Get Ready For The Future Of Gene Variant Interpretation With Molecular .
For molecular pathologists28,000 genevariant-drugrelations.Get ready for the future of gene variantinterpretation with Molecular Health GuideWith MH Guide you get full access to the global clinical knowledge dataplatform Dataome, with today over 28,000 gene variant-drug relations.
About MH GuideMH Guide is an automated clinical interpretation software that accepts any variant list inVCF file format. These files contain structured information regarding the beginning and endpositions of the genetic variant, a measure for the observation quality, the variant type, andcopy number changes, total read count, and reference and alternate allele frequencies.With MH Guide Premium, MH Guide can be expanded with a bioinformatic pipeline thataccepts raw sequencing data (FASTQ files) or aligned sequencing data (BAM files).Dataome, the backbone of MH GuideDataome, a global clinical knowledge data platform, is based onlarge biomedical and drug data sets combined with novel artificialintelligence and machine learning (AI/ML) technologies. It providesunparalleled evidence by connecting real-world patient outcomedata to up-to-date state of clinical and molecular knowledge.MH Guide also supports output from non-NGS methods such as FISH, IHC, (q)PCR, andmicroarrays. Data that is not compatible with VCF format can be added manually(e.g. protein expression data).28,000 curated genedrug relationsvariantRegardless of the origin of the VCF file, the MH Guide automated analysis interprets thepatient’s genetic variants using data derived from the global clinical knowledge dataplatform, Dataome, containing up-to-date published scientific and biomedical evidenceon cancer treatments, pathways, genes, variants, and clinical trials.Quality assurance by curation of dataScientific peer-reviewedliteratureScientifically relevantAutomated/assisted tools(TDM, TREX)ClinicalMedical review of relevant contentScientific curation of relevant contentClinically and contextuallyrelevant informationMolecular Health provides quality assurance by curation of data – a sophisticated process,in which the data is regularly updated and finally curated by medical and scientific experts.Our regular updates of MH Guide assure that information about new biomarkers andapproved drugs is implemented quickly so that you get the information you need.
Dataome is the ultimate data source for MH GuideFrom NGS data to treatment options:Clinical Variant Interpretation (CVI)MH Guide analyzes NGS data from commercial orcustomized panels, and WES to identify and interpretrelevant gene variants detected in the patientʼs tumor.We call this clinical variant interpretation.Patient ID ——Case IDDate of birth —SexEthnicityCountryTrial ZIPcodeUnstructureddata withoutrelated evidenceMale—US—Lung adenocarcinomaDiagnosis—ICD-10-CM code—MeSH ID/termAdditional MeSH IDs —Primary tumor site —Surgical pathology ——Tissue type—MetastaticCollectedTumor cellularityBarcodeSample typeGeneral dataset ID —CVI dataset ID—Organizational unit EmailPhoneFaxProductReport——————MH Guide—Mutational status of commonly mutated genes in the patient diseaseABCB1notidentifiedALK1 fusion, 1SNVBRAFnotidentifiedROS11 entifiedSUMMARYOverview of prognostic and diagnostic findingsOverview of potential treatment impacts32Potential impact1 SafetyTreatment0 PrognosticDrug approval*Biomarker0 DiagnosticVAFBiomarker scoreStructured data related toclinical evidence, curated byscientific and medical ovedALK/EML4(fusion)—DabrafenibApprovedG6PD p.R285H(SNV)99.56%CrizotinibApprovedALK p.L1196M(SNV)23.80%AlectinibApprovedALK p.L1196M(SNV)23.80%DiseasesList of diseasesrelated to thevariant* in the patient's disease; VAF Variant allele frequencyBiomarker score: AMP score and CVI score. Clinically approved:disease. Clinical:drug. Preclinical:translational data.You can find more details on the biomarker score (AMP and CVI score) in the glossary.Dataome integrates data from various data resources:Order date 14 Nov 2019Report Version 5Signed by11 Dec 2019 12:20 (UTC 01:00)Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg www.molecularhealth.com 49 6221 43851-150 For variant identification and biomarker annotation: ACMG variant classification1,COSMIC2, BRCA Exchange3, CVIs (proprietary of Molecular Health), AMP/CAP/ASCOclassification4, GNOMAD based population frequencies5, and others For recommendation of drugs and clinical trials: WHO and NCT clinical trials, Drug DevStages (Global), NCCN guidelines, curated ESMO guidelines, Clinical Trial NGS Biomarker,and othersVariants Gene name Variant name(HGVS) Somatic orgermline ZygosityPhone —Treatments List oftreatments CVI score andAMP scoreImpact Predictive(effective,ineffective,safety) Diagnostic PrognosticBiomarker score CVI score:preclinical(1-3), clinical(4-6), clinicallyapproved (7) AMP scoreNarrativeSummary of theCVIReferencesList ofpublicationsand theircorrespondingPubMed IDsDataome contains structured data that were integrated using ETL (extract, transform, load)processes, and data from unstructured sources (free text).?Interested in becoming acuration expert for MH Guide?Let us know!Each CVI is based on published biomedical knowledge.Each CVI lists the relevant information regarding the variant, lineage (germ line or somatic),disease association, treatment (drug or drug combination), treatment impact (effective,ineffective, toxic), prognostic or diagnostic biomarkers, biomarker validity (pre clinical,clinical, clinically approved), and a narrative summarizing the clinical knowledge availablefor the variant.If relevant, information on developmental stage of the drug(s) and potentially recruitingclinical trials is added.Any conflicting evidence is also reported. Standard output formats are PDF, JSON and XML.An adapter is available to adapt the output to other formats, if required.
From NGS data to MH Guide reportYou can use MH Guide default or customized filters and rulesets according to your needs1. Variant filter Define variants to be consideredfor report2. Lineage and zygosityNGS data fromtumor sampleClinical variantinterpretationIdentifiedbiomarkersVariant identification Classify variants according tolineage and zygosity Filter out germline variants withno matching CVI3. CVI match qualityPatient ID ——Case IDDate of birth —SexEthnicityCountryTrial ZIPcodeMale—US—Primary tumor site —Surgical pathology ——Tissue type—MetastaticCollectedTumor cellularityBarcodeSample type————General dataset ID —CVI dataset ID—Organizational unit —Labtest—Software xProductReport————MH Guide—Mutational status of commonly mutated genes in the patient diseaseABCB1notidentifiedALK1 fusion, 1SNVBRAFnotidentifiedROS11 entifiedSUMMARYOverview of prognostic and diagnostic findingsOverview of potential treatment impacts3 EffectivePotential impactEffectiveEffectiveIdentified therapeuticoptions and ve2 IneffectiveReport summarizes andclassifies identified treatmentoptions, as well as prognosticand diagnostic variants relevantfor treatment by a traffic-lightcolor code as potentiallyeffective, ineffective, or withpotential safety issue.Lung adenocarcinomaDiagnosis—ICD-10-CM code—MeSH ID/termAdditional MeSH IDs —1 Safety0 Prognostic0 DiagnosticClinical trials found8TrialsTreatmentDrug ML4(fusion)—5ApprovedG6PD p.R285H(SNV)99.56%—ApprovedALK p.L1196M(SNV)23.80%—ApprovedALK bCrizotinibAlectinibBiomarker scoreRETnotidentifiedTrials* in the patient's disease; VAF Variant allele frequencyBiomarker score: AMP score and CVI score. Clinically approved: Approved biomarker (by the FDA, EMA, or NCCN) to predict a specific effect in the patient'sdisease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effect of thedrug. Preclinical: This biomarker has not yet been observed/tested in patients to predict a specific effect of the drug. It is supported by preclinical evidence ortranslational data.You can find more details on the biomarker score (AMP and CVI score) in the glossary.Order date 14 Nov 2019Report Version 5Signed by11 Dec 2019 12:20 (UTC 01:00)Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg www.molecularhealth.com 49 6221 43851-150Phone —Page 1 of 11The CE-marked IVD software MH Guide and MH Guide Premium supply curated variantinterpretations, which are reviewed by scientific and medical experts. These provideunparalleled evidence for treatment decisions by connecting real-world patient outcomedata with up-to-date clinical and molecular knowledge.MH Guide data analysis starts with the variant call format (VCF) of the NGS data, fromeither customized or commercial panels, or from WES. Moreover, MH Guide can analyzedata from other assays that report detected variants in VCF format.MH Guide Premium allows interpretation of NGS data from FASTQ files, from eithercustomized or commercial panels, or from WES. SNVsIndelsFusions aCNAs bMSI b TMB Geneexpression c Proteinexpression c Methylation c Define matching parametersbetween variants and CVIs4. TMB calculation Define counting methods for TMBcalculation Set thresholds for low and high TMB1)2)3)5. Prioritization settings Define sort order of treatmentsand findings based on CVI or AMPscores6. Labtest appendix Define labtest-specific appendixDefinitions and abbreviations:a: detected in unpaired analyses or from RNAseq data, full suport from VCF inputb: detected from FASTQ or BAM data for paired analyses, full suport from VCF inputc: only possible via additional test resultSNVs: single nucleotide variantsIndels: insertions-deletions (indels, ins, dels, frameshifts)CNAs: copy number alterationsMSI: Microsatellite instabilityTMB: Tumor mutational burdenFilterspassed –variant isincluded inthe analysisMH Guide reportFiltersfailed –variant isexcluded fromthe analysis
Examples of CVI narrativesETV6/NTRK3 fusionSolid TumorsExamples of CVI narrativesLarotrectinib, Entrectinib,SelitrectinibThe neurotrophic receptor tyrosine kinase NTRK3 activates thePI3K/AKT and RAS/MAPK signaling pathways to promote cellsurvival and differentiation. ETV6-NTRK3 translocations wereidentified in several cancer types. Pan-NTRK inhibitors such aslarotrectinib or entrectinib led to tumor responses in tumors thatharbored the ETV6-NTRK3 fusion gene, regardless of tumor type.Larotrectinib and entrectinib are indicated for the treatmentof patients with solid tumors who have an NTRK gene fusion.Entrectinib led to tumor responses in salivary gland, parotid,and neuroendocrine neoplasms. In a preclinical study, cellsthat harbored this translocation were sensitive to larotrectinib,entrectinib, and selitrectinib (LOXO-195).MLH1 premature stop codonColorectal CancerMLH1 is important for DNA mismatch repair, and mutations in thisgene are frequently seen in colon adenocarcinomas. Althoughmutations in this gene are associated with Lynch syndrome,a majority of tumors that harbor these mutations are not theresult of genetic predisposition but are acquired spontaneously.Mutations in this pathway prevent adequate DNA repair, andtumors that harbor these defects show microsatellite instability(MSI), meaning that DNA regions with single nucleotide repeatsare expanded or contracted without control. This typically resultsin a higher-than-normal mutation rate. It may render such tumorssusceptible to novel immune-modulating drugs like the PD-1inhibitor pembrolizumab. Colon cancer patients with MSI haveshown better overall survival than patients with colon cancersthat are driven by other mechanisms. It remains controversialwhether colon cancers with MSI show an increased sensitivityto 5-FU-based treatment regimens. MSI can be tested for MHL1,MSH2, or PMS2 by immunohistochemical staining.EGFR p.L861QLung NeoplasmsEGFR is a receptor tyrosine kinase that regulates the PI3K and RAS/MAPK pathways. In preclinical studies, the EGFR.L861Q mutationwas shown to activate the PI3K and RAS/MAPK pathways. Afatinibis indicated for the treatment of non-small cell lung tumors thatharbor this mutation. Patients with lung adenocarcinoma and thismutation showed response to erlotinib or gefitinib. In comparisonto common EGFR mutations, the response to erlotinib or gefitinibwas less favorable if L861Q occurred as a single mutation.However, when co-occurring with L858R, exon 19 deletion, or aG719X mutation, it led to a better response rate and progressionfree survival. Preclinical data confirm the sensitivity of this variantto afatinib, osimertinib, neratinib, and lazertinib, but reducedsensitivity to erlotinib and gefitinib.PembrolizumabERBB2 p.V659ELung NeoplasmsThe receptor tyrosine-protein kinase ERBB2 (HER2) activatesthe RAS/MAPK, PI3K/AKT, and JAK/STAT signaling pathways topromote cell proliferation and survival. The ERBB2.V659E mutationlocated in the transmembrane domain activates ERBB2 signaling.The tumor of a lung cancer patient with this mutation has beenreported to show response to afatinib. Another patient whoselung cancer had this mutation was first treated with trastuzumab,achieving stable response for five months, followed by afatinib,achieving symptomatic improvement and metabolic response forfive months. Preclinical studies have shown that cell lines with thismutation are sensitive to tesevatinib, afatinib, or lapatinib.AfatinibErlotinib, GefitinibOsimertinib, Neratinib,LazertinibAfatinib, Lapatinib,Trastuzumab, Tesevatinib
Variant evaluationExample of first page of our customizable MH Guide reportMH Guide gives you full access to the evidence underlying the analysis, and providesvaluable additional information about annotated variants.Header section with general casespecific informationDisplay of biomarkers and their validityFilter failed Allele frequencyVariant countCoverageObservation qualityPopulation frequenciesVariant filterQuality control ofvariants in NGS data COSMIC databaseConditional passFilter passedSexEthnicityCountryTrial ZIPcodeDrug approval state in patientindication/locationOptions for the physicians to customize thereport with their personal amendmentsDifferentiation betweensomatic and germlinevariants based on#COSMIC, PF, and VAFCVI match qualityMatching patientinformation to CVIdescriptionand variantsPrimary tumor site LungSurgical pathologyTissue typeMetastaticCollectedTumor cellularityBarcodeSample typeGeneral dataset IDLabtestCVI dataset IDOrganizational unitSoftware versionOverview of potential treatment impacts6 EffectiveSummary and classification of identifiedtreatment options by a traffic-lightcolor code2 IneffectiveTreatmentOverview of prognostic and diagnostic findings13 Safety0 PrognosticDrug approval*BiomarkerVAFEGFR p.E746 A750del(del)29.52%EGFR p.E746 A750del(del)29.52%EGFR p.T790M (SNV)29.46%EGFR p.E746 A750del(del)29.52%EGFR p.T790M ertinibApprovedEffectiveAfatinibSafetyVariant tab: annotation, and classification of variants0 DiagnosticBiomarker FacilityEmailPhoneFaxProductReportSUMMARYPotential impactLineage and zygosityDiagnosisLung cancerICD-10-CM code—MeSH ID/termD002289 (Carcinoma, Non-Small-Cell Lung)Additional MeSH IDs D008175Patient IDCase IDEU000004Date of birthEffectiveErlotinibApprovedEGFR p.E746 A750del(del)29.52%EffectiveDacomitinibOtherEGFR p.E746 A750del(del)29.52%EffectiveAzd3759OtherEGFR p.E746 A750del(del)29.52%IneffectiveErlotinibApprovedEGFR p.T790M (SNV)29.46%IneffectiveGefitinibApprovedEGFR p.T790M (SNV)29.46%SafetyCisplatinApprovedTPMT p.Y240C (SNV)100.00%Electronic signature of pathologistOrder date 23 May 2018Report Version 1Signed by Dr. John Doe09 Apr 2019 12:23 (UTC 02:00)Phone 2266Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg www.molecularhealth.com 49 6221 43851-150!Customize your MH Guidereport, add other labresults like IHC and FISH,or a specific appendix.Page 1 of 18
How to orderMolecular Health Order portal (MH Order portal)Order MH Guide or MH Guide Premium using our user-friendly,browser-based MH Order portal. After uploading the patient’sNGS data or VCF, and diagnosis, the analysis is performed andthe individual molecular profile is generated. Once completed,you will be notified automatically. In your MH Guide account,you have full access to the data and the analysis. You canmake amendments and add attachments, and sign the report.Literature:1 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensusrecommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.302 Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res.2019;47(D1):D941-D947. doi:10.1093/nar/gky10153 Cline MS, Liao RG, Parsons MT, et al. BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.PLoS Genet. 2018;14(12):e1007752. Published 2018 Dec 26. doi:10.1371/journal.pgen.10077524 Li MM, Datto M, Duncavage EJ, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants inCancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology,and College of American Pathologists. J Mol Diagn. 2017;19(1):4-23. doi:10.1016/j.jmoldx.2016.10.0025 Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020;581(7809):434-443. doi:10.1038/s41586-020-2308-7 2020 Molecular Health GmbHPhone: 49-6221-4385-1150E-mail: CustomerCareEU@molecularhealth.comSince 2004, Molecular Health stands for transforming big clinical data intoimproved treatment decisions. Using our cloud-based Dataome technologyplatform, we analyze molecular and clinical data of individual patients andcompare it to the world’s most up-to-date comprehensive medical, biological,and pharmacological knowledge. Our software products MH Guide, MH Mendel,and MH BRCA enable physicians to take the most informed treatment decisions.MH-20-011-3Better data. Better insights.Better outcomes.molecularhealth.comMolecular Health GmbHGlobal HeadquartersKurfuersten-Anlage 2169115 HeidelbergGermany
Ordering physician — Facility — Email Phone — Fax — Product MH Guide Report — Mutational status of commonly mutated genes in the patient disease ABCB1 not identified ALK 1 fusion, 1 SNV BRAF not identified EGFR not identified ERBB2 not identified KRAS not identified MET not identified NF1 not identified NRAS not identified PIK3CA not .
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