Implications of genetic testing and informed consent before and after genetic testing in individuals with cancer

Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians.Given the lack of access to geneticists,medical oncologists and other treating physicians have begun ordering and interpreting genetic tests for individuals with cancer through the process of"mainstreaming".While this process has allowed for quicker access to genetic tests,the process of"mainstreaming"has also brought several challenges including the dissemination of variants of unknown significance results,ordering of appropriate tests,and accurate interpretation of genetic results with appropriate followup testing and interventions.In this editorial,we seek to explore the process of informed consent of individuals before obtaining genetic testing and offer potential solutions to optimize the informed consent process including categorization of results as well as a layered consent model.

An Optimized Test Case Minimization Technique Using Genetic Algorithm for Regression Testing

Regression testing is a widely used approach to confirm the correct functionality of the software in incremental development.The use of test cases makes it easier to test the ripple effect of changed requirements.Rigorous testingmay help in meeting the quality criteria that is based on the conformance to the requirements as given by the intended stakeholders.However,a minimized and prioritized set of test cases may reduce the efforts and time required for testingwhile focusing on the timely delivery of the software application.In this research,a technique named Test Reduce has been presented to get a minimal set of test cases based on high priority to ensure that the web applicationmeets the required quality criteria.A new technique TestReduce is proposed with a blend of genetic algorithm to find an optimized and minimal set of test cases.The ultimate objective associated with this study is to provide a technique that may solve the minimization problem of regression test cases in the case of linked requirements.In this research,the 100-Dollar prioritization approach is used to define the priority of the new requirements.

Value-Based Test Case Prioritization for Regression Testing Using Genetic Algorithms

Test Case Prioritization(TCP)techniques perform better than other regression test optimization techniques including Test Suite Reduction(TSR)and Test Case Selection(TCS).Many TCP techniques are available,and their performance is usually measured through a metric Average Percentage of Fault Detection(APFD).This metric is value-neutral because it only works well when all test cases have the same cost,and all faults have the same severity.Using APFD for performance evaluation of test case orders where test cases cost or faults severity varies is prone to produce false results.Therefore,using the right metric for performance evaluation of TCP techniques is very important to get reliable and correct results.In this paper,two value-based TCP techniques have been introduced using Genetic Algorithm(GA)including Value-Cognizant Fault Detection-Based TCP(VCFDB-TCP)and Value-Cognizant Requirements Coverage-Based TCP(VCRCB-TCP).Two novel value-based performance evaluation metrics are also introduced for value-based TCP including Average Percentage of Fault Detection per value(APFDv)and Average Percentage of Requirements Coverage per value(APRCv).Two case studies are performed to validate proposed techniques and performance evaluation metrics.The proposed GA-based techniques outperformed the existing state-of-the-art TCP techniques including Original Order(OO),Reverse Order(REV-O),Random Order(RO),and Greedy algorithm.

Advances of Genetic Testing Technology in Etiology Diagnosis of Recurrent Spontaneous Abortion

Recurrent spontaneous abortion (RSA) is a complex and heterogeneous disorder with multiple etiologies. Genetic factors are thought to play an important role in the etiology of RSA. With recent advances in genetic testing technologies, there has been an increasing interest in using these tools to diagnose the etiology of RSA. This review discusses the different types of genetic testing methods, such as karyotyping, chromosomal microarray analysis, next-generation sequencing, and their applications in the diagnosis of the etiology RSA. The use of genetic testing in the diagnosis of RSA has the potential to improve the accuracy of diagnosis and the understanding of the underlying mechanisms of the disorder, which could lead to better management and treatment of affected individuals.

A dual-RPA based lateral flow strip for sensitive,on-site detection of CP4-EPSPS and Cry1Ab/Ac genes in genetically modified crops

Traditional transgenic detection methods require high test conditions and struggle to be both sensitive and efficient.In this study,a one-tube dual recombinase polymerase amplification(RPA)reaction system for CP4-EPSPS and Cry1Ab/Ac was proposed and combined with a lateral flow immunochromatographic assay,named“Dual-RPA-LFD”,to visualize the dual detection of genetically modified(GM)crops.In which,the herbicide tolerance gene CP4-EPSPS and the insect resistance gene Cry1Ab/Ac were selected as targets taking into account the current status of the most widespread application of insect resistance and herbicide tolerance traits and their stacked traits.Gradient diluted plasmids,transgenic standards,and actual samples were used as templates to conduct sensitivity,specificity,and practicality assays,respectively.The constructed method achieved the visual detection of plasmid at levels as low as 100 copies,demonstrating its high sensitivity.In addition,good applicability to transgenic samples was observed,with no cross-interference between two test lines and no influence from other genes.In conclusion,this strategy achieved the expected purpose of simultaneous detection of the two popular targets in GM crops within 20 min at 37°C in a rapid,equipmentfree field manner,providing a new alternative for rapid screening for transgenic assays in the field.

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B

Background:Bitter taste receptors(Tas2rs)are generally considered to sense various bitter compounds to escape the intake of toxic substances.Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.Methods:To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues,multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene-editing technique.A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes.Then,T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice.Quantitative real-time polymerase chain reaction(qRT-PCR)and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds.Perception to taste substance was also studied using twobottle preference tests.Results:We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique.Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice.But qRT-PCR results revealed the changed expression profile of m Tas2rs gene in taste buds of these mutant mice.With two-bottle preference tests,these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105.In addition,these mutant mice showed a loss of taste perception to quinine dihydrochloride,denatonium benzoate,and cucurbitacin B(CuB).Gnat3-mediated taste receptor and its signal pathway contribute to CuB perception.Conclusions:These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound-induced responses mediated by these TAS2Rs in many extraoral tissues.

Generating of Test Data by Harmony Search Against Genetic Algorithms

Many search-based algorithms have been successfully applied in sev-eral software engineering activities.Genetic algorithms(GAs)are the most used in the scientific domains by scholars to solve software testing problems.They imi-tate the theory of natural selection and evolution.The harmony search algorithm(HSA)is one of the most recent search algorithms in the last years.It imitates the behavior of a musician tofind the best harmony.Scholars have estimated the simi-larities and the differences between genetic algorithms and the harmony search algorithm in diverse research domains.The test data generation process represents a critical task in software validation.Unfortunately,there is no work comparing the performance of genetic algorithms and the harmony search algorithm in the test data generation process.This paper studies the similarities and the differences between genetic algorithms and the harmony search algorithm based on the ability and speed offinding the required test data.The current research performs an empirical comparison of the HSA and the GAs,and then the significance of the results is estimated using the t-Test.The study investigates the efficiency of the harmony search algorithm and the genetic algorithms according to(1)the time performance,(2)the significance of the generated test data,and(3)the adequacy of the generated test data to satisfy a given testing criterion.The results showed that the harmony search algorithm is significantly faster than the genetic algo-rithms because the t-Test showed that the p-value of the time values is 0.026<α(αis the significance level=0.05 at 95%confidence level).In contrast,there is no significant difference between the two algorithms in generating the adequate test data because the t-Test showed that the p-value of thefitness values is 0.25>α.

Genetic testing in congenital heart disease:A clinical approach

Congenital heart disease(CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient followup. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.

Predictive potential of IL-28B genetic testing for interferon based hepatitis C virus therapy in Pakistan: Current scenario and future perspective

In Pakistan which ranked second in terms of hepatitis C virus(HCV) infection, it is highly needed to have an established diagnostic test for antiviral therapy responseprediction. Interleukin 28B(IL-28B) genetic testing is widely used throughout the world for interferon based therapy prediction for HCV patients and is quite helpful not only for health care workers but also for the patients. There is a strong relationship between single nucleotide polymorphisms at or near the IL-28 B gene and the sustained virological response with pegylated interferon plus ribavirin treatment for chronic hepatitis C. Pakistan is a resource limited country, with very low per capita income and there is no proper social security(health insurance) system. The allocated health budget by the government is very low and is used on other health emergencies like polio virus and dengue virus infection. Therefore it is proposed that there should be a well established diagnostic test on the basis of IL-28 B which can predict the antiviral therapy response to strengthen health care set-up of Pakistan. This test once established will help in better management of HCV infected patients.

Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing

Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.

Genetic testing vs microforceps biopsy in pancreatic cysts:Systematic review and meta-analysis

BACKGROUND Carcinoembryonic antigen(CEA)and cytology in pancreatic cystic fluid are suboptimal for evaluation of pancreatic cystic neoplasms.Genetic testing and microforceps biopsy are promising tools for pre-operative diagnostic improvement but comparative performance of both methods is unknown.AIM To compare the accuracy of genetic testing and microforceps biopsy in pancreatic cysts referred for surgery.METHODS We performed a literature search in Medline,Scopus,and Web of Science for studies evaluating genetic testing of cystic fluid and microforceps biopsy of pancreatic cysts,with endoscopic ultrasound with fine-needle aspiration(EUSFNA)prior to surgery and surgical pathology as reference standard for diagnosis.We evaluated the diagnostic accuracy for:1-benign cysts;2-mucinous low-risk cysts;3-high-risk cysts,and the diagnostic yield and rate of correctly identified cysts with microforceps biopsy and molecular analysis.We also assessed publication bias,heterogeneity,and study quality.RESULTS Eight studies,including 1206 patients,of which 203(17%)referred for surgery who met the inclusion criteria were analyzed in the systematic review,and seven studies were included in the meta-analysis.Genetic testing and microforceps biopsies were identical for diagnosis of benign cysts.Molecular analysis was superior for diagnosis of both low and high-risk mucinous cysts,with sensitivities of 0.89(95%CI:0.79-0.95)and 0.57(95%CI:0.42-0.71),specificities of 0.88(95%CI:0.75-0.95)and 0.88(95%CI:0.80-0.93)and AUC of 0.9555 and 0.92,respectively.The diagnostic yield was higher in microforceps biopsies than in genetic analysis(0.73 vs 0.54,respectively)but the rates of correctly identified cysts were identical(0.73 with 95%CI:0.62-0.82 vs 0.71 with 95%CI:0.49-0.86,respectively).CONCLUSION Genetic testing and microforceps biopsies are useful second tests,with identical results in benign pancreatic cysts.Genetic analysis performs better for low-and high-risk cysts but has lower diagnostic yield.

Should multi-gene panel testing replace limited BRCA1/2 testing? A review of genetic testing for hereditary breast and ovarian cancers

Clinical testing of patients for hereditary breast and ovarian cancer syndromes began in the mid-1990s with the identification of the BRCA1 and BRCA2 genes.Since then,mutations in dozens of other genes have been correlated to increased breast,ovarian,and other cancer risk.The following decades of data collection and patient advocacy allowed for improvements in medical,legal,social,and ethical advances in genetic testing.Technological advances have made it possible to sequence multiple genes at once in a panel to give patients a more thorough evaluation of their personal cancer risk.Panel testing increases the detection of mutations that lead to increased risk of breast,ovarian,and other cancers and can better guide individualized screening measures compared to limited BRCA testing alone.At the same time,multi-gene panel testing is more time-and cost-efficient.While the clinical application of panel testing is in its infancy,many problems arise such as lack of guidelines for management of newly identified gene mutations,high rates of variants of uncertain significance,and limited ability to screen for some cancers.Through on-going concerted efforts of pooled data collection and analysis,it is likely that the benefits of multi-gene panel testing will outweigh the risks in the near future.

Clinicopathological analysis of early-stage breast cancer patients that meet indications for BRCA 1/2 genetic testing

Objective:To investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer patients with indications for breast cancer susceptibility genes 1/2(BRCA1/2)genetic testing in China.Methods:Based on the indication criteria for BRCA genetic testing specified in the National Comprehensive Cancer Network(NCCN)clinical practice guidelines in oncology,genetic/familial high-risk assessment:Breast and ovarian(Version 2.2019),a retrospective analysis was performed on patients with early-stage invasive breast cancer treated at Breast Disease Center,Peking University First Hospital between January 2008 and December 2016.Clinicopathological characteristics of all patients were analyzed,and prognoses were calculated using the KaplanMeier method and a Cox proportionate hazards model.Results:A total of 906 early-stage breast cancer patients who had indications for BRCA genetic testing and had complete clinicopathological data and follow-up information were included in the study group,accounting for34.7%of all breast cancer patients treated in Breast Disease Center,Peking University First Hospital during the study period.Compared with breast cancer patients without indications for BRCA genetic testing,the overall survival(OS)and disease-free survival(DFS)of patients with indications were not significantly different.In the study group,patients with premenopausal status,high T stage,lymph node positive,estrogen receptor(ER)negative,Ki-67>20%and presence of a vascular tumor thrombus had worse prognosis.There were more family histories of gastrointestinal cancer in patients with related indications than in patients without such indications.Conclusions:Single-center data showed that more than 30%of patients with early-stage breast cancer had indications for BRCA genetic testing.There was no prognostic difference in patients with or without indications for BRCA genetic testing.Premenopausal status,high T stage,lymph node positive,ER negative,Ki-67>20%,and presence of a vascular tumor thrombus were associated with poor prognosis.

Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing

The introduction of next-generation sequencing(NGS) technology in testing for hereditary cancer susceptibility allows testing of multiple cancer susceptibility genes simultaneously. While there are many potential benefits to utilizing this technology in the hereditary cancer clinic, including efficiency of time and cost, there are also important limitations that must be considered. The best panel for the given clinical situation should be selected to minimize the number of variants of unknown significance. The inclusion in panels of low penetrance or newly identified genes without specific actionability can be problematic for interpretation.Genetic counselors are an essential part of the hereditary cancer risk assessment team, helping the medical team select the most appropriate test and interpret the often complex results. Genetic counselors obtain an extended family history, counsel patients on the available tests and the potential implications of results for themselves and their family members(pre-test counseling), explain to patients the implications of the test results(post-test counseling), and assist in testing family members at risk.

Genetic testing in neurology exploiting next generation sequencing:state of art

Next generations sequencing (NGS) is definitely one of the most revolutionary technology of the last years in genetic and medical field (Kricka and Di Resta, 2013). It brought important changes in genetic testing of inherited human disorders, in particular in neurological Mendelian forms, such as inherited neuropathies, ataxias or monogenic form of epilepsy, where “diagnostic odyssey” is quite common.

Role of genetic testing in cardiomyopathies:Αprimer for cardiologists

Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies.As novel mutations have been identified,understanding when to consider genetic testing has emerged as an important consideration in the management of these cases.Specific genetic testing has a paramount importance in the risk stratification of family members,in the prognosis of probands at higher risk of a serious phenotype expression,and finally in the identification of new mutations,all of which are discussed in this review.The indications for each type of cardiomyopathy are described,along with the limitations of genetic testing.Finally,the importance of public sharing of variants in large data sets is emphasized.The ultimate aim of this review is to present key messages about the genetic testing process in order to minimize potential harms and provide suggestions to specialized clinicians who act as a part of a multidisciplinary team in order to offer the best care to families with inherited cardiomyopathies.

2+0 CYP21A2 deletion carrier—a limitation of the genetic testing and counseling:A case report

BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.

Whole-genome amplification/preimplantation genetic testing for propionic acidemia of successful pregnancy in an obligate carrier Mexican couple:A case report

BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.

Subjective Cognitive Concerns and Attitudes toward Genetic Testing Are Associated with Depressive Symptoms and Quality of Life after Genetic Testing for the Cerebral Cavernous Malformation Common Hispanic Mutation (CCM1)

Purpose: This study aimed to characterize mood and quality of life and to examine the associations of these areas with subjective cognitive concerns and attitudes toward genetic testing for the Common Hispanic Mutation, a gene that has been associated with increased risk for CCM1. Method: Fifty-four adults with previous genetic testing for the Common Hispanic Mutation completed a mail survey that included assessments of the above identified areas. Results: Self-reported depressive symptoms and quality of life did not differ between those with positive and negative genetic test results. The negative group expressed a more favorable attitude toward genetic testing (p p = 0.06). Using generalized linear regression, more subjective cognitive concerns were associated with poorer quality of life and more depressive symptoms (p p Conclusions: Subjective cognitive concerns and negative attitudes toward genetic testing may influence emotional well-being after genetic testing for the Common Hispanic Mutation. Additional research is needed that uses objective neuropsychological measures to understand the associations of subjective cognitive concerns, emotional well-being, and cognitive test performance in individuals with CCM1. There is also a need for research that focuses on protective factors and resiliency following genetic testing for CCM1 and the development of mental health interventions to preempt psychosocial difficulties.

Implementation of Hybrid Particle Swarm Optimization for Optimized Regression Testing

Software test case optimization improves the efficiency of the software by proper structure and reduces the fault in the software.The existing research applies various optimization methods such as Genetic Algorithm,Crow Search Algorithm,Ant Colony Optimization,etc.,for test case optimization.The existing methods have limitations of lower efficiency in fault diagnosis,higher computa-tional time,and high memory requirement.The existing methods have lower effi-ciency in software test case optimization when the number of test cases is high.This research proposes the Tournament Winner Genetic Algorithm(TW-GA)method to improve the efficiency of software test case optimization.Hospital Information System(HIS)software was used to evaluate TW-GA model perfor-mance in test case optimization.The tournament Winner in the proposed method selects the instances with the best fitness values and increases the exploitation of the search to find the optimal solution.The TW-GA method has higher exploita-tion that helps to find the mutant and equivalent mutation that significantly increases fault diagnosis in the software.The TW-GA method discards the infor-mation with a lower fitness value that reduces the computational time and mem-ory requirement.The TW-GA method requires 5.47 s and the MOCSFO method requires 30 s for software test case optimization.