Predictive Testing Research Articles

Building the What Comes Next Cohort for BRCA1 and BRCA2 testing: a descriptive analysis.

Background:Our understanding of how testing for and mutations of the BRCA1 and BRCA2 genes affect cancer risk and the use of risk-reduction strategies comes largely from studies of women recruited from specialized genetics clinics. Our aim was to assemble a generalizable cohort of women who underwent BRCA1/BRCA2 testing (the What Comes Next Cohort), irrespective of test result, to enable study of health care utilization and outcomes after testing.Methods:This descriptive study included adult women (≥ 18 yr) who met at least 1 of 13 provincial criteria for BRCA1/BRCA2 testing and who underwent genetic testing at sites in Ontario, Canada, from 2007 to 2016. Most of the women were tested at 1 of 2 main sites, which together capture about 70% of all BRCA1/BRCA2 testing in the province. We collected detailed demographic, genetic testing and family history data through chart review for linkage with data from administrative health databases providing information on cancer history before and after testing. We followed all women to September 2019, evaluating the demographic characteristics of the cohort, indications for testing and test results.Results:We identified 15 986 women (mean age 52.5 [standard deviation 13.9] yr) who underwent BRCA1/BRCA2 testing. Of these, 2033 women had positive results, 1175 women had variants of uncertain significance, and 12 778 women had negative results. Positive yields were 41.0% (955/2329) for predictive testing (for familial variants), 10.4% (216/2072) for Ashkenazi Jewish founder testing and 7.4% (862/11 585) for complete gene analysis. Six of the 13 provincial testing criteria had less than 10% positive yield. Among 403 women who tested negative for Ashkenazi Jewish founder mutations and subsequently underwent complete gene analysis, 12 (3.0%) tested positive for alternate pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 gene.Interpretation:Several provincial eligibility criteria for BRCA1/BRCA2 testing led to positive results in less than 10% of cases. How testing influences women’s health care behaviours, particularly those with negative results and those found to carry variants of uncertain significance, is unknown; the What Comes Next Cohort will be instrumental in the study of long-term implications of BRCA1/BRCA2 testing.

Willingness to Pay for Cancer Genetic Testing in a Tertiary Healthcare Centre

INTRODUCTION: Increasing use of predictive genetic testing to address hereditary cancer risk has been commonly assessed by cost sharing practices. Little is known about how demographics, knowledge, attitude and practices may influence these individuals’ willingness to pay for cancer genetic testing. The objective of this research was to determine factors associated with willingness to pay for cancer genetic testing. MATERIALS AND METHODS: A self-administered questionnaire was distributed to 175 respondents in the oncology and day care unit in one of tertiary healthcare centre. The respondents comprised cancer patients, their family members and the community. RESULTS: A total of 117 (66.9%) participants were willing to pay for cancer genetic testing. Ninety three (79.5%) of respondents were willing to pay from their own pocket with a mean of MYR1201.77 (SD976.72) and 95 (54.3%) respondents were willing to pay, shared with insurance. There were significant associations between willingness to pay with status of respondent as patients or family members or community, gender, race, educational level, income, knowledge and attitude. CONCLUSION: This is the first study to evaluate factors associated with willingness to pay not only among cancer patients but also their family members and the community. These findings reveal that majority of respondents believe there is valuable personal benefit based on genetic risk information and they are willing to pay for it.

The Out-of-Sample Predictability of Asymmetric Dependence of Portfolio Returns - The Multivariate Copula Distribution Function Approach (포트폴리오 수익률 분포의 비대칭적 의존성의 표본외 예측가능성: Copula 분포함수에 의한 추정)

English Abstract: Armed with the copula distribution function that describes the asymmetric tail dependence, and the marginal distributions that capture the fat-tailed behavior, we estimate risk measures such as the Value-at-Risk and expected shortfall and evaluate whether those from the Gaussian copula function underestimate or overestimate true risk measures. We also investigate the impact of asymmetric tail dependence between the portfolio returns on the out-of-sample predictability of the returns. We fit the GPD as the two margins and a variety of copula functions in the extant literature in evaluating the risk measures. We compute the VaR and ES from the benchmark Gaussian copula model and the competing copula models and confirm that the benchmark model underestimate the levels of risk regardless of the measures of dependence. We use the out-of-sample predictability test to evaluate the performance of the competing copula models. We compare the out-of-sample predictability of the three copula-based competing models by calculating the out-of-sample log-likelihood. The Gaussian and the Student’s t copula models are the representative symmetric copulas, while the Clayton copula is selected as the representative asymmetric copula model. According to the test statistics, the out-of-sample predictability of the Clayton and the Student’s t copula models are superior to that of the Gaussian copula model. Overall, the Clayton copula model turns out to be the best out-of-sample forecasting copula model. Korean Abstract: 주식수익률의 표본외 예측가능성은 동태적 자산배분과 포트폴리오 위험관리에 중요한 역할을 한다. 위험관리에서 다변량 정규분포의 가정과 주식수익률간 선형의존성 가정이 주로 이용되는 반면, 실제 데이터에서 다변량 정규분포와 선형의존성 가정은 위배되는 것이 일반적이다. 본 연구는 포트폴리오를 구성하는 주식수익률간 꼬리부분의 비대칭 의존성과 비정규성을 코퓰라 분포함수로 모형화하고 포트폴리오를 구성하는 자산의 한계분포는 일반화 파레토분포로 모형화하여 KOSPI 200과 S&P 500으로 구성된 지수포트폴리오의 위험척도를 측정하였다. 일반화 파레토분포와 가우스 코퓰라함수를 결합하여 측정하는 모형은 일반화 파레토분포와 Clayton 코퓰라함수를 이용하는 모형에 비해 지수 포트폴리오의 위험을 과소추정하는 것으로 나타났다. 또한 지수포트폴리오의 꼬리부분의 비대칭 의존성이 표본외 예측력에 미치는 영향을 평가하였는데, Clayton 코퓰라함수에 의한 지수포트폴리오 수익률의 표본외 예측력이 가장 뛰어난 것으로 나타났다. Clayton 코퓰라함수는 다변량 수익률분포에서 왼쪽 꼬리분포간의 비대칭 의존성을 반영하는, 즉 포트폴리오 구성자산들에서 동시에 양의 수익률이 나타나는 경우에 비해 동시에 음의 수익률이 나타나는 경우가 확률적으로 높은 사실을 반영하는, 통계적 특성을 가진 코퓰라 함수이다. 본 연구는 위험척도 추정과 수익률의 표본외 예측력 검정에서 Clayton 코퓰라함수가 우월한 것은 이러한 통계적 특성에 기인한 것임을 실증하였다.

Mutations in BRCA-related breast and ovarian cancer in the South African Indian population: A descriptive study

Knowledge of the genetic landscape of a specific population group is vital for population-specific diagnosis and treatment of familial breast cancer. Although BRCA-related diagnostic testing has long been implemented in South Africa, the genotyping approach previously failed for the SA Indian population as it was based on other SA population groups. Because this population is uniquely admixed, the lack of population-specific data resulted in the implementation of comprehensive mutation screens for BRCA1/2. A total of 223 female patients were screened for clinically actionable variants. High-resolution melting analysis (HRMA) was used to screen 88 patients for DNA alterations in the coding and splice site boundaries of BRCA1 exons 2–9, BRCA1 exons 11–23, BRCA2 exons 2–9 and BRCA2 exons 12–27. The protein truncation test (PTT) was used to screen the three larger exons (BRCA1 exon 10 and BRCA2 exons 10 and 11) for protein termination changes. Multiplex ligation-dependent probe amplification (MLPA) was used to determine the presence of larger indels and possible copy number differences. Next Generation Sequencing (NGS) was performed on the remaining 135 samples. All potential variants were confirmed by performing Sanger DNA sequencing. The search revealed 28 different pathogenic heterozygotic variants, together with nine variants of unknown significance (VUS). The results suggested that the SA Indian population represents a different genetic admixture compared to that of mainland India, as only five pathogenic variants corresponded to those reported for mainland India. Familial breast cancer testing for SA Indian patients should therefore be performed as comprehensively as possible as the pathogenic variants seem to be family- rather than population-specific. Furthermore, predictive testing of family members will contribute to relieve the financial burden on the country's healthcare system, as increased surveillance and appropriate management could prevent disease.

First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7, in Advanced Solid Tumors.

We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922). Patients received PF-06647020 intravenously every 3 weeks at 0.2-3.7 mg/kg or every 2 weeks at 2.1-3.2 mg/kg, in sequential dose escalation, following a modified toxicity probability interval method. In dose expansion, pretreated patients with advanced, platinum-resistant ovarian cancer, non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC) received PF-06647020 2.8 mg/kg every 3 weeks. The most common, treatment-related adverse events for PF-06647020 administered every 3 weeks were nausea, alopecia, fatigue, headache, neutropenia, and vomiting (45%-25%); 25% of patients had grade ≥ 3 neutropenia. Two patients experienced dose-limiting toxicities (grade 3 headache and fatigue) at the highest every 3 weeks dose evaluated. The recommended phase II dose was 2.8 mg/kg every 3 weeks. The overall safety profile observed with PF-06647020 administered every 2 weeks was similar to that of the every 3 weeks regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27% in ovarian cancer (n = 63), 19% in NSCLC (n = 31), and 21% in TNBC (n = 29). Responders tended to have moderate or high PTK7 tumor expression by IHC. This PTK7-targeted ADC demonstrated therapeutic activity in previously treated patients with ovarian cancer, NSCLC, and TNBC at a dose range of 2.1-3.2 mg/kg, supporting further clinical evaluation to refine dose, schedule, and predictive tissue biomarker testing in patients with advanced malignancies.

An ensemble‐based predictive mutation testing approach that considers impact of unreached mutants

SummaryPredictive mutation testing (PMT) is a technique to predict whether a mutant is killed, using machine learning approaches. Researchers have proposed various methods for PMT over the years. However, the impact of unreached mutants on PMT is not fully addressed. A mutant is unreached if the statement on which the mutant is generated is not executed by any test cases. We aim at showing that unreached mutants can inflate PMT results. Moreover, we propose an alternative approach to PMT, suggesting a different interpretation for PMT. To this end, we replicated the previous PMT research. We empirically evaluated the suggested approach on 654 Java projects provided by prior literature. Our results indicate that the performance of PMT drastically decreases in terms of area under a receiver operating characteristic curve (AUC) from 0.833 to 0.517. Furthermore, PMT performs worse than random guesses on 27% of the projects. The proposed approach improves the PMT results, achieving the average AUC value of 0.613. As a result, we recommend researchers to remove unreached mutants when reporting the results.

Performance monitoring of EBUS for the staging and diagnosis of lung cancer: auditing the Greater Manchester EBUS service against new national standards

IntroductionEndobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a pivotal test in lung cancer staging and diagnosis, mandating robust audit and performance monitoring of EBUS services. We present the first regional...

Patient and Relative Experiences and Decision-making About Genetic Testing and Counseling for Familial ALS and FTD: A Systematic Scoping Review.

Genetic testing and counseling is an emerging part of care for patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and their families. This scoping review aimed to map patients' and relatives' experiences of genetic testing and counseling for familial ALS and FTD and the factors influencing their decision to proceed with testing or counseling. Informed by the Joanna Briggs Institute methodology, 5 databases were systematically searched. Thirty studies from 39 references were included. A descriptive numerical summary analysis and narrative synthesis was conducted. Mostly positive diagnostic testing experiences were reported, but issues arose due to progressive disease and discordant results. Predictive testing impacted at-risk relatives, regardless of the result received, and psychosocial sequelae ranged from relief to guilt, worry or contemplating suicide. Four reproductive testing experiences were reported. Personal, familial and practical factors, and the lived experience of disease, informed decision-making. Greater uncertainty and complexity may be faced in familial ALS/FTD than in other late-onset neurodegenerative diseases due to clinical and genetic heterogeneity, and testing limitations. Genetic counseling models of care should consider this difference to ensure that individuals with, or at risk of, ALS/FTD are effectively managed. Implications for research and practice are discussed.

KETIDAKPASTIAN DAN KOMPLEKSITAS RANTAI PASOK DALAM KINERJA OPERASIONAL YANG BERKELANJUTAN

The purpose of this research plan is analyzing the different types of uncertainties and complexity in the supply chain and provide suggestion on strategies to deliver superior operational performance (OP) in disruption and dynamic situation using symmetrical and asymmetrical modeling approaches. Symmetrical modeling is applied via PLS-SEM in order to assess the theoretical relationships among the latent variables, while asymmetrical modeling is applied via fuzzy set qualitative comparative analysis (fsQCA) to emphasize their combinatory causal relation. This research contributes by providing an illustration of a PLS-SEM and fsQCA based estimation for the rapidly emerging field of sustainable supply chain management. This study assumes to provide empirical support for resource dependence theory (RDT) in explaining the relation between SCU and SCS as well as SCO and SCC which leads to sustainable OP. From a methodological standpoint, this study also illustrates predictive validation testing of models using holdout samples and testing for causal asymmetry.

Predictive testing in non-small cell lung carcinoma.

Predictive testing is a crucial part of the complete diagnostic process of non-small cell lung cancer (NSCLC) and a necessary requirement in order to determine proper course of treatment. However, the possibilities of testing and the spectrum of examined markers are quickly evolving as a result of the progress in diagnostic and therapeutic possibilities, and as such it is necessary to regularly update the current guidelines to achieve proper standards of care in routine practice. To provide a complex overview of the current problematics of predictive testing in NSCLC at a molecular level, considering also the evaluation of PD-L1 expression based on the international and national guidelines. To summarize the current state of predictive testing employed in NSCLC in the Czech Republic. Predictive testing in NSCLC is a part of routine diagnostic practice; however, as a result of the expanding spectrum of diagnostic and therapeutic possibilities, it is undergoing significant development. The existing method of the sequential testing of individual markers is becoming unsuitable; given the increasing number of potential predictors and complex molecular testing, the use of new generation sequencing appears to represent a more suitable solution. The immunohistochemical evaluation of PD-L1 expression is also a necessary part of predictive testing in NSCLC.

Predictive molecular pathology in the time of coronavirus disease (COVID-19) in Europe

AimsLung cancer predictive biomarker testing is essential to select advanced-stage patients for targeted treatments and should be carried out without delays even during health emergencies, such as the coronavirus (COVID-19)...

Invasive breast Cancer treatment in Tanzania: landscape assessment to prepare for implementation of standardized treatment guidelines

BackgroundIncidence of breast cancer continues to rise in low- and middle-income countries, with data from the East African country of Tanzania predicting an 82% increase in breast cancer from 2017 to 2030. We aimed to characterize treatment pathways, receipt of therapies, and identify high-value interventions to increase concordance with international guidelines and avert unnecessary breast cancer deaths.MethodsPrimary data were extracted from medical charts of patients presenting to Bugando Medical Center, Tanzania, with breast concerns and suspected to have breast cancer. Clinicopathologic features were summarized with descriptive statistics. A Poisson model was utilized to estimate prevalence ratios for variables predicted to affect receipt of life-saving adjuvant therapies and completion of therapies. International and Tanzanian guidelines were compared to current care patterns in the domains of lymph node evaluation, metastases evaluation, histopathological diagnosis, and receptor testing to yield concordance scores and suggest future areas of focus.ResultsWe identified 164 patients treated for suspected breast cancer from April 2015–January 2019. Women were predominantly post-menopausal (43%) and without documented insurance (70%). Those with a confirmed histopathology diagnosis (69%) were 3 times more likely to receive adjuvant therapy (PrR [95% CI]: 3.0 [1.7–5.4]) and those documented to have insurance were 1.8 times more likely to complete adjuvant therapy (1.8 [1.0–3.2]). Out of 164 patients, 4% (n = 7) received concordant care based on the four evaluated management domains. The first most common reason for non-concordance was lack of hormone receptor testing as 91% (n = 144) of cases did not undergo this testing. The next reason was lack of lymph node evaluation (44% without axillary staging) followed by absence of abdominopelvic imaging in those with symptoms (35%) and lack of histopathological confirmation (31%).ConclusionsPatient-specific clinical data from Tanzania show limitations of current breast cancer management including axillary staging, receipt of formal diagnosis, lack of predictive biomarker testing, and low rates of adjuvant therapy completion. These findings highlight the need to adapt and adopt interventions to increase concordance with guidelines including improving capacity for pathology, developing complete staging pathways, and ensuring completion of prescribed adjuvant therapies.

주택가격의 초과수익률 예측가능성과 초과변동성 검정

본 논문은 동태적 고든 모형을 서울과 6개 광역시 아파트 매매시장에 적용하여 다음 주요 결과를 도출했다. 첫 번째로 모든 지역에서 아파트 초과수익률의 예측가능성이 높게 나타나 아파트 매매시장에는 투기적 수요가 존재하는 것으로 나타났다. 두 번째로 초과변동성 검정은 적정 시차에 따라 대도시 지역에 적용가능 여부는 달라지는 것으로 나타났다. 세 번째로 로그 임대료-가격 비율이 단위근을 가지는 경우에는 동태적 고든 모형을 결과 해석에 유의할 필요가 있다. 네 번째로 동태적 고든 모형을 이용한 지역별 아파트 근본가치평가를 실제 주택가격과 비교하여 과다 또는 과소 평가 여부를 파악할 수 있다.

Macroeconomic variables for predicting bear stock markets of Taiwan and China

PurposeThis research examines how macroeconomic variables can precisely predict bull/bear stock markets in China and Taiwan.Design/methodology/approachThis paper adopts a two-state Markov switching model to characterize the bull and bear markets spanning from 1994 to 2019 and then conduct a bear stock market predictability test by running regressions between the filtered probabilities of bear markets and a series of macroeconomic variables in turn at different horizons of 1, 3, 6, 12 and 24 months.FindingsThis paper shows that inflation rates, changes in real exchange rates, and foreign currency reserve growth are key predictors of bear markets in China, while term spreads, unemployment rates and foreign reserve growth are major factors that can predict bear markets in Taiwan. Remarkably, industrial production growth does not have predictive power for bear markets, which may suggest emerging markets are driven by fund flows rather than real economic activities. Besides, the impact directions of foreign currency reserve growth are opposite, which may be due to different proportions of the financial accounts in their balance of payments.Practical implicationsIn practical respect, this paper provides market participants the usefulness, impact direction and implications of bear market predictors when building their market-timing strategies in China and Taiwan stock markets. The government institutions may also thereby make appropriate policies to prevent huge stock market downturns and serious drawbacks.Originality/valueIt highlights the “fund-driven market hypothesis” and “foreign currency reserve effects” that commonly dominate Taiwan and China stock markets since both are highly affected by international funds.

Nationwide evaluation of mutation-tailored treatment of gastrointestinal stromal tumors in daily clinical practice

BackgroundMolecular analysis of KIT and PDGFRA is critical for tyrosine kinase inhibitor treatment selection of gastrointestinal stromal tumors (GISTs) and hence recommended by international guidelines. We performed a nationwide study into the application of predictive mutation testing in GIST patients and its impact on targeted treatment decisions in clinical practice.MethodsReal-world clinical and pathology information was obtained from GIST patients with initial diagnosis in 2017–2018 through database linkage between the Netherlands Cancer Registry and the nationwide Dutch Pathology Registry.ResultsPredictive mutation analysis was performed in 89% of the patients with high risk or metastatic disease. Molecular testing rates were higher for patients treated in expertise centers (96%) compared to non-expertise centers (75%, P < 0.01). Imatinib therapy was applied in 81% of the patients with high risk or metastatic disease without patient’s refusal or adverse characteristics, e.g., comorbidities or resistance mutations. Mutation analysis that was performed in 97% of these imatinib-treated cases, did not guarantee mutation-tailored treatment: 2% of these patients had the PDGFRA p.D842V resistance mutation and 7% initiated imatinib therapy at the normal instead of high dose despite of having a KIT exon 9 mutation.ConclusionIn conclusion, nationwide real-world data show that over 81% of the eligible high risk or metastatic disease patients receive targeted therapy, which was tailored to the mutation status as recommended in guidelines in 88% of cases. Therefore, still 27% of these GIST patients misses out on mutation-tailored treatment. The reasons for suboptimal uptake of testing and treatment require further study.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

BackgroundPediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices.Methods and ResultsChildren with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes.ConclusionsA definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators.

The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs. Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as "carcinogenic to humans." In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk-benefit analyses (if warranted), and (3) based on the respective risk-benefit analyses, to re-evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.

Genetic counseling: development of requirements, contents, and quality management in Germany.

To carry out quality management of genetic counseling, it is important to know what genetic counseling exactly means and who the players are. The term "genetic counseling" was first defined by Reed in 1947. It describes a communication process dealing with genetic facts and psychosocial aspects and is an education process, too. It has always been understood in the context of individual and family problems, and is unrelated to eugenics. In 1975 the Ad Hoc Committee of the American Society of Human Genetics published a more detailed description. With the development of new diagnostic techniques and methods in human genetics, the requirements of genetic counseling and its contents changed. Today a genetic counselor has to apply diagnostic, predictive, susceptibility, pharmacogenetic, carrier, prenatal, and preimplantation testing, as well as genetic screening. The German Human Genetic Examination Act (Genetic Diagnosis Act - GenDG) and national and international associations recommend to embed genetic testing into genetic counseling. Based on experiences of the author, some examples of pitfalls in genetic counseling are illustrated, as there are so many individual situations and requests that it seems impossible to carry out quality management. Nevertheless, the Commission for Quality in Genetic Counseling and Clinical Genetics of the Professional Association of German Human Geneticists started a pilot ring trial in 2018 with a given counseling situation. The task was to write the human genetics comment with the help of a checklist containing all issues necessary. The evaluation was conducted with the help of a catalogue of criteria which had been established beforehand and a score adjusted to the individual situation. The first genuine pilot trial was launched in 2020. It represents a possibility for quality management in genetic counseling.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome: Surveillance and Diagnostic strategies

Introduction: Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is an autosomal dominant genetic disease. The disease is caused by a mutation in one of four genes of the DNA mismatch repair system and increases the risk for various cancers, especially the uterine and colon cancers. The prevalence of this disease in the general population is about 1 in 500 and it causes about 2-3% of colorectal cancers. Lynch syndrome is diagnosed in two stages: 1) the person is suspected of having the disease (because a patient is unusually diagnosed with cancer at a young age), and 2) evidence of incomplete repair defect is seen in the tumor tissue (microsatellite instability). The detection of a pathogenic mutation confirms the diagnosis in these patients and enables predictive testing for other family members. Diagnostic evaluation of Lynch syndrome should be performed with appropriate genetic counseling. Systemic colonoscopy surveillance could identify colon cancers at an earlier stage before patients present clinical symptoms. Conclusion: Although many studies have been done, but the benefits of an individualized, risk-adapted surveillance strategy are still unclear. Until this is identified, Lynch syndrome patients and healthy carriers with causative mutations should be monitored by annual colonoscopy and annual gynecological examination (for women).

Impact of national guidelines on use of BRCA1/2 germline testing, risk management advice given to women with pathogenic BRCA1/2 variants and uptake of advice

BackgroundThis nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients.MethodsClinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008–July 2009 (i.e. before guideline release), July 2010–July 2011 and July 2012–July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate.ResultsThere were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively (χ = 0.25, p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30–50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women.ConclusionsGuidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care.