Toward harmonization of clinical molecular diagnostic reports: findings of an international survey

Abstract Background: The International Organization for Standardization (ISO) 15189 standard provides recommendations for the postexamination reporting phase to enhance quality in clinical laboratories. The purpose of this study was to encourage a broad discussion on current reporting practices for molecular diagnostic tests by conducting a global survey of such practices. Methods: The International Federation of Clinical Chemistry and Laboratory Medicine’s Committee for Molecular Diagnostics (IFCC C-MD) surveyed laboratories on selected ISO 15189 recommendations and topics. The survey addressed the following aspects: (1) laboratory demographics, (2) report format, (3) result reporting/layout, (4) comments in report and (5) interpretation and clinical decision-making information. Additionally, participants indicated categories needing standardization. Results: Sixteen responses from laboratories located in Asia, Europe, the Middle East, North America and South America were received. Several categories yielded 100% agreement between laboratories, whereas other categories had less than or equal to 50% concordance. Participants scored “nomenclature” and “description of methodologies” as the two most frequently cited aspects needing standardization. Conclusions: The postexamination phase requires extensive and consistent communication between the laboratory, the healthcare provider and the end user. Surveyed laboratories were most likely to follow explicit ISO 15189 recommendations vs. recommendations when the term(s) “where appropriate or where applicable” was used. Interpretation and reporting of critical values varied among participants. Although the outcome of this study may not fully represent the practices of all molecular testing laboratories in countries around the world, the survey identified and specified several recommendations that are requirements for harmonized reporting in molecular diagnostics.

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Molecular Diagnostics in Pediatric Brain Tumors: Impact on Diagnosis and Clinical Decision-Making — A Selected Case Series

Klinische Pädiatrie ◽

10.1055/a-0637-9653 ◽

2018 ◽

Vol 230 (06) ◽

pp. 305-313 ◽

Cited By ~ 1

Author(s):

Heidi Bächli ◽

Jonas Ecker ◽

Cornelis van Tilburg ◽

Dominik Sturm ◽

Florian Selt ◽

...

Keyword(s):

Decision Making ◽

Molecular Diagnostics ◽

Clinical Management ◽

Clinical Decision Making ◽

Case Series ◽

Clinical Decision ◽

Cns Tumors ◽

Molecular Testing ◽

Cancer Predisposition Syndrome ◽

Pediatric Cns Tumors

AbstractCentral nervous system (CNS) tumors account for the highest mortality among pediatric malignancies. Accurate diagnosis is essential for optimal clinical management. The increasing use of molecular diagnostics has opened up novel possibilities for more precise classification of CNS tumors. We here report a single-institutional collection of pediatric CNS tumor cases that underwent a refinement or a change of diagnosis after completion of molecular analysis that affected clinical decision-making including the application of molecularly informed targeted therapies. 13 pediatric CNS tumors were analyzed by conventional histology, immunohistochemistry, and molecular diagnostics including DNA methylation profiling in 12 cases, DNA sequencing in 8 cases and RNA sequencing in 3 cases. 3 tumors had a refinement of diagnosis upon molecular testing, and 6 tumors underwent a change of diagnosis. Targeted therapy was initiated in 5 cases. An underlying cancer predisposition syndrome was detected in 5 cases. Although this case series, retrospective and not population based, has its limitations, insight can be gained regarding precision of diagnosis and clinical management of the patients in selected cases. Accuracy of diagnosis was improved in the cases presented here by the addition of molecular diagnostics, impacting clinical management of affected patients, both in the first-line as well as in the follow-up setting. This additional information may support the clinical decision making in the treatment of challenging pediatric CNS tumors. Prospective testing of the clinical value of molecular diagnostics is currently underway.

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External quality assessment (EQA) and alternative assessment procedures (AAPs) in molecular diagnostics: findings of an international survey

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0101 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Deborah A. Payne ◽

Graciela Russomando ◽

Mark W. Linder ◽

Katarina Baluchova ◽

Tester Ashavaid ◽

...

Keyword(s):

Quality Assessment ◽

Molecular Diagnostics ◽

Alternative Assessment ◽

External Quality Assessment ◽

Clinical Chemistry ◽

Molecular Diagnostic ◽

Internal Quality ◽

External Quality ◽

Iso 15189 ◽

Eqa Schemes

AbstractObjectivesQuality management for clinical laboratories requires the establishment of internal procedures including standard operating procedures (SOPs), internal quality control (QC), validation of test results and quality assessment. External quality assessment (EQA) and alternativeassessment procedures (AAPs) are part of the quality hierarchy required for diagnostic testing. The International Organization for Standardization (ISO) document with requirements for conformance ISO 15189 and the Clinical and Laboratory Standards Institute document (CLSI) QMS24 require participation in EQA schemes and AAPs where applicable. The purpose of this study was to perform a global survey of EQA and AAPs for key procedures in molecular diagnostic laboratories.MethodsThe Committee for Molecular Diagnostics of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC C-MD) conducted a survey of international molecular laboratories that covered specific topics of molecular diagnostic services as well as methods for EQA and AAPs. The survey addressed the following aspects: (1) usage of laboratory-developed test (LDT), (2) participation in EQA schemes and (3) performance of AAPs.ResultsA total of 93 responses from laboratories located in Asia, Europe, the Middle East, North America and South America were received. The majority of the participating laboratories (65.9%) use LDTs and 81.3% stated that it is mandatory for them to participate in EQA programs, while 22% of the laboratories reported not performing AAPs. Thirty-one percent of the laboratories use EQAs for fewer than 50.0% of their reported parameters/analytes.ConclusionsWhile the majority of laboratories perform EQA and AAPs to improve their quality in molecular diagnostics, the amount of AAPs as quality procedures differs within the laboratories. Further surveys are necessary to clarify the existing needs in additional EQAs and standardized AAPs. The survey will also guide future efforts of the IFCC C-MD for identifying quality practices in need to improve harmonization and standardization within molecular diagnostics.

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Assessing the utility and attitudes toward molecular testing in neuro-oncology: a survey of the Society for Neuro-Oncology members

Neuro-Oncology Practice ◽

10.1093/nop/npab003 ◽

2021 ◽

Author(s):

Shannon Fortin Ensign ◽

Maya Hrachova ◽

Susan Chang ◽

Maciej M Mrugala

Keyword(s):

Online Survey ◽

Clinical Decision Making ◽

Unmet Needs ◽

Practice Patterns ◽

Response Rate ◽

Clinical Decision ◽

Molecular Testing ◽

Newly Diagnosed ◽

Tumor Boards ◽

Oncology Practice

Abstract Background Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT. Methods We conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019. Results We received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT. Conclusion This survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.

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ACR TI-RADS and ATA US scores are helpful for the management of thyroid nodules with indeterminate cytology

BMC Endocrine Disorders ◽

10.1186/s12902-019-0429-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 11

Author(s):

Thayse Lozovoy Madsen Barbosa ◽

Cleo Otaviano Mesa Junior ◽

Hans Graf ◽

Teresa Cavalvanti ◽

Marcus Adriano Trippia ◽

...

Keyword(s):

Thyroid Nodules ◽

Clinical Decision Making ◽

Clinical Decision ◽

Needle Aspiration ◽

Molecular Testing ◽

American Thyroid Association ◽

Institutional Review ◽

The Us ◽

Risk Of Malignancy ◽

Indeterminate Cytology

Abstract Background Cytologically indeterminate thyroid nodules currently present a challenge for clinical decision-making. The main aim of our study was to determine whether the classifications, American College of Radiology (ACR) TI-RADS and 2015 American Thyroid Association (ATA) guidelines, in association with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), could be used to stratify the malignancy risk of indeterminate thyroid nodules and guide their clinical management. Methods The institutional review board approved this retrospective study of a cohort of 140 thyroid nodules in 139 patients who were referred to ultrasound-guided fine-needle aspiration cytology (FNAC) from January 2012 to June 2016 with indeterminate cytological results (44 Bethesda III, 52 Bethesda IV and 44 Bethesda V) and in whom pre-FNAC thyroid US images and histological results after surgery were available. Each included nodule was classified by one radiologist blinded to the cytological and histological diagnoses according to the ACR TIRADS scores and the US patterns as recommended in the 2015 ATA guidelines. The risk of malignancy was estimated for Bethesda, TI-RADS scores, ATA US patterns and their combination. Results Of the 140 indeterminate thyroid nodules examined, 74 (52.9%) were histologically benign. A different rate of malignancy (p < 0.001) among Bethesda III, IV and V was observed. The rate of malignancy increased according to the US suspicion categories (p < 0.001) in both US classifications (TI-RADS and ATA). Thyroid nodules classified as Bethesda III and the lowest risk US categories (very low, low and intermediate suspicion by ATA and 2, 3 and 4a by TI-RADS) displayed a sensitivity of 95.3% for both classifications and a negative predictive value of 94.3 and 94.1%, respectively. The highest risk US categories (high suspicion by ATA and 4b,4c and 5 by TI-RADS) were significantly associated with cancer (odds ratios [ORs] 14.7 and 9.8, respectively). Conclusions Ultrasound classifications, ACR TI-RADS and ATA guidelines, may help guide the management of indeterminate thyroid nodules, suggesting a conservative approach to nodules with low-risk US suspicion and Bethesda III, while molecular testing and surgery should be considered for nodules with high-risk US suspicion and Bethesda IV or V.

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INNV-28. MOLECULAR TESTING IN NEURO-ONCOLOGY – ASSESSMENT OF UTILITY AND PRACTICE PATTERNS. A SOCIETY FOR NEURO-ONCOLOGY MEMBERSHIP SURVEY

Neuro-Oncology ◽

10.1093/neuonc/noz175.569 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi136-vi136

Author(s):

Maciej Mrugala ◽

Susan Chang

Keyword(s):

Decision Making ◽

Clinical Decision Making ◽

Practice Patterns ◽

Clinical Decision ◽

Educational Programs ◽

Molecular Testing ◽

Targeted Agents ◽

Younger Patients ◽

Tumor Boards ◽

The Subject

Abstract BACKGROUND Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. Multiple molecular panels are available providing a spectrum of information. We were interested in learning how this information is acquired, what are the practice patterns regarding this type of testing, how are the results utilized in patient care and how prepared neuro-oncologists are to interpret these results. METHODS We conducted a survey using the Society for Neuro-Oncology membership database. We developed a set of 13 questions and administered the survey to 2022 members using the online platform. RESULTS We received 153 responses (7.5% of membership). 89% percent of responders routinely order MT. Of those who do not order MT on all patients, 50% test younger patients and 57% midline tumors. 83% use MT in recurrent glioma. Other common indications for MT included: metastatic tumors, meningioma, medulloblastoma, ATRT. Majority (60%) use in-house panels, followed by Foundation One (35%), TEMPUS (13%), CARIS (10%) and other panels (23%). For 57% of respondents, the data from MT was somewhat useful and for 41% it was very useful. 78% used the results of MT for clinical decision-making. BRAF, EGFR/ALK, H3K27 mutations were most commonly used for treatment decisions. 50% of respondents have molecular tumor boards at their institutions and a majority of practitioners share the results of MT with their patients (95%). Respondents would like to see SNO-endorsed official guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials and more educational programs on the subject. CONCLUSIONS Molecular testing is neuro-oncology is commonly done. Many providers rely on the information for clinical decision making where appropriate. In-house and commercial genetic panels are equally used in practice. There continues to be a need for more education on the subject and development of neuro-oncology specific guidelines.

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NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2011.0138 ◽

2011 ◽

Vol 9 (Suppl_6) ◽

pp. S-1-S-16 ◽

Cited By ~ 29

Author(s):

Paul F. Engstrom ◽

Mara G. Bloom ◽

George Daniel Demetri ◽

Phillip G. Febbo ◽

William Goeckeler ◽

...

Keyword(s):

Clinical Decision Making ◽

Work Group ◽

Clinical Decision ◽

White Paper ◽

Molecular Testing ◽

Molecular Tests ◽

Provider Knowledge ◽

Coverage Policy ◽

Testing Work ◽

Analytic Validity

Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence.

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2181. Yield and Impact of Molecular Diagnostics for Pathogen Detection in Pediatric Patients: 16/18S rRNA PCR and Noninvasive Assays

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1861 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S740-S741

Author(s):

Angela Chun ◽

Taylor Heald-Sargent ◽

Michael Malczynski ◽

William J Muller ◽

Chao Qi ◽

...

Keyword(s):

Molecular Diagnostics ◽

18S Rrna ◽

Pediatric Patients ◽

Clinical Care ◽

High Yield ◽

Molecular Diagnostic ◽

Clinical Samples ◽

Molecular Testing ◽

Rrna Gene ◽

Fungal Culture

Abstract Background Molecular diagnostic tests can identify bacterial and fungal pathogens from clinical samples. Nucleic acid detection tests include 16S and 18S rRNA gene PCR (16/18S PCR) and plasma next-generation sequencing (NGS). Other assays (fungal galactomannan and 1,3-β-d-glucan) detect structural factors. Our objective was to assess the utilization, yield, and impact of molecular diagnostics in pediatric patients who had samples sent for 16/18S PCR. Methods Sterile site fluid or tissue specimens were collected as part of standard care at Lurie Children’s Hospital, cultured, and sent to Northwestern Memorial Hospital for 16/18S PCR as clinically indicated. Medical records were reviewed for diagnostics, antibiotics, and clinical course. Results From 1/2016–8/2018, 236 samples were sent for 16 and/or 18S PCR from 183 patients. 83% had a concurrent ID consult. 16S PCR was done on 215 samples, 42 (20%) were positive, and 36 yielded species identification (Table 1). Antibacterial agents were administered prior to specimen collection in 73% and did not affect likelihood of positive 16S PCR. 18S PCR was sent on 163 samples; 12 (7.4%) were positive (Table 2) of which 10 were from immunocompromised hosts. 40% of patients were on antifungals prior to sample acquisition. 16/18S PCR impacted antimicrobial decision-making in 70 cases (30%). A pathogenic fungus was detected by PCR but not culture in 2 cases. Time to positivity of fungal culture was 1–15 days. Fungal culture was positive in 5 cases with-negative 18S PCR. Seventeen patients had positive serum 1,3-ß-D-glucan and/or galactomannan: 3 of which had positive 18S PCR, 5 with fungal growth, 5 presumed infection based on imaging, 1 Nocardia, and 3 noninfectious etiology. Plasma NGS was sent on 45 cases, was positive in 34, and affected clinical management in 10. Conclusion 16S PCR can identify bacterial pathogens in the setting of negative culture and impact clinical care. Abscess, bronchial/pleural fluid, and brain/organ tissue were high yield specimens. 18S PCR can provide expeditious fungal identification in cases of suspected invasive disease, but fungal culture and serum molecular testing increase diagnostic yield. No single fungal test is comprehensive. Plasma NGS had relatively high yield and clinical impact in selected patients. Disclosures All authors: No reported disclosures.

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Establishment of Reference Intervals for Alkaline Phosphatase in Pakistani Children Using a Data Mining Approach

Laboratory Medicine ◽

10.1093/labmed/lmz096 ◽

2019 ◽

Vol 51 (5) ◽

pp. 484-490 ◽

Cited By ~ 1

Author(s):

Sibtain Ahmed ◽

Jakob Zierk ◽

Aysha Habib Khan

Keyword(s):

Data Mining ◽

Alkaline Phosphatase ◽

Clinical Decision Making ◽

Clinical Chemistry ◽

Age Groups ◽

Clinical Decision ◽

German Society ◽

Reference Intervals ◽

Photometric Method ◽

Data Mining Approach

Abstract Objective To establish reference intervals (RIs) for alkaline phosphatase (ALP) levels in Pakistani children using an indirect data mining approach. Methods ALP levels analyzed on a Siemens Advia 1800 analyzer using the International Federation of Clinical Chemistry’s photometric method for both inpatients and outpatients aged 1 to 17 years between January 2013 and December 2017, including patients from intensive care units and specialty units, were retrieved. RIs were calculated using a previously validated indirect algorithm developed by the German Society of Clinical Chemistry and Laboratory Medicine’s Working Group on Guide Limits. Results From a total of 108,845 results, after the exclusion of patients with multiple specimens, RIs were calculated for 24,628 males and 18,083 females with stratification into fine-grained age groups. These RIs demonstrate the complex age- and sex-related ALP dynamics occurring during physiological development. Conclusion The population-specific RIs serve to allow an accurate understanding of the fluctuations in analyte activity with increasing age and to support clinical decision making.

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Immunohistochemistry should undergo robust validation equivalent to that of molecular diagnostics

Journal of Clinical Pathology ◽

10.1136/jclinpath-2015-203178 ◽

2015 ◽

Vol 68 (10) ◽

pp. 766-770 ◽

Cited By ~ 24

Author(s):

Kelly Elliott ◽

Stephen McQuaid ◽

Manuel Salto-Tellez ◽

Perry Maxwell

Keyword(s):

Molecular Diagnostics ◽

Clinical Care ◽

Treatment Options ◽

Subjective Assessment ◽

Molecular Diagnostic ◽

Evidence Based ◽

Uncertainty Of Measurement ◽

Prognostic Information ◽

Iso 15189 ◽

Diagnostic Histopathology

Immunohistochemistry (IHC) is a widely available and highly utilised tool in diagnostic histopathology and is used to guide treatment options as well as provide prognostic information. IHC is subjected to qualitative and subjective assessment, which has been criticised for a lack of stringency, while PCR-based molecular diagnostic validations by comparison are regarded as very rigorous. It is essential that IHC tests are validated through evidence-based procedures. With the move to ISO15189 (2012), not just of the accuracy, specificity and reproducibility of each test need to be determined and managed, but also the degree of uncertainty and the delivery of such tests. The recent update to ISO 15189 (2012) states that it is appropriate to consider the potential uncertainty of measurement of the value obtained in the laboratory and how that may impact on prognostic or predictive thresholds. In order to highlight the problems surrounding IHC validity, we reviewed the measurement of Ki67and p53 in the literature. Both of these biomarkers have been incorporated into clinical care by pathology laboratories worldwide. The variation seen appears excessive even when measuring centrally stained slides from the same cases. We therefore propose in this paper to establish the basis on which IHC laboratories can bring the same level of robust validation seen in the molecular pathology laboratories and the principles applied to all routine IHC tests.

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Whole Locus Sequencing Identifies a Prevalent Founder Deep Intronic RPGRIP1 Pathologic Variant in the French Leber Congenital Amaurosis Cohort

Genes ◽

10.3390/genes12020287 ◽

2021 ◽

Vol 12 (2) ◽

pp. 287

Author(s):

Isabelle Perrault ◽

Sylvain Hanein ◽

Xavier Gérard ◽

Nelson Mounguengue ◽

Ryme Bouyakoub ◽

...

Keyword(s):

High Throughput ◽

Clinical Decision Making ◽

Genetic Diagnosis ◽

Clinical Decision ◽

Molecular Testing ◽

Compound Heterozygous ◽

Leber Congenital Amaurosis ◽

Disease Allele ◽

Coding Regions ◽

Intronic Mutation

Leber congenital amaurosis (LCA) encompasses the earliest and most severe retinal dystrophies and can occur as a non-syndromic or a syndromic disease. Molecular diagnosis in LCA is of particular importance in clinical decision-making and patient care since it can provide ocular and extraocular prognostics and identify patients eligible to develop gene-specific therapies. Routine high-throughput molecular testing in LCA yields 70%–80% of genetic diagnosis. In this study, we aimed to investigate the non-coding regions of one non-syndromic LCA gene, RPGRIP1, in a series of six families displaying one single disease allele after a gene-panel screening of 722 LCA families which identified 26 biallelic RPGRIP1 families. Using trio-based high-throughput whole locus sequencing (WLS) for second disease alleles, we identified a founder deep intronic mutation (NM_020366.3:c.1468-128T>G) in 3/6 families. We employed Sanger sequencing to search for the pathologic variant in unresolved LCA cases (106/722) and identified three additional families (two homozygous and one compound heterozygous with the NM_020366.3:c.930+77A>G deep intronic change). This makes the c.1468-128T>G the most frequent RPGRIP1 disease allele (8/60, 13%) in our cohort. Studying patient lymphoblasts, we show that the pathologic variant creates a donor splice-site and leads to the insertion of the pseudo-exon in the mRNA, which we were able to hamper using splice-switching antisense oligonucleotides (AONs), paving the way to therapies.

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