma based on either their family history of HD or genetic testing for the HD gene mutation. We report on the overall incidence of discrimination and stigma in the domains of insurance (25.9%), employment (6.5%), relationships (32.9%), and other transactions (4.6%) in the United States, Canada, and Australia combined. The incidence of self-reported discrimination is less than the overall worry about the risk of discrimination, which is more prevalent in each domain. Despite a relatively low rate of perceived genetic discrimination in the areas of health insurance and employment, compared to the perception of discrimination and stigma in personal relationships, the cumulative burden of genetic discrimination across all domains of experience represents a challenge to those at risk for HD. The effect of this cumulative burden on daily life decisions remains unknown.
doi:10.1002/ajmg.b.31079
PMCID: PMC3593716  PMID: 20468061
survey; employment; insurance; family history; genetic testing
2.  Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study 
A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of ‘DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.
doi:10.1038/ejhg.2012.5
PMCID: PMC3376271  PMID: 22293687
familial hypercholesterolemia; hyperlipoproteinemia Type II; genetic testing; genetic testing and adverse effects; life insurance
3.  Unravelling fears of genetic discrimination: an exploratory study of Dutch HCM families in an era of genetic non-discrimination acts 
European Journal of Human Genetics  2012;20(10):1018-1023.
Since the 1990s, many countries in Europe and the United States have enacted genetic non-discrimination legislation to prevent people from deferring genetic tests for fear that insurers or employers would discriminate against them based on that information. Although evidence for genetic discrimination exists, little is known about the origins and backgrounds of fears of discrimination and how it affects decisions for uptake of genetic testing. The aim of this article is to gain a better understanding of these fears and its possible impact on the uptake of testing by studying the case of hypertrophic cardiomyopathy (HCM). In a qualitative study, we followed six Dutch extended families involved in genetic testing for HCM for three-and-a-half years. Semi-structured interviews were conducted with 57 members of these families. Based on the narratives of the families, we suggest that fears of discrimination have to be situated in the broader social and life-course context of family and kin. We describe the processes in which families developed meaningful interpretations of genetic discrimination and how these interpretations affected family members' decisions to undergo genetic testing. Our findings show that fears of genetic discrimination do not so much stem from the opportunity of genetic testing but much more from earlier experiences of discrimination of diseased family members. These results help identify the possible limitations of genetic non-discrimination regulations and provide direction to clinicians supporting their clients as they confront issues of genetic testing and genetic discrimination.
doi:10.1038/ejhg.2012.53
PMCID: PMC3449067  PMID: 22453290
genetic discrimination; fear; insurance; family experiences; hypertrophic cardiomyopathy
4.  The Role of the Geneticist and Genetic Counselor in an ACHD Clinic 
There is a growing population of adults with congenital heart disease due to the advancements in surgical repair and medical management. At the same time, the understanding of the genetic basis of both syndromic and isolated congenital heart disease has grown tremendously and is being rapidly translated into changes in clinical care, resulting in an increasing need for incorporation of genetic expertise into the care of adult congenital heart disease patients. Here we review the importance of delivery of genetic information to the adult congenital heart disease population and highlight the shared and distinct roles of clinical geneticists and genetic counselors in provision of services. The adult congenital heart disease patient population has unique needs and clinical geneticists and genetic counselors can play an important role in the diagnostic evaluation and assessment of these patients to provide an accurate etiologic diagnosis and to counsel regarding genetic testing, recurrence risk, family screening, and prenatal diagnosis.
doi:10.1016/j.ppedcard.2012.05.004
PMCID: PMC3462440  PMID: 23049235
Genetics; genetic counseling; recurrence risk; syndrome
5.  Should healthcare providers have a duty to warn family members of individuals with an HNPCC‐causing mutation? A survey of patients from the Ontario Familial Colon Cancer Registry 
Journal of Medical Genetics  2007;44(6):404-407.
Background
As genetic testing becomes more common and increasingly intertwined with medical care, the issues of genetic privacy and doctor–patient confidentiality are being examined. Hereditary non‐polyposis colorectal cancer (HNPCC) is a genetic predisposition to colorectal and certain other cancers. Effective screening that can prevent colorectal cancer is an important incentive for genetic testing.
Methods
A survey regarding the duty to warn family members of the risks associated with an HNPCC‐causing mutation was mailed to 227 participants in the Ontario Familial Colon Cancer Registry (OFCCR). To our knowledge, the opinions of patients on this subject have not been reported previously in the literature. Responses were analysed quantitatively using the SAS system and qualitatively by the review of written comments.
Results
Completed surveys were returned by 105 participants, with a response rate of 46.3%. The majority felt a personal responsibility to warn relatives, but there was no significant agreement that doctors or genetic counsellors should have a duty to warn relatives without a patient's permission.
Conclusions
Patients undergoing genetic testing for HNPCC generally understand that relatives could benefit from being informed of genetic risk, but may not be willing or able to inform each family member. Healthcare professionals should engage patients in a discussion of familial implications before genetic testing. An agreement should be formulated regarding which of the relatives should be informed. Patients should be encouraged to personally disseminate the information, given the unrealistic burden on practitioners to perform this task and patients' preference for control over the information.
doi:10.1136/jmg.2006.047357
PMCID: PMC2740891  PMID: 17551085
6.  Genetic Testing in Psychiatry: A Review of Attitudes and Beliefs 
Psychiatry  2011;74(4):315-331.
The advent of genetic testing for psychiatric conditions raises difficult questions about when and how the tests should be used. Development of policies regarding these issues may be informed in a variety of ways by the views of key stakeholders: patients, family members, healthcare professionals, and the general public. Here we review empirical studies of attitudes towards genetic testing among these groups. Patients and family members show strong interest in diagnostic and predictive genetic testing, and to a considerable extent psychiatrists share their enthusiasm. Prenatal test utilization seems likely to depend both on parental views on abortion and the seriousness of the disorder. Parents show a surprising degree of interest in predictive testing of children, even when there are no preventive interventions available. Many persons report themselves ready to alter their lifestyles and plans for marriage and family in response to test results. Respondents also fear negative consequences, from discrimination to being unable to cope with knowledge of their “genetic fate.” Empirical studies of beliefs about genetic testing suggest tests are likely to be embraced widely, but the studies have methodologic limitations, reducing the certainty of their conclusions, and indicating a need for further research with more representative samples.
doi:10.1521/psyc.2011.74.4.315
PMCID: PMC3285424  PMID: 22168293
genetic testing; psychiatry; ethics
7.  Medical and ethical issues in genetic screening--an academic view. 
Environmental Health Perspectives  1996;104(Suppl 5):987-990.
This article is intended to acquaint those whose principal concerns are the health and safety of workers with genetic screening and some of the medical and ethical issues it raises. Population-based genetic screening increasingly is being considered for predicting future disease in the person being screened. A major problem in screening for alleles that contribute to the development of common, multifactorial disorders is low sensitivity and positive predictive value. In many instances, no demonstrably effective prophylaxis or treatment is available to help those with positive test results. This creates ethical problems of assuring that testing is in the person's best interest and raises in turn issues of autonomy, discrimination, and privacy. Instead of screening for genetic predispositions to harm from workplace exposures, other means of improving the health of workers may bring greater benefits to a higher proportion of workers. The current state of genetic tests for chronic beryllium disease are considered. None are suitable for screening.
PMCID: PMC1469693  PMID: 8933046
8.  Clinical Utility of Serologic Testing for Celiac Disease in Ontario 
Executive Summary
Objective of Analysis
The objective of this evidence-based evaluation is to assess the accuracy of serologic tests in the diagnosis of celiac disease in subjects with symptoms consistent with this disease. Furthermore the impact of these tests in the diagnostic pathway of the disease and decision making was also evaluated.
Celiac Disease
Celiac disease is an autoimmune disease that develops in genetically predisposed individuals. The immunological response is triggered by ingestion of gluten, a protein that is present in wheat, rye, and barley. The treatment consists of strict lifelong adherence to a gluten-free diet (GFD).
Patients with celiac disease may present with a myriad of symptoms such as diarrhea, abdominal pain, weight loss, iron deficiency anemia, dermatitis herpetiformis, among others.
Serologic Testing in the Diagnosis Celiac Disease
There are a number of serologic tests used in the diagnosis of celiac disease.
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibodies (DGP)
Serologic tests are automated with the exception of the EMA test, which is more time-consuming and operator-dependent than the other tests. For each serologic test, both immunoglobulin A (IgA) or G (IgG) can be measured, however, IgA measurement is the standard antibody measured in celiac disease.
Diagnosis of Celiac Disease
According to celiac disease guidelines, the diagnosis of celiac disease is established by small bowel biopsy. Serologic tests are used to initially detect and to support the diagnosis of celiac disease. A small bowel biopsy is indicated in individuals with a positive serologic test. In some cases an endoscopy and small bowel biopsy may be required even with a negative serologic test. The diagnosis of celiac disease must be performed on a gluten-containing diet since the small intestine abnormalities and the serologic antibody levels may resolve or improve on a GFD.
Since IgA measurement is the standard for the serologic celiac disease tests, false negatives may occur in IgA-deficient individuals.
Incidence and Prevalence of Celiac Disease
The incidence and prevalence of celiac disease in the general population and in subjects with symptoms consistent with or at higher risk of celiac disease based on systematic reviews published in 2004 and 2009 are summarized below.
Incidence of Celiac Disease in the General Population
Adults or mixed population: 1 to 17/100,000/year
Children: 2 to 51/100,000/year
In one of the studies, a stratified analysis showed that there was a higher incidence of celiac disease in younger children compared to older children, i.e., 51 cases/100,000/year in 0 to 2 year-olds, 33/100,000/year in 2 to 5 year-olds, and 10/100,000/year in children 5 to 15 years old.
Prevalence of Celiac Disease in the General Population
The prevalence of celiac disease reported in population-based studies identified in the 2004 systematic review varied between 0.14% and 1.87% (median: 0.47%, interquartile range: 0.25%, 0.71%). According to the authors of the review, the prevalence did not vary by age group, i.e., adults and children.
Prevalence of Celiac Disease in High Risk Subjects
Type 1 diabetes (adults and children): 1 to 11%
Autoimmune thyroid disease: 2.9 to 3.3%
First degree relatives of patients with celiac disease: 2 to 20%
Prevalence of Celiac Disease in Subjects with Symptoms Consistent with the Disease
The prevalence of celiac disease in subjects with symptoms consistent with the disease varied widely among studies, i.e., 1.5% to 50% in adult studies, and 1.1% to 17% in pediatric studies. Differences in prevalence may be related to the referral pattern as the authors of a systematic review noted that the prevalence tended to be higher in studies whose population originated from tertiary referral centres compared to general practice.
Research Questions
What is the sensitivity and specificity of serologic tests in the diagnosis celiac disease?
What is the clinical validity of serologic tests in the diagnosis of celiac disease? The clinical validity was defined as the ability of the test to change diagnosis.
What is the clinical utility of serologic tests in the diagnosis of celiac disease? The clinical utility was defined as the impact of the test on decision making.
What is the budget impact of serologic tests in the diagnosis of celiac disease?
What is the cost-effectiveness of serologic tests in the diagnosis of celiac disease?
Methods
Literature Search
A literature search was performed on November 13th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st 2003 and November 13th 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Studies that evaluated diagnostic accuracy, i.e., both sensitivity and specificity of serology tests in the diagnosis of celiac disease.
Study population consisted of untreated patients with symptoms consistent with celiac disease.
Studies in which both serologic celiac disease tests and small bowel biopsy (gold standard) were used in all subjects.
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, and retrospective cohort studies.
At least 20 subjects included in the celiac disease group.
English language.
Human studies.
Studies published from 2000 on.
Clearly defined cut-off value for the serology test. If more than one test was evaluated, only those tests for which a cut-off was provided were included.
Description of small bowel biopsy procedure clearly outlined (location, number of biopsies per patient), unless if specified that celiac disease diagnosis guidelines were followed.
Patients in the treatment group had untreated CD.
Studies on screening of the general asymptomatic population.
Studies that evaluated rapid diagnostic kits for use either at home or in physician’s offices.
Studies that evaluated diagnostic modalities other than serologic tests such as capsule endoscopy, push enteroscopy, or genetic testing.
Cut-off for serologic tests defined based on controls included in the study.
Study population defined based on positive serology or subjects pre-screened by serology tests.
Celiac disease status known before study enrolment.
Sensitivity or specificity estimates based on repeated testing for the same subject.
Non-peer-reviewed literature such as editorials and letters to the editor.
Population
The population consisted of adults and children with untreated, undiagnosed celiac disease with symptoms consistent with the disease.
Serologic Celiac Disease Tests Evaluated
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibody (DGP)
Combinations of some of the serologic tests listed above were evaluated in some studies
Both IgA and IgG antibodies were evaluated for the serologic tests listed above.
Outcomes of Interest
Sensitivity
Specificity
Positive and negative likelihood ratios
Diagnostic odds ratio (OR)
Area under the sROC curve (AUC)
Small bowel biopsy was used as the gold standard in order to estimate the sensitivity and specificity of each serologic test.
Statistical Analysis
Pooled estimates of sensitivity, specificity and diagnostic odds ratios (DORs) for the different serologic tests were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance for differences in sensitivity and specificity between serologic tests was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. The bivariate regression analyses were performed using SAS version 9.2 (SAS Institute Inc.; Cary, NC, USA). Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced using Review Manager 5.0.22 (The Nordiac Cochrane Centre, The Cochrane Collaboration, 2008). The area under the sROC curve (AUC) was estimated by bivariate mixed-efects binary regression modeling framework. Model specification, estimation and prediction are carried out with xtmelogit in Stata release 10 (Statacorp, 2007). Statistical tests for the differences in AUC estimates could not be carried out.
The study results were stratified according to patient or disease characteristics such as age, severity of Marsh grade abnormalities, among others, if reported in the studies. The literature indicates that the diagnostic accuracy of serologic tests for celiac disease may be affected in patients with chronic liver disease, therefore, the studies identified through the systematic literature review that evaluated the diagnostic accuracy of serologic tests for celiac disease in patients with chronic liver disease were summarized. The effect of the GFD in patiens diagnosed with celiac disease was also summarized if reported in the studies eligible for the analysis.
Summary of Findings
Published Systematic Reviews
Five systematic reviews of studies that evaluated the diagnostic accuracy of serologic celiac disease tests were identified through our literature search. Seventeen individual studies identified in adults and children were eligible for this evaluation.
In general, the studies included evaluated the sensitivity and specificity of at least one serologic test in subjects with symptoms consistent with celiac disease. The gold standard used to confirm the celiac disease diagnosis was small bowel biopsy. Serologic tests evaluated included tTG, EMA, AGA, and DGP, using either IgA or IgG antibodies. Indirect immunoflurorescence was used for the EMA serologic tests whereas enzyme-linked immunosorbent assay (ELISA) was used for the other serologic tests.
Common symptoms described in the studies were chronic diarrhea, abdominal pain, bloating, unexplained weight loss, unexplained anemia, and dermatitis herpetiformis.
The main conclusions of the published systematic reviews are summarized below.
IgA tTG and/or IgA EMA have a high accuracy (pooled sensitivity: 90% to 98%, pooled specificity: 95% to 99% depending on the pooled analysis).
Most reviews found that AGA (IgA or IgG) are not as accurate as IgA tTG and/or EMA tests.
A 2009 systematic review concluded that DGP (IgA or IgG) seems to have a similar accuracy compared to tTG, however, since only 2 studies identified evaluated its accuracy, the authors believe that additional data is required to draw firm conclusions.
Two systematic reviews also concluded that combining two serologic celiac disease tests has little contribution to the accuracy of the diagnosis.
MAS Analysis
Sensitivity
The pooled analysis performed by MAS showed that IgA tTG has a sensitivity of 92.1% [95% confidence interval (CI) 88.0, 96.3], compared to 89.2% (83.3, 95.1, p=0.12) for IgA DGP, 85.1% (79.5, 94.4, p=0.07) for IgA EMA, and 74.9% (63.6, 86.2, p=0.0003) for IgA AGA. Among the IgG-based tests, the results suggest that IgG DGP has a sensitivity of 88.4% (95% CI: 82.1, 94.6), 44.7% (30.3, 59.2) for tTG, and 69.1% (56.0, 82.2) for AGA. The difference was significant when IgG DGP was compared to IgG tTG but not IgG AGA. Combining serologic celiac disease tests yielded a slightly higher sensitivity compared to individual IgA-based serologic tests.
IgA deficiency
The prevalence of total or severe IgA deficiency was low in the studies identified varying between 0 and 1.7% as reported in 3 studies in which IgA deficiency was not used as a referral indication for celiac disease serologic testing. The results of IgG-based serologic tests were positive in all patients with IgA deficiency in which celiac disease was confirmed by small bowel biopsy as reported in four studies.
Specificity
The MAS pooled analysis indicates a high specificity across the different serologic tests including the combination strategy, pooled estimates ranged from 90.1% to 98.7% depending on the test.
Likelihood Ratios
According to the likelihood ratio estimates, both IgA tTG and serologic test combinationa were considered very useful tests (positive likelihood ratio above ten and the negative likelihood ratio below 0.1).
Moderately useful tests included IgA EMA, IgA DGP, and IgG DGP (positive likelihood ratio between five and ten and the negative likelihood ratio between 0.1 and 0.2).
Somewhat useful tests: IgA AGA, IgG AGA, generating small but sometimes important changes from pre- to post-test probability (positive LR between 2 and 5 and negative LR between 0.2 and 0.5)
Not Useful: IgG tTG, altering pre- to post-test probability to a small and rarely important degree (positive LR between 1 and 2 and negative LR between 0.5 and 1).
Diagnostic Odds Ratios (DOR)
Among the individual serologic tests, IgA tTG had the highest DOR, 136.5 (95% CI: 51.9, 221.2). The statistical significance of the difference in DORs among tests was not calculated, however, considering the wide confidence intervals obtained, the differences may not be statistically significant.
Area Under the sROC Curve (AUC)
The sROC AUCs obtained ranged between 0.93 and 0.99 for most IgA-based tests with the exception of IgA AGA, with an AUC of 0.89.
Sensitivity and Specificity of Serologic Tests According to Age Groups
Serologic test accuracy did not seem to vary according to age (adults or children).
Sensitivity and Specificity of Serologic Tests According to Marsh Criteria
Four studies observed a trend towards a higher sensitivity of serologic celiac disease tests when Marsh 3c grade abnormalities were found in the small bowel biopsy compared to Marsh 3a or 3b (statistical significance not reported). The sensitivity of serologic tests was much lower when Marsh 1 grade abnormalities were found in small bowel biopsy compared to Marsh 3 grade abnormalities. The statistical significance of these findings were not reported in the studies.
Diagnostic Accuracy of Serologic Celiac Disease Tests in Subjects with Chronic Liver Disease
A total of 14 observational studies that evaluated the specificity of serologic celiac disease tests in subjects with chronic liver disease were identified. All studies evaluated the frequency of false positive results (1-specificity) of IgA tTG, however, IgA tTG test kits using different substrates were used, i.e., human recombinant, human, and guinea-pig substrates. The gold standard, small bowel biopsy, was used to confirm the result of the serologic tests in only 5 studies. The studies do not seem to have been designed or powered to compare the diagnostic accuracy among different serologic celiac disease tests.
The results of the studies identified in the systematic literature review suggest that there is a trend towards a lower frequency of false positive results if the IgA tTG test using human recombinant substrate is used compared to the guinea pig substrate in subjects with chronic liver disease. However, the statistical significance of the difference was not reported in the studies. When IgA tTG with human recombinant substrate was used, the number of false positives seems to be similar to what was estimated in the MAS pooled analysis for IgA-based serologic tests in a general population of patients. These results should be interpreted with caution since most studies did not use the gold standard, small bowel biopsy, to confirm or exclude the diagnosis of celiac disease, and since the studies were not designed to compare the diagnostic accuracy among different serologic tests. The sensitivity of the different serologic tests in patients with chronic liver disease was not evaluated in the studies identified.
Effects of a Gluten-Free Diet (GFD) in Patients Diagnosed with Celiac Disease
Six studies identified evaluated the effects of GFD on clinical, histological, or serologic improvement in patients diagnosed with celiac disease. Improvement was observed in 51% to 95% of the patients included in the studies.
Grading of Evidence
Overall, the quality of the evidence ranged from moderate to very low depending on the serologic celiac disease test. Reasons to downgrade the quality of the evidence included the use of a surrogate endpoint (diagnostic accuracy) since none of the studies evaluated clinical outcomes, inconsistencies among study results, imprecise estimates, and sparse data. The quality of the evidence was considered moderate for IgA tTg and IgA EMA, low for IgA DGP, and serologic test combinations, and very low for IgA AGA.
Clinical Validity and Clinical Utility of Serologic Testing in the Diagnosis of Celiac Disease
The clinical validity of serologic tests in the diagnosis of celiac disease was considered high in subjects with symptoms consistent with this disease due to
High accuracy of some serologic tests.
Serologic tests detect possible celiac disease cases and avoid unnecessary small bowel biopsy if the test result is negative, unless an endoscopy/ small bowel biopsy is necessary due to the clinical presentation.
Serologic tests support the results of small bowel biopsy.
The clinical utility of serologic tests for the diagnosis of celiac disease, as defined by its impact in decision making was also considered high in subjects with symptoms consistent with this disease given the considerations listed above and since celiac disease diagnosis leads to treatment with a gluten-free diet.
Economic Analysis
A decision analysis was constructed to compare costs and outcomes between the tests based on the sensitivity, specificity and prevalence summary estimates from the MAS Evidence-Based Analysis (EBA). A budget impact was then calculated by multiplying the expected costs and volumes in Ontario. The outcome of the analysis was expected costs and false negatives (FN). Costs were reported in 2010 CAD$. All analyses were performed using TreeAge Pro Suite 2009.
Four strategies made up the efficiency frontier; IgG tTG, IgA tTG, EMA and small bowel biopsy. All other strategies were dominated. IgG tTG was the least costly and least effective strategy ($178.95, FN avoided=0). Small bowel biopsy was the most costly and most effective strategy ($396.60, FN avoided =0.1553). The cost per FN avoided were $293, $369, $1,401 for EMA, IgATTG and small bowel biopsy respectively. One-way sensitivity analyses did not change the ranking of strategies.
All testing strategies with small bowel biopsy are cheaper than biopsy alone however they also result in more FNs. The most cost-effective strategy will depend on the decision makers’ willingness to pay. Findings suggest that IgA tTG was the most cost-effective and feasible strategy based on its Incremental Cost-Effectiveness Ratio (ICER) and convenience to conduct the test. The potential impact of IgA tTG test in the province of Ontario would be $10.4M, $11.0M and $11.7M respectively in the following three years based on past volumes and trends in the province and basecase expected costs.
The panel of tests is the commonly used strategy in the province of Ontario therefore the impact to the system would be $13.6M, $14.5M and $15.3M respectively in the next three years based on past volumes and trends in the province and basecase expected costs.
Conclusions
The clinical validity and clinical utility of serologic tests for celiac disease was considered high in subjects with symptoms consistent with this disease as they aid in the diagnosis of celiac disease and some tests present a high accuracy.
The study findings suggest that IgA tTG is the most accurate and the most cost-effective test.
AGA test (IgA) has a lower accuracy compared to other IgA-based tests
Serologic test combinations appear to be more costly with little gain in accuracy. In addition there may be problems with generalizability of the results of the studies included in this review if different test combinations are used in clinical practice.
IgA deficiency seems to be uncommon in patients diagnosed with celiac disease.
The generalizability of study results is contingent on performing both the serologic test and small bowel biopsy in subjects on a gluten-containing diet as was the case in the studies identified, since the avoidance of gluten may affect test results.
PMCID: PMC3377499  PMID: 23074399
9.  A Computational Method to Classify Variants of Uncertain Significance Using Functional Assay Data With Application to BRCA1 
Background
Besides revealing cancer–predisposition variants or the absence of any changes, genetic testing for cancer predisposition genes can also identify variants of uncertain clinical significance (VUS). Classifying VUSs is a pressing problem as ever more patients seek genetic testing for disease syndromes and receive non–informative results from those tests. In cases like the breast–ovarian cancer syndrome where prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical.
Methods
We describe a computational approach for inferring the disease relevance of VUSs in disease genes from data derived from an in vitro functional assay. It is based upon a Bayesian hierarchical model that accounts for sources of experimental heterogeneity.
Results
The functional data correlate well with the pathogenicity of BRCA1 BRCT VUSs, thus providing evidence regarding pathogenicity when family and genetic data are absent or uninformative.
Conclusions
We demonstrate the utility of the model by using it to classify 76 VUSs located in the BRCT region of BRCA1. The approach is both sensitive and specific when evaluated on variants previously classified using independent sources of data. While the functional data are very informative, they will need to be combined with other forms of data in order to meet the more stringent requirements of clinical application.
Impact
Our work will lead to improved classification of VUSs and will aid in the clinical decision making of their carriers.
doi:10.1158/1055-9965.EPI-10-1214
PMCID: PMC3111818  PMID: 21447777
breast cancer; ovarian cancer; genetic testing; variants of uncertain significance; BRCA1; Bayes classification; functional assay; transcription
10.  CARD4/NOD1 is not involved in inflammatory bowel disease 
Gut  2003;52(1):71-74.
Background and aims: Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD.
Patients and methods: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test.
Results: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence.
Conclusion: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.
PMCID: PMC1773516  PMID: 12477763
inflammatory bowel disease; Crohn’s disease; ulcerative colitis; CARD4/NOD1; linkage disequilibrium
11.  Progress with genetic cardiomyopathies: Screening, counseling, and testing in dilated, hypertrophic and arrhythmogenic right ventricular dysplasia/cardiomyopathy 
Circulation. Heart failure  2009;2(3):253-261.
Summary
This review focuses on the genetic cardiomyopathies: principally dilated cardiomyopathy (DCM), with salient features of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), regarding genetic etiology, genetic testing, and genetic counseling. Enormous progress has recently been made in identifying genetic causes for each cardiomyopathy, and key phenotype and genotype information is reviewed. Clinical genetic testing is rapidly emerging with a principal rationale of identifying at-risk asymptomatic or disease-free relatives. Knowledge of a disease-causing mutation can guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions. Genetic counseling is also indicated for patients and their family members regarding the symptoms of their cardiomyopathy, its inheritance pattern, family screening recommendations, and genetic testing options and possible results.
doi:10.1161/CIRCHEARTFAILURE.108.817346
PMCID: PMC2927103  PMID: 19808347
genetics; cardiomyopathy; genetic testing; genetic counseling
12.  Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia 
BMJ : British Medical Journal  2000;321(7275):1497.
Objectives
To assess the feasibility of detecting new cases of heterozygous familial hypercholesterolaemia by using a nurse led genetic register.
Design
Case finding among relatives of patients with familial hypercholesterolaemia.
Setting
Two lipid clinics in central and south Manchester.
Subjects
259 (137 men and 122 women) probands and 285 first degree relatives.
Results
Of the 200 first degree relatives tested, 121 (60%) had inherited familial hypercholesterolaemia. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. Concentrations of serum cholesterol were, respectively, 8.4 (1.7 SD) mmol/l and 8.1 (1.9 SD) mmol/l in affected men and women and 5.6 (1.0 SD) mmol/l and 5.6 (1.1 SD) mmol/l in unaffected men and women. Screening for risk factors as recommended in recent guidelines for coronary heart disease prevention would have failed to identify most of the affected relatives in whom hypertension, diabetes mellitus, cigarette smoking, and obesity were uncommon.
Conclusions
By performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolaemia were discovered. Because 1 in 500 people in the UK are affected by this condition, to detect a similar number by population screening over 60 000 tests would be required, and only a few of these patients would have been detected had cholesterol testing been restricted to those with other risk factors for coronary heart disease. A case exists for organising a genetic register approach, linking lipid clinics nationally.
PMCID: PMC27551  PMID: 11118175
13.  Attitudes and Practices Among Internists Concerning Genetic Testing 
Journal of genetic counseling  2012;22(1):90-100.
Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8%), followed by Breast/Ovarian Cancer (15.0%). In the past 6 months, 65% had counseled patients on genetic issues, 44% had ordered genetic tests, 38.5% had referred patients to a genetic counselor or geneticist, and 27.5% had received ads from commercial labs for genetic testing. Only 4.5% had tried to hide or disguise genetic information, and <2% have had patients report genetic discrimination. Only 53.4% knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7%) and guidelines for genetic testing (87.1%). Most felt needs for more training on when to order tests (79%), and how to counsel patients (82%), interpret results (77.3%), and maintain privacy (80.6%). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p<.001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p<.002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p<.019), counseled patients about genetics, larger practices (p<.032), fewer African-American patients (p<.027), and patients who had reported genetic discrimination (p<.044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests., These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education.
doi:10.1007/s10897-012-9504-z
PMCID: PMC3433636  PMID: 22585186
genetic testing; medical education; doctor-patient communication; ethics; genetic discrimination; decision-making; genetic counseling
14.  Ethical issues in predictive genetic testing: a public health perspective 
Journal of Medical Ethics  2006;32(3):143-147.
As a result of the increase in genetic testing and the fear of discrimination by insurance companies, employers, and society as a result of genetic testing, the disciplines of ethics, public health, and genetics have converged. Whether relatives of someone with a positive predictive genetic test should be notified of the results and risks is a matter urgently in need of debate. Such a debate must encompass the moral and ethical obligations of the diagnosing physician and the patient. The decision to inform or not will vary depending on what moral theory is used. Utilising the utilitarian and libertarian theories produces different outcomes. The principles of justice and non‐maleficence will also play an important role in the decision.
doi:10.1136/jme.2004.010272
PMCID: PMC2564466  PMID: 16507657
genetics; public health; primary care
15.  Familial hypercholesterolaemia: pilot study to identify children at risk. 
Journal of Clinical Pathology  1993;46(8):730-733.
AIMS--To evaluate a more effective method of identifying children with familial hypercholesterolaemia by screening a population at high risk. METHODS--Domiciliary measurement of random cholesterol concentration was made in 200 children who were first or second degree relatives of subjects with premature onset coronary artery disease. Measurements were taken by a health visitor using a portable analyser. RESULTS--Twelve new cases of familial hypercholesterolaemia were identified during the first nine months of the study. Random cholesterol concentrations were within the normal range (< 5.2 mmol/l) in 70.5% of samples tested. Forty two (21%) of patients tested had a borderline cholesterol (5.2-5.9 mmol/l) but 50% of these fell within the normal range when fasting capillary samples were analysed. Children with significant hypercholesterolaemia on random testing (concentrations of > 5.9 mmol/l) (8.5%) also had fasting venous blood assayed for high density lipoprotein (HDL) cholesterol and tri-glyceride in the laboratory. Results indicated that 6.5% of patients screened were at high risk of cardiovascular disease (ratio of total: HDL cholesterol of > 4.5), and 1% had a moderately increased risk (ratio 3.5-4.5). CONCLUSIONS--Children with familial hypercholesterolaemia can be identified from a selected "high risk" population by measuring random capillary cholesterol concentration.
PMCID: PMC501458  PMID: 8408697
16.  Intrafamilial disclosure of risk for hereditary breast and ovarian cancer: points to consider 
Journal of Community Genetics  2012;4(2):203-214.
The primary goal of breast and ovarian cancer screening is to minimize the cases of advanced disease and therefore its mortality rate. For hereditary breast and ovarian cancer, one method to reach this goal is to disseminate genetic risk information among family members. However, experience tells us that this information does not always reach family members in a timely manner, if at all. There are many moving parts to a decision to disclose genetic risk information within a family, and the lack of detail and cohesion in current guidelines do a disservice to hereditary breast cancer prevention. Utilizing legal, medical, and policy databases for literature, case law and policy documents relating to communication of genetic test results within families, as well as a consultative process with representative stakeholders, a points to consider has been developed to address a number of issues that might impact the ability and willingness of patients to inform family members of genetic risk. These include: what is “genetic information”; who is the “family”; why should patients inform their family members; and how should health professionals be involved in this process? This represents only an initial step towards fostering better communication within families. Additional research is needed to determine the best methods for encouraging this communication and motivations for disclosing or not and to promote the development of a solution, considering the complexity of human relationships and the probabilistic nature of genetic information.
doi:10.1007/s12687-012-0132-y
PMCID: PMC3666841  PMID: 23275181
Family; Communication; Genetic information; Breast cancer; Intrafamilial
17.  Rare Genetic Variants and Treatment Response: Sample Size and Analysis Issues 
Statistics in medicine  2012;31(25):3041-3050.
Incorporating information about common genetic variants may help improve the design and analysis of clinical trials. For example, if genes impact response to treatment, one can pre-genotype potential participants to screen out genetically determined non-responders and substantially reduce the sample size and duration of a trial. Genetic associations with response to treatment are generally much larger than those observed for development of common diseases, as highlighted here by findings from genome-wide association studies. With the development and decreasing cost of next generation sequencing, more extensive genetic information—including rare variants—is becoming available on individuals treated with drugs and other therapies. We can use this information to evaluate whether rare variants impact treatment response. The sparseness of rare variants, however, raises issues of how the resulting data should be best analyzed. As shown here, simply evaluating the association between each rare variant and treatment response one-at-a-time will require enormous sample sizes. Combining the rare variants together can substantially reduce the required sample sizes, but require a number of assumptions about the similarity among the rare variants’ effects on treatment response. We have developed an empirical approach for aggregating and analyzing rare variants that limit such assumptions and work well under a range of scenarios. Such analyses provide a valuable opportunity to more fully decipher the genomic basis of response to treatment.
doi:10.1002/sim.5428
PMCID: PMC3766744  PMID: 22736504
aggregation; clinical trials; GWAS; pharmacogenomics; rare variants; treatment response
18.  Personalized medicine: hope or hype? 
European Heart Journal  2012;33(13):1564-1570.
Medicine has always been personalized. For years, physicians have incorporated environmental, behavioural, and genetic factors that affect disease and drug response into patient management decisions. However, until recently, the ‘genetic’ data took the form of family history and self-reported race/ethnicity. As genome sequencing declines in cost, the availability of specific genomic information will no longer be limiting. Rather, our ability to parse these data and our decision whether to use it will become primary. As our understanding of genetic association with drug responses and diseases continues to improve, clinically useful genetic tests may emerge to improve upon our previous methods of assessing genetic risks. Indeed, genetic tests for monogenic disorders have already proven useful. Such changes may usher in a new era of personalized medicine. In this review, we will discuss the utility and limitations of personal genomic data in three domains: pharmacogenomics, assessment of genetic predispositions for common diseases, and identification of rare disease-causing genetic variants.
doi:10.1093/eurheartj/ehs112
PMCID: PMC3388016  PMID: 22659199
Pharmacogenomics; Common disease risk assessment; Rare genetic variant discovery; Personalized medicine; Genomic medicine
19.  Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic☆ 
Atherosclerosis  2013;229(1):161-168.
Aim
To determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate.
Methods
289 patients (272 probands) were screened sequentially over a 2-year period for mutations in LDLR, APOB and PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria were used to classify patients and a separate cohort of 409 FH patients was used for replication.
Results
An FH-causing mutation was found in 101 unrelated patients (LDLR = 54 different mutations, APOB p.(Arg3527Gln) = 10, PCSK9 p.(Asp374Tyr) = 0). In the 60 SB Definite FH patients the mutation detection rate was 73% while in the 142 with Possible FH the rate was significantly lower (27%, p < 0.0001), but similar (14%, p = 0.06) to the 70 in whom there was insufficient data to make a clinical diagnosis. The mutation detection rate varied significantly (p = 9.83 × 10−5) by untreated total cholesterol (TC) levels (25% in those <8.1 mmol/l and 74% in those >10.0 mmol/l), and by triglyceride levels (20% in those >2.16 mmol/l and 60% in those <1.0 mmol/l (p = 0.0005)), with both effects confirmed in the replication sample (p for trend = 0.0001 and p = 1.8 × 10−6 respectively). There was no difference in the specificity or sensitivity of the SB criteria versus the Dutch Lipid Clinic Network score in identifying mutation carriers (AROC respectively 0.73 and 0.72, p = 0.68).
Conclusions
In this genetically heterogeneous cohort of FH patients the mutation detection rate was significantly dependent on pre-treatment TC and triglyceride levels.
Highlights
•54 different LDLR mutations found in a cohort of 272 FH probands.•The cohort was found to be genetically heterogeneous with no specific FH mutation.•Mutation detection rate was highly dependent on pre-treatment TC and TG levels.•No difference in specificity/sensitivity between 2 clinical FH diagnosis approaches.•Inadequate LDL-C reduction marks the need for more effective lipid-lowering therapy.
doi:10.1016/j.atherosclerosis.2013.04.011
PMCID: PMC3701838  PMID: 23669246
Cholesterol; Diagnostics; Familial hypercholesterolaemia; Genetic; Lipids; Mutations; FH, familial hypercholesterolaemia; ARMS, amplification refractory mutation system; HRM, high resolution melting; MLPA, multiplex ligation probe-dependent amplification; TC, total cholesterol; TG, triglycerides; CHD, coronary heart disease; DLCN, Dutch Lipid Clinic Network; NGS, next generation sequencing; NICE, National Institute for Health and Clinical Excellence; DFH, definite FH; PFH, possible FH; UH, unclassified hypercholesterolaemia
20.  “In Sickness and in Health”? Disclosures of Genetic Risks in Dating 
Journal of genetic counseling  2010;20(1):98-112.
Individuals who have, or are at risk for, various genetic disorders face many challenges concerning disclosures of genetic information in dating situations. We conducted a qualitative interview study of 64 individuals confronting Huntington’s disease, breast cancer, or Alpha-1 antitrypsin deficiency, examining what issues these individuals encountered, and how they viewed and addressed these—including issues of understandings, privacy, and disclosures of genetic information to various groups (e.g., family members). Incidental to the primary research questions addressed, participants also often described a series of dilemmas in dating situations that they and/or family members, friends, and fellow patients faced of whether to date, and if so, whether, what, how, why, and when to disclose their genetic risk or illness. At times, these individuals feared and experienced rejection, and hence delayed, avoided, or opposed disclosure, or disclosed indirectly or inadvertently. These data are reported in this paper and highlight the importance of patients, their loved ones, genetic counselors, and other health care providers being aware of these issues, and appreciating the complex factors involved, which can affect patients’ coping and social support. This paper, the first to explore several key aspects of disclosures of genetic information in dating, thus suggests needs for public and professional education, and future research in this area.
doi:10.1007/s10897-010-9331-z
PMCID: PMC3152490  PMID: 20890722
Risk communication; Decision-making; Health behaviors; Confidentiality; Ethics; Family relationships; Reproductive choices; Reproductive decisions; Qualitative research
21.  Psychological impact of genetic testing for Huntington's disease: an update of the literature 
Genetic testing has been available for Huntington's disease for longer than any other adult onset genetic disorder. The discovery of the genetic mutation causing Huntington's disease made possible the use of predictive testing to identify currently unaffected carriers. Concerns have been raised that predictive testing may lead to an increase in deaths by suicide among identified carriers, and these concerns set in motion research to assess the psychological impact of predictive testing for Huntington's disease. This review article provides an overview of the literature and draws implications for clinical practice. About 10%-20% of people at risk request testing when approached by registries or testing centres. Most of the evidence suggests that non-carriers and carriers differ significantly in terms of short term, but not long term, general psychological distress. Adjustment to results was found to depend more on psychological adjustment before testing than the testing result itself. Although risk factors for psychological sequelae have been identified, few adverse events have been described and no obvious contraindications for testing people at risk have been identified. The psychological impact of testing may depend on whether testing was based on linkage analysis or mutation detection. Cohorts enrolled in mutation detection programmes have higher levels of depression before and after testing, compared with people who sought genetic testing when linkage analysis was available. There is evidence that people who choose to be tested are psychologically selected for a favourable response to testing. The impact of testing on people in settings where less intensive counselling protocols and eligibility criteria are used is unknown, and genetic testing is therefore best offered as part of comprehensive specialist counselling.


doi:10.1136/jnnp.69.5.574
PMCID: PMC1763433  PMID: 11032605
22.  Should we genetically test everyone for haemochromatosis? 
Journal of Medical Ethics  1999;25(2):209-214.
The increasing availability of DNA-based diagnostic tests has raised issues about whether these should be applied to the population at large in order to identify, treat or prevent a range of diseases. DNA tests raise concerns in the community for several reasons. There is the possibility of stigmatisation and discrimination between those who test positive and those who don't. High-risk individuals may be identified for whom no proven effective intervention is possible, or conversely may test "positive" for a disease that does not eventuate. Controversy concerning prenatal diagnosis and termination of affected pregnancies may arise. Haemochromatosis, however, is a disease that is not only treatable but also preventable if those at high risk are identified presymptomatically. This paper will identify and discuss key issues regarding DNA-based population screening for haemochromatosis, and argue that population-based genetic screening for haemochromatosis should be supported when a number of contentious issues are addressed. In the context of a health system with limited resources haemochromatosis is the paradigm of a disorder where there is an ethical and clinical imperative to encourage presymptomatic DNA testing for all in ethnically relevant communities.
PMCID: PMC479209  PMID: 10226930
23.  Antenatal screening and the gendering of genetic responsibility 
Background
The objective of this study is to explore men's and women's perceptions of antenatal blood screening. The study will assess the impact of these perceptions on decision-making regarding diagnostic testing and selective abortion, and on parental feelings of genetic responsibility. By exploring gender and antenatal screening in this way, the research aims to contribute to our understanding of lay perceptions of genetic screening and increase our knowledge of the decision-making process in screening.
Research design
This qualitative study will be based on semi-structured interviews with twenty pregnant women and twenty male partners in the post-industrial city of Sheffield, UK. All interviews will be taped, transcribed and analysed thematically using NVIVO, a qualitative software package.
Discussion
The findings of this study have relevance to existing debates on the social and ethical implications of reproductive genetics. A better understanding of male and female perceptions of the screening process could improve guidance and practice in antenatal screening and genetic counselling. It will also inform and contribute to the development of theory on gender and genetic screening.
doi:10.1186/1742-4755-4-8
PMCID: PMC2082013  PMID: 17903256
24.  Cholesterol screening and family history of vascular disease. 
Archives of Disease in Childhood  1994;71(3):239-242.
Hypercholesterolaemia is a major risk factor for the development of coronary heart disease (CHD). Early detection and management of hypercholesterolaemia could retard the atherosclerotic process. Given that CHD and hypercholesterolaemia cluster within families, a screening strategy based on a family history of vascular disease has been advocated. Serum total cholesterol concentrations were measured in a random stratified sample of 1012 children aged from 12-15 years old participating in a coronary risk factor surveillance study in Northern Ireland. Information about vascular disease in close family members was obtained by means of a questionnaire. The study population was divided into two groups according to total cholesterol values: (i) normal, < 5.2 mmol/l (n = 822) and (ii) raised, > or = 5.2 mmol/l (n = 190). A family history identified 63 out of 190 individuals with hypercholesterolaemia yielding a sensitivity of 33.2% and specificity of 71.5%. Our data indicated that a strategy whereby only children from high risk families are screened for hypercholesterolaemia is ineffective. While primary prevention emphasising a healthy diet for all is essential, the role of universal screening deserves further appraisal.
PMCID: PMC1029979  PMID: 7979498
25.  Risk perception after genetic counseling in patients with increased risk of cancer 
Background
Counselees are more aware of genetics and seek information, reassurance, screening and genetic testing. Risk counseling is a key component of genetic counseling process helping patients to achieve a realistic view for their own personal risk and therefore adapt to the medical, psychological and familial implications of disease and to encourage the patient to make informed choices [1,2].
The aim of this study was to conceptualize risk perception and anxiety about cancer in individuals attending to genetic counseling.
Methods
The questionnaire study measured risk perception and anxiety about cancer at three time points: before and one week after initial genetic counseling and one year after completed genetic investigations. Eligibility criteria were designed to include only index patients without a previous genetic consultation in the family. A total of 215 individuals were included. Data was collected during three years period.
Results
Before genetic counseling all of the unaffected participants subjectively estimated their risk as higher than their objective risk. Participants with a similar risk as the population overestimated their risk most. All risk groups estimated the risk for children's/siblings to be lower than their own. The benefits of preventive surveillance program were well understood among unaffected participants.
The difference in subjective risk perception before and directly after genetic counseling was statistically significantly lower in all risk groups. Difference in risk perception for children as well as for population was also statistically significant. Experienced anxiety about developing cancer in the unaffected subjects was lower after genetic counseling compared to baseline in all groups. Anxiety about cancer had clear correlation to perceived risk of cancer before and one year after genetic investigations.
The affected participants overestimated their children's risk as well as risk for anyone in population. Difference in risk perception for children/siblings as for the general population was significant between the first and second measurement time points. Anxiety about developing cancer again among affected participants continued to be high throughout this investigation.
Conclusion
The participant's accuracy in risk perception was poor, especially in low risk individuals before genetic counseling. There was a general trend towards more accurate estimation in all risk groups after genetic counseling. The importance of preventive programs was well understood. Cancer anxiety was prevalent and associated with risk perception, but decreased after genetic counseling.
[1] National Society of Genetic Counselors (2005), Genetic Counseling as a Profession. Available at (accessed November 25th 2007)
[2] Julian-Reynier C., Welkenhuysen M-, Hagoel L., Decruyenaere M., Hopwood P. (2003) Risk communication strategies: state of the art and effectiveness in the context of cancer genetic services. Eur J of Human Genetics 11, 725-736.
doi:10.1186/1897-4287-7-15
PMCID: PMC2744911  PMID: 19698175

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