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PubMed2004

uPM3, a new molecular urine test for the detection of prostate cancer.

OBJECTIVES: To evaluate, in a multicenter study, the diagnostic performance of a new molecular test uPM3 for detecting prostate cancer cells in urine because of the need for better methods to identify patients at risk of prostate cancer. METHODS: The uPM3 test is a nucleic acid amplification assay detecting simultaneously in the urine the relative expression of prostate-specific antigen (PSA) mRNA as a marker of prostate cells and PCA3RNA, which is selectively expressed in most types of prostate cancer. The test is performed using the isothermic nucleic acid-based amplification method, and the two targets are simultaneously detected in real-time fluorescence using specific beacons as probes in a thermostated spectrofluorometer. The test was performed on the first voided urine obtained after careful digital rectal examination of the prostate in men undergoing transrectal ultrasound-guided prostate biopsy. RESULTS: Of 517 patients undergoing biopsy at five centers, 443 (86%) had an assessable sample. Of those, 21%, 55%, and 24% had a total PSA level of less than 4 ng/mL, between 4 and 10 ng/mL, and greater than 10 ng/mL. The corresponding percentage of biopsies positive for cancer in these three groups was 20%, 35%, and 44%. The overall uPM3 sensitivity and specificity was 66% and 89%, respectively. In men with a PSA level less than 4 ng/mL, the sensitivity was 74% and specificity 91%. In those with a PSA level of 4 to 10 ng/mL, the sensitivity was 58% and specificity 91%. In those with a PSA level greater than 10 ng/mL, the sensitivity and specificity was 79% and 80%, respectively. The positive predictive value of uPM3 was 75% compared with 38% for total PSA, and the negative predictive value was 84% compared with 89% and 80% for a PSA cutoff of 2.5 and 4.0 ng/mL, respectively. The overall accuracy was 81% compared with 43% and 47% for total PSA at a cutoff of 2.5 and 4.0 ng/mL, respectively. CONCLUSIONS: These results suggest that the uPM3 molecular urine test may be an important adjunct to current methods for the detection of early prostate cancer.

Adenocarcinoma↗

PubMed2001

Successful testing protocols in virology.

Molecular methods have had a significant impact on the diagnosis of viral infections because of their superior sensitivity and rapid turnaround time compared with conventional diagnostic methods. These characteristics have allowed molecular tests to play a central role in the use of testing protocols for managing viral infections. Several examples of such protocols are reviewed in this report, including the use of molecular testing for early disease detection to improve overall disease management and to direct antiviral therapy.

Antiviral Agents↗

PubMed2025

Molecular Biomarker Testing Patterns and Turnaround Time in US Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Patients with advanced non-small cell lung cancer (aNSCLC) are recommended to undergo molecular testing for targetable genomic alterations. However, as high-throughput methods are increasingly used, long test turnaround time (TAT) may lead to lower receipt of appropriate targeted therapy. Guidelines recommend a 2-week TAT for ALK and EGFR testing, 2 prevalent pathogenic alterations with highly effective targeted therapies. PATIENTS AND METHODS: Using an electronic health record-derived, deidentified database, we conducted a retrospective cohort study of patients with aNSCLC diagnosed between 2011 and 2023 who received testing for ≥1 of 8 molecular markers. We assessed the number of biomarkers tested per patient, testing modality, and TAT (defined as the interval between specimen collection and result date) over time. We also evaluated patients with ALK/EGFR-altered aNSCLC who initiated early nontargeted treatment prior to test result availability, examining associations with TAT and clinical outcomes. RESULTS: The study sample comprised 33,945 patients, with a mean age of 68.2 years; 49.4% were female, 58.3% were White, and 83.4% reported a history of smoking. From 2011 to 2023, the mean number of biomarkers tested per patient (range, 2.0-6.8) and the use of next-generation sequencing (NGS) increased, whereas the mean TAT converged to 3 weeks. Fewer than half of the patients with ALK/EGFR-altered aNSCLC had a TAT of ≤2 weeks, and 1 in 8 initiated early nontargeted treatment. Longer TAT was associated with early nontargeted treatment when analyzed as both a continuous variable (odds ratio, 1.83 per week) and a binary variable (TAT >2 vs ≤2 weeks; odds ratio, 6.02). Early treatment was associated with worse median progression-free survival (9 vs 11 months) in patients with ALK/EGFR-altered aNSCLC. CONCLUSIONS: Biomarker testing and NGS use have increased over time in US patients with aNSCLC. TAT has plateaued and remains longer than recommended in consensus guidelines. Longer TAT was associated with early nontargeted therapy in patients with ALK+/EGFR+ aNSCLC, leading to suboptimal first-line treatment and poorer clinical outcomes.

Humans↗

PubMed2003

Interaction of genetic counselors with molecular genetic testing laboratories: implications for non-geneticist health care providers.

The availability of molecular genetic tests for the identification of mutant gene carriers, and for assessing individual genetic response to pharmacologic agents, infectious agents, and other environmental exposures, is expected to result in the increased use of the molecular genetic testing laboratory by primary care physicians. However, a number of concerns have been raised about such testing including the need for safeguards to protect patient privacy, and if the interface between genetic testing laboratories and the ordering physician facilitates the appropriate clinical use of the test result. In this study, genetic counselors were surveyed to determine their practices with regard to the clinical issues of informed consent and confidentiality in the context of genetic testing, and to assess their level of satisfaction with the reporting practices of molecular genetic testing laboratories. The results of this survey revealed that there is variability in the practices of genetic counselors with regard to obtaining informed consent, and that there are areas for improvement with regard to molecular genetic test reports, particularly in terms of interpretation of results.

Counseling↗

PubMed2006

Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

OBJECTIVES: To evaluate selected molecular tests in diagnosis and screening of cytomegalovirus (CMV) infection in immunosuppressed patients. DESIGN: Clinical and cost-effectiveness were assessed through a prospective two-stage trial of CMV screening regimes in a routine service setting. Different molecular test results were fed back to clinicians in each stage, plus antigenaemia results. The technical performance of the molecular methods was assessed through an independent masked comparison of each molecular test against the established (antigenaemia) test. Scientists performing a particular test were blind to the other test results for that sample. Diagnostic and therapeutic impact were recorded prospectively for all tests, to include any effect on diagnostic certainty, changes to CMV therapy and any other reported impact on patient management. The cost of each test was estimated under different laboratory conditions. Prospective patients undergoing CMV screening were compared with consecutive historical controls in the same unit. Towards the end of the study, a survey of all UK virology laboratories was undertaken to identify current CMV screening practice and test preferences. In addition, all UK renal transplant surgeons and haematology transplant centres were surveyed in order to identify current clinical practice and perceptions of the benefits of CMV screening. SETTING: Study patients were recruited from University Hospital Wales (UHW), Cardiff. Staff in the Cardiff Public Health Laboratory Service virology laboratory performed the tests. PARTICIPANTS: A consecutive series of transplant patients was recruited to the prospective study over a 42-month period, totalling 98 renal and 140 haematology patients. A consecutive series of historical controls was identified, with 199 renal and 136 haematology patients who underwent transplants in the UHW during the 29 months prior to the prospective CMV screening trial. INTERVENTIONS: A predefined CMV screening protocol was applied to all patients in the prospective trial. Renal patients were tested every 4 weeks until 16 weeks post-transplant (five tests in total). Haematology patients were tested every 2 weeks until 12 weeks post-transplant, and then every 4 weeks until 24 weeks (10 tests in total). The assays used for CMV screening were as follows: non-molecular test, (1) pp65 antigenaemia assay; molecular tests, semi-quantitative in-house polymerase chain reaction (PCR), (2) single-round (PCR1) and (3) two-round, nested (PCR2); and qualitative commercial tests, (4) Roche Amplicor Assay (Amplicor) and (5) pp67 NASBA assay (NASBA). MAIN OUTCOME MEASURES: Test failure rates, sensitivity/specificity values and positive predictive value (PPV) and negative predictive value (NPV) were measured for each assay. The laboratory cost of undertaking various CMV tests was measured and other NHS costs associated with false-positive or false-negative test results were estimated. The likelihood of CMV disease and the likely impact of positive or negative test result on therapy and further investigations were recorded. On receipt of the test result, interim outcome measures were recorded to include the impact of test result on diagnostic certainty, changes to planned patient management (e.g. therapy, investigations) and perceived benefit. All definitive diagnoses of CMV disease, prescribing of CMV therapy and interim patient outcome at the end of the screening period were recorded. RESULTS: In haematology and renal transplant patients, all tests had a similar NPV (0.976--0.997 and 0.935--0.995, respectively) when used in CMV screening. PCR1 is the least expensive molecular test (7.80-13.70 UK pounds). Commercial tests, NASBA and Amplicor, are both more expensive (22.50-34.70 UK pounds NASBA; 23.20-29.20 UK pounds Amplicor). Antigenaemia costs 12.50-27.40 pounds depending on staff grade and batch size. Quantitative PCR (COBAS) is the most expensive at around 50 UK pounds per sample. No clear link between screening test results and CMV prescribing was detected; clinicians appear to consider screening results in the context of other factors. There was no evidence that the introduction of CMV screening led to reductions in CMV deaths or improved transplant success rates. For cost per positive test result, PCR1 was the most cost-effective screening test on this indicator (renal patients 116 UK pounds per true positive, haematology patients 518 pounds). Antigenaemia was the least cost-effective screening test (renal patients 643 UK pounds per true positive, haematology patients 2475 pounds). Cost-effectiveness analysis and cost per "beneficial result" (as judged by clinicians) confirmed that PCR1 remained the most cost-effective test. Modelling outputs for targeted screening protocols also supported this. CONCLUSIONS: The study findings offer some evidence that a CMV screening regime is more cost-effective than diagnostic testing alone, based on the cost per true positive detected and interim outcome such as changes in patient management. However, the study was unable to demonstrate any benefits in terms of longer term patient outcomes. If CMV screening is introduced, the use of antigenaemia pp65 is clearly less cost-effective than the use of molecular tests. The study identified the optimum test for CMV screening as an in-house molecular test (single-round PCR test). This test was less costly to perform and also resulted in lower costs linked to false positives and negatives than other tests. The in-house, semi-quantitative test was two to three times more cost-effective than the commercial molecular tests assessed; however changes to European Union legislation may mean that it may not be feasible to use in-house tests. The use of targeted screening (limiting CMV screening to high-risk transplants) as opposed to universal screening offers a significant improvement in the cost-effectiveness ratio for haematology transplant patients, but has limited impact in the case of renal transplants. Economic analyses could be expanded to model the cost-effectiveness of more frequent screening tests (as reported nationally), and screening in other "at risk" groups. Subgroup specific disease groups should be investigated across a larger population to allow more accurate modelling of the impact of CMV screening on disease progression. Further studies of CMV screening programmes should address a range of outcome measures, including patient outcomes.

Biological Assay↗

PubMed2002

[Molecular diagnostic tests availability in view of remuneration for medical services].

By the remarkable development of recent molecular biology and genetic technology, the molecular diagnostic tests had put into practice as the routine test in the field of the clinical laboratory examinations. For molecular diagnostic tests, there are mainly infectious disease, hematological malignancies, hereditary disease, cancers, etc. In especially infectious disease and hematological malignancies, the adaptation of health insurance are examined in the facilities. It is usefully utilized for early detection, early diagnosis, selection of the treatment, follow-up, especially in the hematological malignancies such as leukemia and malignant lymphoma. It is possible to determine the clonal origin of malignant cells, and to detect minimal residual disease (MRD) after achieving complete remission. The usage of the molecular diagnostic tests is variable in infectious disease and hematological malignancies on the medical reimbursement, and there are restrictions like the following; in the case of any tests of the infectious disease, only which or main test can be calculated, facilities standards are necessary in order to calculate the health insurance treatment cost of the once in 6 months. In this article, we describe utilization and restrictions of the medical reimbursement for molecular diagnostic tests, focusing on the fiscal 2002 revision of the medical service fee schedule implemented in April.

Clinical Laboratory Techniques↗

PubMed2001

Molecular diagnostic testing for infectious diseases using TMA technology.

Molecular diagnostic tests based on nucleic acid amplification technologies (NAATs) have become widely established in clinical microbiology laboratories in recent years. The acceptance of these tests has been driven by the development of more accurate and less labor-intensive commercial assay kits by diagnostic manufacturers. Infectious disease diagnostic assays using transcription-mediated amplification (TMA) NAAT have become increasingly popular in many clinical microbiology laboratories. Recent technology developments have improved the performance and simplified the use of the TMA assays. These new technologies have been applied to the development of multiplex TMA tests to improve the testing accuracy for organisms, such as Chlamydia trachomatis and Neisseria gonorrhoeae in clinical microbiology laboratories. TMA tests for HIV-1 and HCV have also led to improvements in blood bank testing which can improve the safety of the public blood supply.

Blood↗

PubMed1991

Use of dried blood spot specimens in the detection of human immunodeficiency virus type 1 by the polymerase chain reaction.

Dried blood spots (DBSs) constitute a potentially valuable source of material for human immunodeficiency virus (HIV) serologic and molecular testing. To facilitate molecular testing, we have adapted the polymerase chain reaction (PCR) to the detection of HIV proviral DNA in DBS samples. The method is highly reproducible, with 75 microliters of whole dried blood providing sufficient DNA for duplicate testing with three primer sets. By using DBS PCR, 66 of 69 (95.6%) seropositive at-risk individuals tested positive by at least two primer sets and 85 of 85 (100%) low-risk seronegative blood donors tested negative by all three sets of primers. The frequency of HIV DNA detection in seronegative at-risk individuals was low, with only 1 of 58 (1.7%) individuals testing positive. These results show that in a clinical environment, HIV PCR analysis of DBS specimens is specific and sensitive. The method is cost effective and presents a useful alternative to the isolation of HIV from seropositive babies with an undefined infection status.

Blood↗

PubMed1997

Clinical molecular genetic testing.

Recent advances in human molecular genetics are rapidly producing clinical genetic tests for a variety of conditions. In addition to tests for rare genetic disorders, tests for common illnesses with mixed genetic and environmental etiologies are being developed. While practice guidelines for test utilization are being developed, many physicians would benefit from additional knowledge about the design and limitations of these tests. This article reviews the genetic background necessary to understand linkage-based and direct mutations tests and discusses some of the issues physicians must consider when selecting an appropriate test for a given clinical situation.

Genetic Techniques↗

PubMed2003

Molecular genetic testing for prenatal diagnosis.

In the past few decades, enormous progress has been made in the field of prenatal molecular genetic testing. Based on the inheritance patterns of the disease and type of mutation, prenatal diagnosis is possible using direct or indirect methods of detection. Although direct mutation analysis is highly accurate, accuracy of indirect mutation analysis depends on the distance of the DNA marker to the disease locus. In the past decade, the discovery of new concepts--such as atypical inheritance patterns due to UPD and imprinting and triplet repeat disorders--have helped to increase understanding of the molecular basis of these unusual genetic disorders. Prenatal diagnosis using a single cell from a blastomere is rapidly becoming routine in clinical practice. Noninvasive procedures to obtain fetal DNA for molecular testing also are progressing very rapidly. With the completion of the genome project, resources now are available for developing new technologies, such as microarrays (DNA chips), for accurate, simultaneous, mutation detection. The next few decades hold the promise of many more advances in genetic testing, drug discovery, and therapy.

Adult↗

PubMed2003

Testing a molecular clock without an outgroup: derivations of induced priors on branch-length restrictions in a Bayesian framework.

We propose a Bayesian method for testing molecular clock hypotheses for use with aligned sequence data from multiple taxa. Our method utilizes a nonreversible nucleotide substitution model to avoid the necessity of specifying either a known tree relating the taxa or an outgroup for rooting the tree. We employ reversible jump Markov chain Monte Carlo to sample from the posterior distribution of the phylogenetic model parameters and conduct hypothesis testing using Bayes factors, the ratio of the posterior to prior odds of competing models. Here, the Bayes factors reflect the relative support of the sequence data for equal rates of evolutionary change between taxa versus unequal rates, averaged over all possible phylogenetic parameters, including the tree and root position. As the molecular clock model is a restriction of the more general unequal rates model, we use the Savage-Dickey ratio to estimate the Bayes factors. The Savage-Dickey ratio provides a convenient approach to calculating Bayes factors in favor of sharp hypotheses. Critical to calculating the Savage-Dickey ratio is a determination of the prior induced on the modeling restrictions. We demonstrate our method on a well-studied mtDNA sequence data set consisting of nine primates. We find strong support against a global molecular clock, but do find support for a local clock among the anthropoids. We provide mathematical derivations of the induced priors on branch length restrictions assuming equally likely trees. These derivations also have more general applicability to the examination of prior assumptions in Bayesian phylogenetics.

Animals↗

PubMed1993

Simple methods for testing the molecular evolutionary clock hypothesis.

Simple statistical methods for testing the molecular evolutionary clock hypothesis are developed which can be applied to both nucleotide and amino acid sequences. These methods are based on the chi-square test and are applicable even when the pattern of substitution rates is unknown and/or the substitution rate varies among different sites. Furthermore, some of the methods can be applied even when the outgroup is unknown. Using computer simulations, these methods were compared with the likelihood ratio test and the relative rate test. The results indicate that the powers of the present methods are similar to those of the likelihood ratio test and the relative rate test, in spite of the fact that the latter two tests assume that the pattern of substitution rates follows a certain model and that the substitution rate is the same among different sites, while such assumptions are not necessary to apply the present methods. Therefore, the present methods might be useful.

Amino Acid Sequence↗

PubMed2004

Laboratory approaches to the diagnosis of hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major and growing health problem worldwide. Laboratory testing plays an important role in the response to the HCV epidemic. Serologic tests for antibody to HCV are useful for screening purposes. The mainstays of laboratory testing for HCV, however, are the molecular approaches. Qualitative molecular tests are useful for confirmation of positive screening tests. Quantitative molecular tests provide prognostic information regarding the likelihood of response to therapy, and allow the monitoring of treatment efficacy. Similarly, genotyping assays predict response to therapy, and allow rational decisions regarding duration of treatment. The combination of continually improving laboratory testing, together with new drugs targeting distinct molecular determinants that are either essential or important in the viral replication cycle, is likely to lead to dramatic improvements in the management of HCV disease.

Genotype↗

PubMed2006

Practical experiences of moving molecular diagnostics into routine use at the Veterinary Laboratories Agency.

The practical bench application of molecular tests (here defined as nucleic acid-based tests) in a routine testing situation is not without its challenges. This paper outlines the approaches we take at the Veterinary Laboratories Agency (VLA) and highlights some of the practical issues which we have found to be important for the successful introduction and use of molecular tests in a routine testing environment. The potential advantages of molecular tests, and factors which dictate which tests are adopted for routine testing, are discussed before giving some examples of molecular tests in routine use at the VLA. The instrumentation, reagents and assays we use are outlined, followed by sections of how we approach validation and how we manage and resource the transfer of molecular tests into routine use.

Laboratories↗

PubMed2006

Monitoring standards for molecular genetic testing in the United Kingdom, the Netherlands, and Ireland.

Molecular genetic techniques have entered many areas of clinical practice. Public expectations from this technology are understandably high. To maintain confidence in this technology, laboratories must implement the highest standards of quality assurance (QA). External quality assessment (EQA) is recognized as an essential component of QA. The United Kingdom National External Quality Assessment Service (UKNEQAS) for Molecular Genetics, first set up in 1991, is currently the longest provider of EQA to molecular genetic testing laboratories in the UK, The Netherlands, and Ireland. Errors in the scheme are sporadic events. However, evidence from this and other EQA schemes suggests that a residual error rate persists, which should be taken into account in clinical practice. This EQA scheme has evolved from the respective scientific bodies of the constituent countries and retains a strong emphasis on collective peer review. It is essential that the steps taken to ensure quality in this rapidly expanding field are clear and transparent to participants and public alike. We describe the procedures developed and the governance imposed to monitor and improve analytical and reporting standards in participant laboratories and we compare our experiences with those of equivalent EQA services in the United States.

Cytogenetic Analysis↗

PubMedDate not supplied

[Importance of genetic counseling and molecular diagnosis testing in families at high risk for cancer].

Individuals with a family history of certain cancer types are at higher risk to develop a malignancy during their lifetime. The availability of the family history is a basic component for genetic counseling of these patients to determine illnesses that may affect other family members. The family history can help us to identify some inheritance patterns of cancer transmission among families. Nowadays it is possible to identify by clinical and molecular testing many of these familial cancer syndromes. The objective of this review is to provide a basis to the physician who the patient contacts first, in order to recognize the possibility of illnesses with a genetic transmission. This will allow the treating physician to refer the patient to a genetic specialist for possible molecular diagnosis of the illness.

Genetic Counseling↗

PubMed2005

Molecular genetic testing of polymorphisms associated with venous thrombosis: a review of molecular technologies.

The growing knowledge of genetic polymorphisms predisposing to venous thrombosis has increased the demand for genetic testing of associated risk factors. This has prompted the need for simple, fast, reliable, and cost-effective genotyping methods for identification of those mutations. In the past decade, a large variety of DNA mutation analysis methods have been developed for detection of genetic variants associated with venous thrombosis, including PCR-based and PCR-independent technologies. Each of these technologies possesses unique advantages, but all have a common goal of simplifying and expediting mutation analysis. This review describes some of the commonly used technologies and commercially available platforms employed in clinical laboratories for genetic testing of thrombophilia. The choice of a technology for each individual laboratory would primarily depend on the specific requirements for the assay's accuracy, reliability, speed, throughput, and cost-effectiveness.

DNA Mutational Analysis↗

PubMed2005

Identification of methicillin-resistant Staphylococcus aureus (MRSA): Comparison of a new molecular genetic test kit (GenoType MRSA) with standard diagnostic methods.

Results obtained from 188 isolates of staphylococci using standard diagnostic methods for identifying MRSA were compared with those achieved with a newly available molecular genetic test kit, the GenoType, Version 1, MRSA (Hain Lifescience GmbH, Nehren, Germany). The GenoType MRSA detects the mecA gene and, in addition, a highly specific sequence for Staphylococcus aureus (S. aureus) by polymerase chain reaction (PCR) and reverse hybridization. There was a 100% overall correlation between the results of conventional and molecular genetic testing. 143 isolates were tested positive for MRSA, 10 isolates were identified as oxacillin-sensitive Staphylococcus aureus strains (MSSA), and 35 isolates were coagulase-negative staphylococci of various species. However, five of the 143 MRSA strains yielded ambiguous results with the first line standard tests and therefore required additional testing leading to delay of definitive diagnosis. As expected, mecA could not only be detected in MRSA strains, but also in coagulase-negative staphylococci. The reliable identification as S. aureus from the same isolate is therefore an essential prerequisite for MRSA diagnosis. The GenoType MRSA fulfills this requirement by parallel detection of a S. aureus-specific sequence and the mecA gene. Molecular genetic testing with the GenoType MRSA kit needs much less time than conventional microbiological methods. Therefore genetic testing provides not only a considerable advantage with respect to reliability but also to speed.

Bacterial Proteins↗