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Point-Of-Care Molecular Diagnostics: the Future

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Point-Of-Care Molecular Diagnostics: the Future Point-of-Care Molecular Diagnostics: The Future Frederick L. Kiechle, MD, PhD Medical Director, Clinical Pathology Memorial Healthcare System Pathology Consultants of South Broward, LLP Hollywood, FL 33021 Outline Molecular Diagnostics 3 steps Miniaturization for POCT application Proof of Concept Cepheid GeneXpert Enigma Diagnostics DxNA LLC: GeneSTAT IQUUM: Liat analyzer DNA Sequencing Genia and Oxford Nanopore Conclusions Molecular Diagnostics The use of DNA/RNA to test for specific states of disease or health Infectious Diseases Oncology Pharmacogenomics Genetic Disease Screening Personalized Medicine Coagulation 3 AACC CPOCT 9/18/2014 Three Basic Steps Extraction & Purification of nucleic acid Amplification (making copies) Detection of amplified product Microarrays Real-Time End-Product Luminex (similar to flow analysis) PCR Detection Sequencing 4 Features of POCT Molecular Device Hand held Portable Cost/test < $25.00 Total time to result < 30 minutes All 3 molecular steps in unit use device Results = clear with no interpretation Accuracy and precision Full process controls (aka internal controls) are extracted, amplified and detected along with target Kiechle & Holland. Clin Lab Med 2009; 29:555-560. 5 Software Features 1. Input user / Patient ID 2. Control assay & System performance 3. Perform data analyses and test interpretation 4. Wireless connectivity 5. Multiplexing and Melting curve analysis 6 Miniaturization Using Microfluidics Behavior, precise control and manipulation of fluids constrained to small (submillimeter) scale Micro features • Small volume (nL = 10-9 L/ pl = 10-12 L) • Small size • Low energy consumption • Effects of the micro domain Used in development of • Inject printheads • DNA chips • Lab-on-a-chip technology • Sia S, Kricka L. Lab Chip 2008; 8:1982-1983. 7 POCT Molecular Diagnosis in Canadian Urban Mobile Health Clinics Interviewed 9 mobile clinic directors and supervisors from 6 clinics All supported further development of rapid molecular testing using: microfluidics microchip-based platform with integrated sample prep, genetic amplification, and detection on one chip Device ~ $1,000; disposable microchip $1 each Infectious disease detection: CT, NG, HPV, HIV Navid EL, et al. Point of Care 2011; 10:40-44. 8 POCT: Benefit to Clients Reduced Fewer or no waiting times follow up visits Immediate Improve discussion of healthcare results and Rx accessibility Navid EL et al. Point of Care 2011; 10:40-44 9 February 2012 Cepheid GeneXpert Features Single step assay Place premeasured reagents into labeled parts in the cartridge 70 minutes for most assays Includes sample processing control to monitor reaction steps and inhibitors Enigma Diagnostics www.enigmadiagnostics.com Founded in 2004 Porton Down, Salisbury UK POC infectious disease CE mark flu A/B + RSV 1/14/14 Development: MDR-TB Assembled Assay Cartridge February 2012 ECP Capillary RSC Special Report. 2009;(No.317):238-244. DxNA LLC St. George, Utah POC Infectious Disease GeneSTAT + 2009 A /H1N1 influenza test, not FDA approved, but authorized by FDA for Emergency Use. Used Roche High Pure RNA Isolation Kit + Also Avian flu H5N1 test evaluated in Vietnam in 2010 1/2/14 acquired PathoGene LLC: MSSA/MRSA; Flu A/B; Coccidioidomycosis in development GeneSTAT Screen shot and results Device Loaded Craig Mosman of DxNA in Hanoi 4/25/2010 GeneSTAT Features Portable, battery powered One button operation after sample is loaded Built to be CLIA waved Disposable, pocket-sized, single use plastic unit Patented close system and photometric cell Sonication with high frequency sound waves to lysis cells PCR chemistry is freeze dried; shelf life 6 months at room temperature CE marked in 2011 Cartridge test ID with RFID embedded IQUUM Liat™ Analyzer Advantages Rapid sample-to-result automation with quantitative analysis Completely closed system eliminates contamination and allows nucleic acid testing in any setting Flexible platform is adaptable to various assays and analytes Flexible tube divided into sealed segments IQUUM Update Purchased by Roche Molecular Diagnostics April 7, 2014 Liat Influenza A/B Assay CE marked and FDA cleared 21 Cost/Sample: $400K ‐ >$1M $25K‐$50K $1K‐$5K Genia <$100 Genia Technologies, Inc. Mountain View, California 6/2/14 acquired by Roche Diagnostics Single molecule nanopore-based sequencing by synthesis Distinguishes 4 bases by detecting 4 different sized tags released from 5´-phosphate modified nucleotides Sci Rep 2, 682: DOI:10.1038/step00684 (2012). Genia Technology Figure 1. Schematic of a single molecule DNA sequencing by a nanopore with phosphate tagged nucleotides. Genia’s NanoTag sequencing approach identifies DNA sequences not by detecting the nucleotides themselves with the nanopore, but by measuring the current changes caused by the passage of each of four different tags that are released from the incorporated nucleotide during the polymerase reaction. Time (ms) DNA Sequencing To Go Oxford Nanopore's MinION device. Credit: Oxford Nanopore 25 Oxford Nanopore MinION – Disposable DNA Sequencing Size of USB memory stick < $900.00 Currently 2,000 nanopores 2013: 8,000 nanopores – 20 node installation – complete human genome sequence in 15 minutes Specimen – whole blood, no extraction or amplification required 2014: New membrane to support nanopore 10,000 base sequenced at one time Science 2014;343:829-830 26 Nanopore Sensing This diagram shows a protein nanopore set in an electrically resistant membrane bilayer. An ionic current is passed through the nanopore by setting a voltage across this membrane. If an analyte passes through the pore or near its aperture, this event creates a characteristic disruption in current. Measurement of that current makes it possible to identify the molecule in question. For example, this system can be used to distinguish between the four standard DNA bases G, A, T and C, and also modified bases. It can be used to identify target proteins and small molecules, or to gain rich molecular information, for example to distinguish between the enantiomers of ibuprofen or study molecular binding dynamics. Conclusion 1. The interest in the miniaturization of the three distinct steps in PCR-based molecular methods is currently under intense investigation. 2. Soon, portable, hand-held, inexpensive POCT devices, equivalent to currently offered full-size systems will become available to aid in the detection of mutations or in the identification of infectious agents. References 1. Holland CA, Kiechle FL. Point-of-care molecular systems – past, present and future. Current Opinion Microbiol 2005; 8:504-509. 2. Kiechle FL, Holland CA. Point-of-care testing and molecular diagnostics: Miniaturization required. Clin Lab Med 2009; 29:555-560. 3. Agrawal N, Ugaz VM. A buoyancy-driven compact thermocycler for rapid PCR. Clin Lab Med 2007; 27:215-223. FINITO The End FIN Thank You.
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