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Verigene RP Flex Package Insert

1. _ Agreement 95 CI B Agreement 95 CI SAUL n Positive Negative speaimen tpe n Positive Negative i 100 100 100 99 9 i Fresh 1041 2 2 1039 1039 i Fresh 1052 1 1 1050 1051e 34 2 100 99 6 100 20 6 100 99 5 100 g 99 9 g 100 99 9 g Frozen 1255 1254 12555 g Frozen 1145 7 1 1137 1138 1 i 99 5 100 i 64 6 100 99 5 100 100 99 9 8 100 99 9 All 2296 2 2 2290 2291 All 2197 8 8 2187 2189 34 2 100 89 8 100 67 6 100 99 7 100 5 71 4 99 8 96 6 100 T Selected 463 5 74 455 456 Selected 516 28 299 487 487 35 9 91 8 98 8 100 82 8 99 4 99 2 100 100 100 100 Contrived 360 104 104 256 256 Contrived 360 360 360 96 4 100 98 5 100 98 9 100 100 100 i Fresh 1043 Vl 1042 1042 20 6 100 99 6 100 9 100 Frozen 1263 1263 1263 i 99 7 100 E 100 100 S All 2306 1 1 2305 2305 20 6 100 99 8 100 50 100 Selected 490 1 29 488 488 9 4 90 1 99 2 100 100 100 Contrived 360 56 56 304 304 93 6 100 98 6 100 PCR BDS analysis is the comparator method for these targets a Repeat PCR BDS was performed B parapertussis bronchiseptica was not detected in 1 2 and detected in 1 2 false negative samples No B bronchiseptica was identified by PCR BDS in all 7 comparator positive specimens eos ef Bordetella pertussis w
2. Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e a OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 nfluenza A was not detected in 1 7 and detected in 1 7 false positive samples using PCR BDS analysis Discordant analysis was not performed in 5 7 alse positive samples nfluenza A was not detected in 2 6 false positive samples using PCR BDS analysis Discordant analysis was not performed in 4 6 false positive samples nfluenza A was not detected in 2 3 false positive samples using PCR BDS analysis Discordant analysis was not performed in 1 3 false positive samples nfluenza A H1 was not detected in 1 1 false negative sample using PCR BDS analysis nfluenza A H1 discordant analysis using P CR BDS was not performed in 2 2 false positive samples nfluenza A H1 was not detected in 2 4 and detected in 1 4 false positive samples using P CR BDS analysis Discordant analysis was not performed in 4 false positive samples fluenza A H1was not detected in 2 2 false positive samples using PCR BDS analysis fluenza A H3 was not detected in 3 4 and detected in 1 4 false positive samples using P CR BDS analysis fluenza A H3 was not detected in 2 2 false positive samples using P CR BDS analysis fluenza B was not detected
3. 358 360 98 0 99 8 98 0 99 8 85 9 95 7 i Fresh 1000 214 49 719 751 81 1 89 7 94 1 97 0 9 71 8 98 3 9 Frozen 1122 193 248 859 8740 i 72 2 82 5 97 2 99 0 i 81 9 97 1 i All 2122 407 497 1578 1625 5 78 3 85 0 96 2 97 8 80 0 98 3 Selected 509 28 35 466 474 64 1 90 0 96 7 99 1 99 7 Contrived 360 359 360 98 4 99 9 a Adenovirus was detected in 1 2 false negative samples using PCR BDS analysis Discordant analysis was not performed in 1 2 false negative samples b Adenovirus was not detected in 5 6 false negative samples using PCR BDS analysis Discordant analysis was not performed in 1 6 false negative samples Discordant analysis was not performed in 1 1 false negative Adenovirus sample Adenovirus was not detected in 8 19 and detected in 2 19 false positive samples using PCR BDS analysis Discordant analysis was not performed in 9 19 false positive samples Adenovirus was not detected in 27 40 and detected in 3 40 false positive samples using PCR BDS analysis Discordant analysis was not performed in 10 40 false positive samples f Adenovirus was not detected in 5 8 and detected in 2 8 false positive samples using PCR BDS analysis Discordant analysis was not performed in 1 8 false positive samples PV was not detected in 1 2 false negative samples using PCR BDS analysis Discordant analysis was not performed in 1 2 false negative samples PV was not detected
4. Brinkac L Sanka R Kim M amp Losada L Genome Sequences of Nine Bordetella holmesii Strains Isolated in the United States Genome Announcements 2014 May Jun 2 3 e00438 14 23 Williams M M Taylor Jr T H Warshauer D M Martin M D Valley M V amp Tondella M L Harmonization of Bordetella pertussis Real Time PCR Diagnostics in the US 2012 Journal of Clinical Microbiology 2014 doi 10 1128 JCM 02368 14 Page 59 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015
5. Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 Nanosphere Table 10 Results Stratified by Target Analyte Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 sea 0 ana n F a x Parainfluenza 1 was n Parainfluenza 2 was n Parainfluenza 3 was n Parainfluenza 3 was n Parainfluenza 3 was n Parainfluenza 4 was not detected in se negative samples 1 5 fal ot detected in ot detected in ot detected in ot detected in ot detected in ot detected in ot detected in Parainfluenza 4 was n ot detected in 3 3 false negative samples using PCR BDS analysis Parainfluenza 1 was detected in 2 2 false positive samples using PCR BDS analysis Parainfluenza 2 was n Parainfluenza 2 was n 1 1 false negative sample using PCR BDS analysis 2 3 and detected in 1 3 false positive samples using PCR BDS analysis 1 1 false negative sample using PCR BDS analysis 2 2 false negative samples using PCR BDS analysis 1 1 false negative sample using PCR BDS analysis 3 3 false positive samples using PCR BDS analysis 2 5 and detected in 2 5 false negative samples using PCR BDS analysis Discordant analysis was not performed in 3 4 and detected in
6. Uil www e labeling eu NAN024 than 5 Type 3 infection is probably the most common type causing between 8 700 and 52 000 hospitalizations annually among children under five Parainfluenza type 4 has been poorly studied due to the difficulty of isolation from cell culture Although epidemiological information is limited a 2009 study used RT PCR to analyze nasopharyngeal aspirates from patients admitted to hospitals in Hong Kong that were negative for other respiratory viruses Human parainfluenza type 4 was detected in 1 2 of patients admitted for respiratory illness who tested negative for other respiratory viruses Human Metapneumovirus hMPV is the second leading cause of bronchiolitis in young children and is associated with between 5 and 15 of lower respiratory tract infections LRTI and approximately 10 of LRTI hospitalizations in young children Human metapneumovirus is associated with up to 5 of upper respiratory tract infections in young children Human metapneumovirus has also been detected with lower frequency in adults with respiratory tract infections Adenovirus infection can cause a wide range of illnesses depending upon the specific adenovirus serotype Respiratory illness is most common and is generally associated with many different serotypes depending on clinical presentation Adenovirus infection is dangerous among immunocompromised children The infection rate in children following bone marrow transplant may be as
7. the Sample Loading Well is located at the right hand side of the Drawer Assembly Place the Extraction Tray in the Drawer Assembly and press down on the corners of the tray to ensure it is level The image below shows a properly loaded Extraction Tray Sample Loading Well Extraction Tray Page 9 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free pai a n O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Cl www e labeling eu NAN024 4 Loading the Tip Holder Assembly onto the Processor SP a The Tip Holder Assembly is a plastic holder that contains two Pipette Tips and a rubber Tip Seal Each Pipette Tip contains a filter and an O ring on top Pipette Tip b Before using the Tip Holder Assembly check the top of each Pipette Tip for the O ring and confirm that the rubber Tip Seal is sitting straight and flush between the tips If either is missing replace with a new Tip Holder Assembly c Insert the Tip Holder Assembly into the Drawer Assembly The image below shows a properly loaded Tip Assembly The Tip Holder Assembly can only be loaded in one location and orientation in the Drawer Assembly For orientation there are two holes on the deck of the Drawer Assembly that fit each Pipette Tip and the opening to the Tip
8. 1 4 false positive samples using PCR BDS analysis Parainfluenza 4 was not detected in 1 2 false positive samples using PCR BDS analysis Discordant analysis was not performed in 1 2 false positive samples S Agreement 95 CI 7 _ Agreement 95 CI Specimen ype Positive Negative Spesimen upe sm Positive Negative 100 100 99 7 Fresh 1052 1052 1052 g Fresh 1052 11 11 1038 10414 99 6 100 74 1 100 99 2 99 9 E g 90 0 99 8 g 50 0 100 g Frozen 1145 27 308 1113 1115 N g Frozen 1145 1 2 1143 1143 i 744 96 5 99 3 99 9 i 9 5 90 5 99 7 100 i 90 0 99 9 92 3 99 9 s All 2197 27 30 2165 2167 All 2197 12 13 2181 2184 74 4 96 5 99 7 100 66 7 98 6 99 6 99 9 100 100 100 99 8 Selected 516 50 50 466 466 Selected 516 28 28 487 488 92 9 100 99 2 100 87 9 100 98 8 100 100 99 7 Contrived 360 360 360 Contrived 360 359 360 98 9 100 98 4 99 9 83 3 99 7 100 100 Fresh 1052 10 12 1037 1040 Fresh 1052 3 3 1049 1049 55 2 95 3 99 2 99 9 43 8 100 99 6 100 g 80 0 100 g 76 2 99 6 r 9 Frozen 1145 4 59 1140 1140 m 9 Frozen 1145 16 21 1120 1124 1 37 5 96 4 99 7 100 54 9 89 4 99 1 99 9 i 82 4 99 9 i 19 296 99 8 All 2197 14 17 2177 2180 AII 2197 19 24 2169 2173 i 59 0 93 8 99 6 99 9 59 3 90 8 99 5 99 9 100 100 100 99 6 Selected 516 31 31 485 485 Sel
9. 67 5 0 141 5 8 gt 21 65 426 39 4 275 20 7 701 29 1 gt 65 163 15 1 155 11 7 318 13 2 Not Provided 19 1 8 188 14 1 207 8 6 Total 100 100 2412 100 Page 29 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a B O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 There were eighteen 18 specimens excluded from the clinical trial due to protocol violations and fifteen 15 specimens which yielded a final No Call result These specimens were not included in the valid dataset utilized in the performance analyses Therefore a total of 3266 specimens were analyzed in this clinical evaluation to establish clinical performance of the test 1069 of which were prospectively collected fresh specimens 1317 of which were prospectively collected frozen specimens 520 of which were selected archived frozen specimens and 360 of which were contrived frozen specimens The clinical performance of RP Flex is summarized below in Table 9 for Influenza A Influenza A H1 Influenza A H3 Influenza B RSV A and RSV B in Table 10 for Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 and Parainfluenza 4 in Table 11 for Adenovirus human Metapneumovirus and Rhinovirus and in Table 12 for Bordetella pertussis
10. Awww cdc gov flu professionals antivirals antiviral drug resistance htm Influenza A H1N1 virus resistance to oseltamivir 2008 June 13 Retrieved December 1 2014 from http www who int influenza patient_care antivirals oseltamivir_summary en About RSV 2008 October 17 Retrieved December 1 2014 from http www cdc gov rsv about index htm Overview 2012 November 5 Retrieved December 1 2014 from http www cdc gov parainfluenza about overview html Counihan M E Shay D K Holman R C Lowther S A amp Anderson L J 2001 Human parainfluenza virus associated hospitalizations among children less than five years of age in the United States The Pediatric Infectious Disease Journal 20 7 646 653 Lau S K Li K S Chau K Y So L Y Lee R A Lau Y L Chan K H Lim W W Woo P C amp Yuen K Y 2009 Clinical and molecular epidemiology of human parainfluenza virus 4 infections in hong kong subtype 4B as common as subtype 4A Journal of clinical microbiology 47 5 1549 1552 Kahn J S 2006 Epidemiology of human metapneumovirus Clinical Microbiology Reviews 19 3 546 557 Echavarria M 2008 Adenoviruses in immunocompromised hosts Clinical Microbiology Reviews 21 4 704 715 Legrand F Berrebi D Houhou N Freymuth F Faye A Duval M Mougenot J F Peuchmaur M amp Vilmer E 2001 Early diagnosis of adenovirus infection and treatment wit
11. Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 LIMITATIONS Performance characteristics of this product were determined with nasopharyngeal swabs NPS Other specimen types have not been validated A trained health care professional should interpret assay results together with the patient s medical history clinical signs and symptoms and the results of other diagnostic tests Viral and or bacterial nucleic acid may persist in vivo independent of viability Detection of analyte target s does not imply that the corresponding viruses and or bacteria are infectious or are the sole causative agents for clinical symptoms The detection of viral and or bacterial nucleic acid is dependent on proper specimen collection handling transport storage and preparation including extraction Failure to observe proper procedures in any of these steps could lead to incorrect results There is a risk of false negative results due to sequence variants in the viral and or bacterial targets of the assay procedural errors amplification inhibitors in the specimen or inadequate viral or bacterial concentration for amplification A specimen yielding a negative result may contain respiratory viruses and or
12. Influenza A H3 88 89 90 90 1254 1259 93 9 99 8 96 2 100 99 1 99 8 100 100 99 8 nfluenza B 90 90 90 90 1255 1258 96 2 100 96 2 100 99 3 99 9 100 100 99 9 Rhinovirus 90 90 90 90 1257 1258 96 2 100 96 2 100 99 6 100 100 100 99 9 hMPV 90 90 89 89 1258 1259 96 2 100 95 9 100 99 6 100 100 100 99 8 Adenovirus 90 90 90 90 1255 1258 96 2 100 96 2 100 99 3 99 9 96 7 100 99 9 B pertussis 87 90 90 90 1257 1258 90 7 98 9 96 2 100 99 6 100 100 100 99 9 B holmesii 90 90 90 90 1257 1258 96 2 100 96 2 100 99 6 100 Negative P ercent Agreement NPA was determined with all samples that did not contain the target analyte Page 40 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 C Analytical Sensitivity Limit of Detection Limit of Detection LoD of the RP Flex test was determined for twenty eight 28 strains of respiratory pathogens representing all sixteen 16 RP Flex reportable target analytes The LoD was defined as the concentration at which the test produces a positive result gt 95 of the time Serial dilutions of the strains were tested and the initial tentati
13. S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Table 26 Bordetella Species Inclusivity Results Bordetella Species Source RP Flex Target orhi Multiples of LoD ATCC 51445 2 4x103 3x ATCC 10380 2 4x103 3x ATCC 9340 2 4x103 3x ATCC BAA 589 2 4x103 3x B pertussis ATCC BAA 1335 B pertussis 24x10 3x ATCC 53894 2 4x103 3x ATCC 9306 2 4x103 3x ATCC 8467 7 3x103 9x ATCC 15237 7 3x103 3x ATCC 9305 Bordetella 7 3x103 3x B parapertussis ATCC BAA 587 parapertussis 7 3x103 3x ATCC 15989 bronchiseptica 7 3x103 3x Zeptometrix 0801461 2 2x104 9x ATCC 4617 7 3x103 3x ATCC 7773 Bordetella 7 3x103 3x B bronchiseptica on parapertussis ORE a ATCC 14064 bronchiseptica 7 3x103 3x ATCC 10580 7 3x103 3x ATCC 19395 7 3x103 3x Zeptometrix 0801464 2 2x104 9x B holmesii ATCC 700053 B holmesii 2 4x103 1x ATCC 700052 2 4x103 1x E Analytical Specificity Exclusivity One hundred and seven 107 organisms consisting of forty six 46 bacterial fungal strains Table 27 tested at 1 0x1 0 CFU mL twenty six 26 viruses Table 28 twenty two 22 in panel tested in the LoD study and thirteen 13 additional influenza A virus strains with other hemagglutinin HA types Table 29 were tested with RP Flex to determine analytical specificity exclusivity The viral and bacterial fungal samples were con
14. bacteria other than those included in this assay There is a risk of false positive results due to cross contamination by target viruses and or bacteria their nucleic acids or amplified product or from non specific signals in the assay Attention should be given to the handling of consumables under the Warnings and Precautions section to help minimize this risk This assay is a qualitative test and does not provide a quantitative assessment of the concentration of the detected organism The performance of this assay has not been evaluated for patients without signs and symptoms of respiratory infection Negative results can occur when the cause on an infection is with an organism not on the panel or respiratory tract infections that cannot be detected by a nasopharyngeal swab This assay has not been evaluated for monitoring treatment of Influenza A and or RSV This assay has not been evaluated for the screening of blood or blood product for the presence of Influenza The performance of this assay has not been established in immunocompromised individuals The effect of interfering substances has only been evaluated for those listed within this document Interference by substances other than those described can lead to erroneous results Organisms on the panel may have different prevalence depending on the time of year a specimen is tested Positive and negative predictive values are highly dependent on prevalence When prevalence is high false ne
15. congestion fatigue and general malaise In the spring of 2009 a novel quadruple reassortant virus now known as pandemic A H1N1 2009 virus emerged in North America and quickly spread becoming a global pandemic by the summer of 2009 The CDC estimates the virus infected between 43 million and 89 million people between April 2009 and April 2010 Importantly this influenza A subtype was found to be susceptible to the antiviral drug Oseltamivir brand name Tamiflu while antiviral resistance varied among other influenza A subtypes Thus treatment decisions may be impacted by the availability of influenza A subtyping information The development of acquired immunity to seasonal influenza viruses is limited because influenza viruses mutate in small but important ways from year to year a process known as antigenic drift In addition to the risks posed by seasonal influenza viruses novel influenza viruses have the potential to cause widespread disease and or disease of unusually high severity because few if any people have prior exposure to these viruses This lack of immunity as well as additional pathogenic factors that may also increase virulence results in a greater likelihood of morbidity and mortality among those infected Respiratory Syncytial Virus infection is the most common causes of bronchiolitis and pneumonia in infants and children Each year 75 000 to 125 000 children in this age group are hospitalized due to RSV infection Infants
16. displayed Note Scanning the barcode ensures the result is associated with the correct sample When the load Substrate Holder prompt occurs it will only display for 20 seconds Analysis will only start if the Substrate Holder is loaded during the animated prompt c Immediately insert the Substrate Holder into the Reader Note To properly insert the Substrate Holder into the Reader hold the Substrate Holder by the handle with the barcode facing away from you Next insert the Substrate Holder into the Analysis Compartment The compartment is designed to hold the Substrate in the correct position do not force the Substrate Holder into the Analysis Compartment Insert the Substrate into the compartment as far as it will go comfortably There should be an audible click sound when the Substrate Holder is inserted properly Close the door of the Analysis Compartment d Analysis will automatically begin A small camera icon will appear on the Reader to indicate that analysis has begun e Once the analysis is completed by the Reader the camera icon will be replaced with an upward facing arrow and the Reader rings Note Confirm that a result other than No Call NO GRID has been generated by touching the substrate icon for the test A Substrate producing a No Call NO GRID result should be reanalyzed Refer to Table 3 in the INTERPRETATION OF RESULTS section f Once the scan is complete dispose of the used Substrate
17. distributed across the United States and one in Mexico The number and percentage of positive cases positivity rate determined by RP Flex stratified by geographic region and collection site for each of the organisms detected by the test are presented in Tables 5 7 Overall RP Flex detected at least one target in 40 1 957 2386 of prospectively collected specimens In routine practice detection rates may vary depending on the institution geographical location and patient population Table 5 Expected Value As Determined by RP Flex Summary by Collection Site for the RP Flex Prospective Clinical Evaluation Fresh Prospective Specimens July 2014 November 2014 Geographic Region Division Region Mid Atlantic Northeast Midwest Southwest Mexico Total Tamet US State MD NY IN MI NM N A rg Site 1 2 3 4 5 6 Total n 34 54 248 4 437 38 815 POS n 0 0 1 0 8 1 10 Influenza A Pos 04 18 26 12 Influenza A POS n 0 0 1 0 1 0 2 subtype H1 Pos 0 4 0 2 0 2 Influenza A POS n 0 0 0 0 6 1 7 subtype H3 Pos 1 4 2 6 0 9 POS n 0 1 0 0 8 3 12 Influenza B Pos 18 18 79 15 POS n 0 0 1 0 0 0 1 RVA Pos 04 01 POS n 0 0 2 0 0 1 3 Here Pos _ 0 8 26 0 4 Parainfluenza 1 DII a 9 o p o i POS n 2 1 2 0 8 0 13 Paralniiuonea Pos 59 18 0 8 18 16 POS n 0 2 1 0 5 0 8 Parainfluenza 3 aa Pe le a
18. e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 region that contains the 1S487 insertion element which is frequently used to diagnose Bordetella pertussis with molecular methodologies This can result in the misidentification of Bordetella holmesii as Bordetella pertussis Most United States public health laboratories have historically targeted IS481 which is present in 218 238 copies in the Bordetella pertussis genome but only 32 65 copies of the Bordetella holmesii genome for the detection of Bordetella pertussis This has likely led to the under detection and reporting of Bordetella holmesii infections PRINCIPLES AND PROCEDURES OF VERIGENE RP Flex AND THE VERIGENE SYSTEM RP Flex is performed using the Verigene System which is a bench top sample to result molecular diagnostics workstation consisting of two modules the Verigene Processor SP and the Verigene Reader The Processor SP automates the RP Flex sample analysis steps including i Specimen Extraction Magnetic bead based RNA DNA extraction from nasopharyngeal swab specimens obtained from symptomatic patients ii Target Amplification Multiplex RT PCR and PCR based amplification of the extracted nucleic acids to generate target specific amplicons iii Hybridization Amplicon hybridization to target specific capture DNA in a microarray format and mediator and gold nanoparticle probe
19. idr ATCC VR 1400 1 1x10 3x Respiratory S yncytial Virus B ATCC VR 955 33 x100 Ox Table 24 Rhinovirus A and B Inclusivity Results 2E Concentration Multiples of Rhinovirus Species Strain Source TCIDs mL LoD 1 Zeptometrix 0810012CF N 2 7x102 3x 2 ATCC VR 482 2 7x102 3x 7 ATCC VR 1601 2 7x102 3x Rhinovirus A 16 ATCC VR 283 2 7x102 3x 34 ATCC VR 507 2 7x102 3x 57 ATCC VR 1600 2 7x102 3x TI ATCC VR 1187 2 7x102 3x 85 ATCC VR 1195 2 7x102 3x 3 ATCC VR 483 2 7x102 3x 17 ATCC VR 1663 2 7x102 3x Rhinovirus B 27 ATCC VR 1137 2 7x102 3x 42 ATCC VR 338 2 7x102 3x 83 ATCC VR 1193 2 7x102 3x Table 25 Rhinovirus C Inclusivity Results snc S ene ea m UW Madison 13x UW Madison 7240 As there is no susceptible cell line to grow Rhinovirus C the strains were cloned into a plasmid vector and transfected into WisL cells primary human lung fibroblasts All were sequenced to confirm identity The titers were established by qPCR using serial dilutions of Rhinovirus 16 as a surrogate to provide actual PFU mL values for the standard curve Therefore it has been assumed that Rhinovirus 16 has similar virulence rates to Rhinovirus C Page 46 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U
20. illness in infants majority of cases in patients lt 1 year children and adults The disease usually starts with cold like symptoms but after 1 to 2 weeks severe coughing begins and can continue for weeks Because pertussis in its early stages appears to be nothing more than the common cold it is often not suspected or diagnosed until the more severe symptoms appear The development of a pertussis vaccine in the mid 1980s has minimized death from pertussis in the U S However the incidence of pertussis is on the rise again Although no one cause has been identified contributing factors could include better diagnostics waning immunity and a decrease in vaccination rates Bordetella holmesii is an organism that can cause pertussis like respiratory tract infections and can be commonly misidentified as Bordetella pertussis by conventional diagnostic methods In an outbreak in Ohio from 2010 2011 Bordetella holmesii was detected in almost 2096 of individuals with pertussis like illness which was significantly increased from 1 incidence recorded in earlier outbreaks in the 1990s The genome of Bordetella holmesii does not encode known virulence factors for Bordetella pertussis yet these organisms share a genomic Page 3 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S
21. in 1 1 false negative sample using P CR BDS analysis nfluenza B was not detected in 4 7 and detected in 2 7 false positive samples using PCR BDS analysis Discordant analysis was not performed in 1 7 alse positive samples nfluenza B was not detected in 1 1 false positive sample using PCR BDS analysis nfluenza B was not detected in 2 2 false positive samples using PCR BDS analysis Discordant analysis using PCR BDS was not performed for the RSV A false negative samples as P CR BDS is part of the reference method algorithm for this target RSV A was not detected in 1 2 and detected in 1 2 false positive samples using P CR BDS analysis RSV A was not detected in 1 1 false positive sample using P CR BDS analysis RSV A was not detected in 1 3 and detected in 1 3 false positive samples using PCR BDS analysis Discordant analysis was not performed in 1 3 false positive samples RSV B was detected in 2 4 and was not detected in 2 4 false positive samples using P CR BDS analysis RSV B was not detected in 16 20 and detected in 2 20 false positive samples using P CR BDS analysis Discordant analysis was not performed in 2 20 false positive samples RSV B was not detected in 5 7 false positive samples using PCR BDS analysis Discordant analysis was not performed in 2 7 false positive samples I n n n n Page 32 of 59 Verigene Respiratory Pathogens F ex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015
22. in 3 5 and detected in 2 5 false positive samples using PCR BDS analysis PV was detected in 1 1 false positive sample using PCR BDS analysis Discordant analysis was not performed in 1 1 false positive hMPV sample Discordant analysis using PCR BDS was not performed for the Rhinovirus false negative samples as PCR BDS is part of the comparator method algorithm for this target Rhinovirus was not detected in 19 32 and detected in 12 32 false positive samples using PCR BDS analysis Discordant analysis was not performed in 1 32 false positive samples Rhinovirus was not detected in 11 15 and detected in 2 15 false positive samples using PCR BDS analysis Discordant analysis was not performed in 2 15 false positive samples P Rhinovirus was not detected in 5 8 and detected in 1 8 false positive samples using PCR BDS analysis Discordant analysis was not performed in 2 8 false positive samples a n af af gl g h J k Page 34 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 Table 12 Results Stratified by Target Analyte Bordetella parapertussis bronchiseptica Bordetella pertussis Bordetella holmesii
23. include i Flu Influenza A Influenza A subtype H1 Influenza A subtype H3 Influenza B ii RSV RSV A RSV B iii Adeno hMPV Adenovirus Human Metapneumovirus iv Para Rhino Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 Rhinovirus V Bordetella Bordetella parapertussis bronchiseptica Bordetella holmesii Bordetella pertussis Note Within each target grouping you can select or de select targets for reporting Choose Select All to report all RP Flex targets TUESDAY 07 22 14 08 08 p m MENU SESSION A Sample sample1 Cartridge 0241 Processing Results A e Press Yes to accept target grouping selections Page 14 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service A In the U S Phone 1 888 837 4436 toll free _ a O S a re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 Note The Reader will automatically default to the selected targets for the next test run 8 Close the Drawer Assembly by pressing the OPEN CLOSE button on the Processor SP The Processor SP will automatically verify that each consumable is properly loaded and begin sample processing 9 Confirm countdown has started on the Processor SP Status Display before leaving the area 10 In order to set u
24. results of the Competitive Interference testing are summarized in Table 31 No evidence of competitive inhibition was observed at the titers tested Page 53 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 Table 31 Competitive Interference Testing Low Positive Titer Strains 3x LoD d mE i Binary Combinations lt lt i i of Strains 13 8 8 ARE lt alj l i i dil d dB E LE B 1l i Influenza A H1 33 8 9 33 33 33 3 3 33 33 33 8 99 33 33 8 9 f Influenza A H3 3 3 33 33 33 8 9 383 33 33 33 33 8 9 33 3 3 Influenza B 33 3n 33 3 3 33 3 3 33 33 33 8 9 3 3 33 3 3 4 hMPV 33 33 33 3 3 33 3 3 33 33 33 33 33 33 8 9 n 3 RSVA 33 33 33 33 9 9 3 3 33 33 33 33 33 33 33 RSVB 33 33 33 33 383 3 3 33 33 33 33 33 33 33 b Parainfluenza 1 33 33 33 33 383 3 3 33 33 33 33 33 33 33 Parainfluenza 2 33 33 33 33 8 9 33 3B 33 33 33 33 33 3 3 7 Parainf
25. the substances at the concentrations tested showed any inhibitory effect on the detection of target respiratory pathogens using the RP Flex test Page 52 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 Nanosphere Table 30 Exogenous Substances Evaluated for Interference Interfering Substance Tested Wal Four Nasal Spray Fluticasone furoate BD Universal Viral Transport Media Anefrin Nasal Spray Menthol Remel M4 Saline Nasal Spray Mupirocin Remel M4 RT Similasan Sinus Relief Tobramycin Remel M5 Anbesol Anesthetic Mucin bovine submaxillary Type I S Remel M6 Beclomethasone dipropionate Mucin porcine stomach Type Il BD Liquid Amies Dexamethasone Mucin porcine stomach Type Ill Remel Regan Lowe Semi S olid Transport Media Flunisolide Oseltamivir Phosphate Ethyl Alcohol Absolute 200 P roof Triamcinolone acetonide Boiron S ulfur Acetonitrile Budesonide Mometasone furoate Boiron Galphimia Glauca Boiron Histaminum Hydrochloricum Copan CLASSIQSwabs Aluminum applicator rayon tipped sterile Copan FLOQS wabs Nylon regular sterile Fluticasone propinoate Zanamivir FluM
26. toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 PATENTS AND TRADEMARKS The Verigene Reader is covered in whole or in part by US patent 7 110 585 The Verigene Processor SP is covered in whole or in part by US patents 7 396 677 and 7 625 746 and other foreign counterparts The Verigene Test Cartridge and or its method of use is covered in whole or in part by one or more of the following US patents 6 506 564 6 602 669 6 645 721 6 673 548 6 677 122 6 720 147 6 730 269 6 750 016 6 767 702 6 759 199 6 812 334 6 818 753 6 903 207 6 962 786 6 986 989 7 321 829 7 695 952 7 773 790 8 323 888 and foreign counterparts Verigene and the Nanosphere Logo are registered trademarks of Nanosphere Inc Copyright 2015 Nanosphere Inc All rights reserved NOTICE TO RECIPIENTS ABOUT LIMITED LICENSE OR RELATED The receipt of this product from Nanosphere Inc or its authorized distributor includes limited non exclusive license under patent rights held by Nanosphere Inc Such license is solely for the purposes of using this product to perform the proprietary nucleic acid analysis method for which it was intended from Nanosphere Inc or its authorized distributor For avoidance of doubt the foregoing license does not include rights to use this product for agriculture or veterinary medicine applications Except as expressl
27. training of personnel in the correct manner to perform specimen collection and handling is highly recommended 1 Use a Nylon or Rayon tipped nasopharyngeal swab NPS for specimen collection 2 Place swab into a vial containing viral transport medium VTM e g M4 M4 RT M5 M6 Universal Transport Media and Universal Viral Transport Media 3 Specimens should be stored according to transport media manufacturer s specifications Specimens used for RP Flex testing must be tested or stored at 2 8 C within 4 hours of collection regardless of manufacturer s specifications 4 Specimens may be stored at 2 8 C for a total of 48 hours from time of collection before testing Optional Once testing is complete the original NPS specimen may be stored at lt 70 C for storage up to 30 days One freeze thaw is permitted if necessary for repeat testing Note Repeat tests should be performed from original NPS specimen B Nasopharyngeal Swab Specimen Processing 1 Put on fresh gloves for each NPS specimen 2 Place NPS specimen in a BSC along with a micropipettor and filtered tips 3 Wipe down the outside of the specimen vial with a decontaminating wipe 4 Vortex NPS specimen for 10 15 seconds immediately before loading sample into the Extraction Tray C RP Flex Procedure Please refer to the Verigene System User s Manual for additional details on performing rests on the Verigene System 1 Processor SP Set up a Remove an Extrac
28. who experience RSV infection especially during the first few months of life are more prone to wheezing and asthma in later years although the cause and effect relationship remains controversial RSV is also recognized as a serious contributor to respiratory ailments in the elderly and individuals with weaker immune systems According to the CDC flu and RSV occur in temperate climates in community outbreaks that last between 4 6 months persisting through fall winter and early spring Parainfluenza is the second most commonly identified viral pathogen especially in young children Parainfluenza has three prominent serotypes Infection with human parainfluenza types 1 and 2 typically causes croup Parainfluenza type 3 causes bronchiolitis and pneumonia Infection rates for each serotype of parainfluenza were reported in a meta analysis published in 2001 Type 1 infection is much more common in the United States leading to between 6 000 and 28 000 hospitalizations among children less than five years of age Type 2 infection is less common and leads to between 1 800 and 15 600 hospitalizations for children younger Page 2 of 59 Verigene Respiratory Pathogens F ex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor
29. 0 98 9 100 98 9 100 100 99 6 98 0 99 3 Fresh 1048 12 2 1032 1036 1 Fresh 1052 49 50 995 1002 2 75 7 100 99 0 99 8 89 5 99 6 98 6 99 7 g 100 100 g 99 9 q Frozen 1142 1 1 1141 1141 q Frozen 1145 1144 11450 1 20 6 100 99 7 100 n 1 99 5 100 f 100 99 8 98 0 99 6 lt q All 2190 13 13 2173 2177 5 AII 2197 49 50 2139 2147 77 2 100 99 5 99 9 89 5 99 6 99 3 99 8 100 99 5 100 99 6 Selected 512 82 82 428 430 Selected 516 26 26 488 490P 95 5 100 98 3 99 9 87 1 100 98 5 99 9 100 100 Contrived 360 360 360 Contrived 360 360 360 98 9 100 98 9 100 100 99 8 100 99 6 i Fresh 1049 11 11 1036 1038 Fresh 1049 8 8 1037 1041 74 1 100 99 3 99 9 67 6 100 96 7 98 6 g 100 99 9 g 100 97 9 Frozen 1121 6 6 1114 11155 o Frozen 1121 165 165 936 956 1 61 0 100 99 5 100 i 97 7 100 96 8 98 6 lt q 100 99 9 m i 100 98 8 gle AI 2170 17 17 2150 2153 AI 2170 173 173 1973 1997 81 6 100 99 6 99 9 97 8 100 98 2 99 2 94 8 99 3 100 98 5 Selected 498 55 584 437 440 Selected 498 23 23 468 475 85 9 98 2 98 0 99 8 85 7 100 87 0 99 3 100 99 7 Contrived 360 360 360 Contrived 360 359 360 98 9 100 98 4 99 9 ab Influenza A was not detected in 1 1 false negative samples using P CR BDS analysis Page 31 of 59
30. 0 B holmesii 47 48 47 47 672 672 89 1 99 6 92 4 100 99 4 100 t NPA was determin ed with all samples th at did not contain the target Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 39 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Table 16 Reproducibility Study Results Verigene RP Flex Target Positive Percent Agreement 95 CI Negative percent Agreement Low Moderate 95 CI 10096 100 100 Parainfluenza 1 90 90 90 90 1258 1258 96 2 100 96 2 100 99 7 100 100 100 99 8 Parainfluenza 2 89 89 90 90 1256 1259 95 9 100 96 2 100 99 3 99 9 10096 100 100 Parainfluenza 3 90 90 90 90 1258 1258 96 2 100 96 2 100 99 7 100 100 100 100 Parainfluenza 4 90 90 89 89 1259 1259 96 2 100 95 9 100 99 7 100 98 9 97 8 100 RSVA 89 90 88 90 1258 1258 94 0 99 8 92 3 99 4 99 7 100 100 100 99 9 RSVB 90 90 90 90 1257 1258 96 2 100 96 2 100 99 6 100 99 4 100 100 nfluenza A 179 179 180 180 1079 1079 97 9 100 97 9 100 99 6 100 100 100 99 8 Influenza A H1 90 90 90 90 1256 1258 96 2 100 96 2 100 99 4 100 98 9 100 99 6
31. 2 Adenovirus Rhinovirus Parainfluenza 4 1 1 Adenovirus 1 Parainfluenza 4 1 Adenovirus Rhinovirus hMPV 1 1 Rhinovirus 1 Adenovirus Parainfluenza 2 RSVB 1 1 Parainfluenza 2 1 Rhinovirus Influenza A and A H1 1 1 Rhinovirus 1 Parainfluenza 1 RSVB 1 1 Parainfluenza 1 1 Parainfluenza 2 Parainfluenza 4 l 1 Parainfluenza 4 1 Total Co infections 23 Total Double Infections 20 Total Triple Infections 3 Total Quadruple Infections 0 This table includes only distinct co infections that were detected by the comparator method s but not by RP Flex the remaining co infections detected by the comparator methods are already represented in Table 12 above Page 37 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us _ Outside the U S Contact your local Nanosphere distributor Ci www e labeling eu NAN024 B Precision and Reproducibility The Precision Study of the RP Flex test involved the testing of a representative test panel daily in duplicate by two 2 operators for twelve 12 non consecutive days for a total of forty eight 48 tests per panel sample The Precision Study used three 3 lots of each of the consumables cartridges extraction trays and amplification trays All precision testing was performed at a sin
32. 2006 nfluenza A H7N2 ew Y ork 107 2003 nfluenza A H7N7 etherlands 219 2003 nfluenza A H7N9 Anhui 01 2013 nfluenza A H9N 22 Hong Kong 1073 99 nfluenza A H2N3 allard Albert79 03 nfluenza A H5N 3a Duck S ingapore 645 1997 nfluenza A H7N7 E quine 1 P rague 1956 nfluenza A H9N2 Chicken Hong Kong G9 97 nfluenza A H10N7 Chick Germany n 1949 nfluenza B Florida 02 2006 TriCore etapneumovirus 9 Type Al TriCore etapneumovirus 8 Type B2 TriCore Parainfluenza 1 TriCore VR 94 Parainfluenza 2 TriCore VR 92 Parainfluenza 3 Zeptometrix 0810016CF Parainfluenza 4a TriCore VR 1378 Respiratory Syncytial Virus Type A2 TriCore VR 1540 Respiratory S yncytial Virus Type B TriCore VR 1580 Rhinovirus 14 Type B TriCore Prepared and tested ata BSL 3 laboratory Page 50 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 All of the organisms tested yielded the expected Not Detected results at the concentrations tested with the exception of the enteroviruses marked with an asterisk in Table 28 above and Pneumocystis jirovecii from a clinical sample marked with an asterisk in Table 27 above which gave Rhinovirus de
33. 37 4436 toll free a B O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 B Waste Disposal e The Amplification Tray contains amplification reagents and internal controls Dispose of the Amplification Tray in accordance with national state and local regulations e The Extraction Tray contains residual nucleic acids extraction reagents and residual sample It also contains a residual volume of the sample buffer which contains formamide a teratogen Dispose of the Extraction Tray in accordance with national state and local regulations e The Test Cartridge contains residual nucleic acids and hybridization reagents It also contains a residual volume of the sample buffer which contains formamide a teratogen Dispose of the Test Cartridge in accordance with national state and local regulations Page 25 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor L www e labeling eu NAN024 EXPECTED VALUES In the RP Flex Clinical Evaluation 2386 prospectively collected fresh and frozen specimens were obtained from six medium to large sized healthcare institutions geographically
34. A 1293 Escherichia coli ATCC 25922 Haemophilus influenzae ATCC 49144 Haemophilus parainfluenzae ATCC 9796 Klebsiella pneumoniae subsp pneumoniae ATCC 13883 Lactobacillus acidophilus Zeptometrix 0801540 Lactobacillus plantarum ATCC BAA 793 Legionella pneumophilia ATCC 33152 Legionella longbechiae ATCC 33462 Legionella micdadei ATCC 33204 Listeria innocua ATCC 51742 Listeria monocytogenes serotype 4b ATCC 19115 oraxella Branhamella catarrhalis ATCC 43617 ycobacterium tuberculosis ATCC BAA 2237D 22 ycoplasma genitalium ATCC 49123 ycoplasma hominis ATCC 27545 TTR ycoplasma pneumoniae ATCC 15531 TTR Neisseria elongata subsp elongata ATCC 25295 Neisseria gonorrhoeae ATCC 31426 Neisseria meningitidis ATCC 53415D 5a Neisseria lactamica ATCC 23970 Neisseria mucosa ATCC 49233 Neisseria sicca ATCC 29256 Pneumocystis jirovecii Erasme Belgium ClinicalS ample Proteus vulgaris ATCC 6380 Pseudomonas aeruginosa ATCC 27853 Serratia marcescens ATCC 29021 Staphylococcus aureus subsp aureus ATCC 12600 Staphylococcus epidermidis ATCC 12228 Staphylococcus haemolyticus ATCC 29970 Streptococcus agalactiae ATCC 12386 Streptococcus pneumoniae ATCC 6303 Streptococcus pyogenes ATCC 14289 Streptococcus Salivarius ATCC 13419 Ureaplasma urealyticum ATCC 276182 Genomic DNA tested at 1 00x106 copies mL Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 48 of 59 027 00050 01 Rev B September 2015 Nanosphere Customer Servi
35. All Analytes Not Detected Detection of influenza A without an influenza A H1 or influenza A H3 subtype may occur at low titer of the virus in the specimen or may indicate a false positive due to contamination The result could also indicate a novel influenza A strain In these cases the sample should be retested If an Influenza A detected result is obtained without detection of an Influenza A H1 or A H3 subtype upon retesting contact local or state public health authorities for confirmatory testing Detection of Influenza A H1 or Influenza A H3 subtypes without an Influenza A Detected result may occur at low titer of the virus in the specimen or may indicate a false positive due to contamination The result could also indicate potential genetic mutations in the Matrix protein gene among circulating seasonal Influenza A viruses In these cases the sample should be retested If an Influenza A H1 or A H3 subtype detected result is obtained again without detection of Influenza A upon repeat testing further investigations may be warranted Since the RP Flex Bordetella parapertussis bronchiseptica probes also detect Bordetella pertussis if a Bordetella pertussis Detected result is obtained the results for Bordetella parapertussis bronchiseptica are not to be considered as they do not indicate the presence or absence of Bordetella parapertussis Bordetella bronchiseptica The result of Bordetella parapertussis bronchiseptica is repo
36. BEI NR 3233 3 0x10 9x TriCore ATCC VR 1782 9 0x101 27x a Zeptometrix 0810060CF 8 1x102 3x Parainfluenza 4 b VR 1377 8 1x102 3x Zeptometrix 0810060BCF 8 1x10 3x For Parainfluenza 3 the extracted eluate from the three strains tested in the inclusivity study were each evaluated with P CR bi directional sequencing and the sequence information were used to assess the homology to the RP Flex oligos Based on the in silico analysis the three strains have the identical homology to the RP Flex oligos indicating that the apparent difference in sensitivity was not due to sequence diversity in the gene targeted by the RP Flex The apparent variation in the sensitivity of the RP Flex test for these strains is likely attributable to inconsistencies in the quantification of the viral stocks Page 45 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 Table 23 RSV Inclusivity Results Concentration Multiples of Subtype Source Strain TCIDso mL LoD e ATCC VR 26 1 0x10 3x Res pito smo IMAA Zeptometrix 0810040ACF 10x10 3x Zeptometrix 0810040CF 11x10 3x
37. Bordetella parapertussis bronchiseptica and Bordetella holmesii Page 30 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 Table 9 Results Stratified by Target Analyte Influenza A Influenza A subtype H1 Influenza A subtype H3 Influenza B Respiratory Syncytial Virus RSV A Respiratory Syncytial Virus RSV B Agreement 95 CI Agreement 95 CI Specimen ype de Positive Negative Spesimen upe p Positive Negative 10096 99 4 99 8 i Fresh 1049 12 2 1030 1037 i Fresh 1048 1046 1048 E 75 7 100 98 6 99 7 99 3 99 9 g 97 9 394 a 9 97 8 99 6 lt g Frozen 1144 46 47 1091 10974 g Frozen 1144 45 46f 1092 1096 i 88 9 99 6 98 8 99 7 i 88 7 99 6 99 1 99 9 9 98 3 99 4 d 97 8 99 7 All 2193 58 59 2121 2134 amp All 2190 45 46 2138 2144 B 91 0 99 7 99 0 99 6 88 7 99 6 89 4 99 9 99 2 99 5 97 6 99 6 Selected 513 122 123 387 3902 Selected 512 40 419 469 471 95 5 99 9 97 8 99 7 87 4 99 6 98 5 99 9 100 100 Contrived 360 360 360 Contrived 360 360 36
38. CTL hi iid i Processing Error Pre Analysis Error Internal checks within the Processor SP detected ani unexpected event Power cycle the Processor SP and repeat RP Flex QUALITY CONTROL Quality control as a component of an overall quality assurance program consists of tests and procedures for monitoring and evaluating the analytical performance of a measurement system to ensure the reliability of patient test results Verigene System The Verigene System uses a series of automated on line quality measurements to monitor instrument functionality software performance fluidics test conditions reagent integrity and procedural steps each time a test is performed A series of automated on line procedural checks guide the user through the testing process each time a test is performed The RP Flex test barcode and sample information are linked upon entry into the Reader to help ensure accurate reporting of results Page 20 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us gt Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Assay Controls Verigene RP Flex is a sample to result detection system wherein nucleic acids are isolated from respiratory specim
39. Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 20 005 024 Test Kit e 20 012 024 Amplification Kit RX Only LJU KE CODE NAN024 INTENDED USE The Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex is a multiplexed qualitative test intended for the simultaneous detection and identification of multiple viral and bacterial nucleic acids in nasopharyngeal swabs NPS obtained from individuals suspected of respiratory tract infection The test is performed on the automated Verigene System utilizing reverse transcription RT polymerase chain reaction PCR and microarray hybridization to detect gene sequences of the following organism types and subtypes Viruses Bacteria Adenovirus Bordetella parapertussis bronchiseptica Human Metapneumovirus Bordetella holmesii Influenza A Bordetella pertussis Influenza A subtype H1 Influenza A subtype H3 Influenza B Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 Respiratory Syncytial Virus A Respiratory Syncytial Virus B Rhinovirus Detecting and identifying specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respi
40. Holder and the used Reagent Pack according to applicable regulations g To access the remaining used consumables raise the Drawer Clamp remove and dispose of the used Extraction and Amplification Trays the capped Amplification Tube and the Tip Holder Assembly according to applicable regulations 13 Printing results a Touch the substrate icon in the session s Processing screen A window displaying the results will open touch the Print option on this screen to print a Detail Report b A Summary Report is available by moving to the Results screen of the Session on the bottom Navigation Bar go to MENU then select Print Summary The Summary Report will provide the results for all samples processed within the current Session Page 16 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ci www e labeling eu NAN024 Detail Reports can also be viewed and printed from the Results window First select the desired Test from the list go to MENU and then touch Print Detail Note Targets not selected for reporting will be described as results not available in the Summary Report 14 At any point following the completion of an RP Flex test users ma
41. SVA Rhinovirus Pos 0 5 Pos 15 7 POS n 185 Bordetella POS n 1 RSV B ag aa l parapertussis aaa Pos 14 0 bronchiseptica Pos 0 1 POS n 29 POS n 8 Parainfluenza 1 Bordetella pertussis Pos 2 2 Pos 0 6 POS n 1 POS n 0 Parainfluenza 2 Bordetella holmesii Pos 0 1 Pos Page 28 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 PERFORMANCE CHARACTERISTICS The results of the analytical and clinical studies conducted to establish the performance characteristics of RP Flex are provided below A Clinical Performance Clinical studies were conducted at multiple external clinical study sites to evaluate the performance of RP Flex by comparing viral and bacterial test results to an FDA cleared molecular respiratory panel and or PCR amplification followed by confirmatory bi directional sequencing PCR BDS Subjects included individuals whose routine care called for respiratory pathogen testing There were 3299 specimens enrolled in the clinical trials 1082 of which were prospectively collected fresh specimens 1330 of which were prospectively collected frozen specimens 526 of which were selected archived froz
42. Seal should face away from Processor SP Tip Holder Assembly Page 10 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S a re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Cl www e labeling eu NAN024 5 Loading the Amplification Tray onto the Processor SP a Remove the cap from the Amplification Tube and save the cap to re cap the Amplification Tube once processing is complete b Insert the Amplification Tray into the Drawer Assembly The Amplification Tray can only be loaded in one location and orientation in the Drawer Assembly When loaded properly the tray sits flat The image below shows a properly loaded Amplification Tray Amplification Tray c Lower and latch the Drawer Clamp over the trays while supporting the Drawer with the opposite hand The image below shows a closed Drawer Clamp over properly loaded trays and Tip Holder Assembly The Drawer Clamp will latch onto the Drawer Assembly when closed properly and the user will be unable to lift the Drawer Clamp without pressing in the silver latch Note If the Drawer Clamp is not latched properly the Processor SP will display an error message on the Status Display when the user attempts to close the Drawer Assembly j JE Z Lower the ra
43. TCIDso mL ATCC VR 1580 B parapertussis j 3 parapertussis ATCC 15311 bronchiseptica 2 4x103 CFU mL sai B parapertussis 3 bronchiseptica ATCC 786 bronchiseptica 2 4x103 CFU mL Bordetella holmesii ATCC 51541 B holmesii 2 4x103 CFU mL pertussis ATCC 9797 B pertussis 8 1x102 CFU mL Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 42 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 D Analytical Reactivity Inclusivity The analytical reactivity inclusivity of the RP Flex test was demonstrated with a comprehensive panel of one hundred and eight 108 strains representing temporal evolutionary and geographic diversity for each of the RP Flex panel organisms Together with the twenty eight 28 strains evaluated as part of the Limit of Detection Study a total of one hundred and thirty six 136 strains were evaluated for analytical inclusivity to RP Flex through empirical testing The organisms in the inclusivity panel were prepared in Simulated NPS Thirteen 13 strains of Influenza A subtypes H2N2 H2N3 H5N1 H5N3 H7N2 H7N7 H7N9 H9N2 amp H10N7 were prepared and tested at a BSL 3 laboratory Each sample was tested wi
44. as not detected in 1 1 false positive samples using PCR BDS analysis 9 Repeat PCR BDS was performed B holmesii was not detected in 1 2 false negative samples Contamination from a strong positive contrived B holmesii sample in a neighboring well during the original PCR BDS analysis is highly suspected Repeat PCR BDS was performed B parapertussis bronchiseptica was not detected in 1 1 false positive sample Repeat PCR BDS was performed B parapertussis bronchiseptica was not detected in 1 1 false positive sample Bordetella pertussis was not detected in 1 1 false negative sample using PCR BDS analysis Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 35 of 59 027 00050 01 Rev B September 2015 Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 The mixed infections tables for the prospective clinical specimens are provided below In summary there were a total of ninety one 91 mixed infections detected by RP Flex in prospectively collected specimens fresh and frozen prospectively collected specimens The comparator methods identified an additional twenty three 23 mixed infections in Table 13 and Table 14 list the distinct mixed infection combinations detected in the prospective clinical studies Table 13 Dis
45. ce or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor LIU www e labeling eu NAN024 Table 28 Viral Organisms Tested for RP Flex Analytical Specificity Virus Name Type Source Strain Number Bocavirus Clinical Sample Coronavirus 229E Zeptometrix 0810229CF Coronavirus NL63 Zeptometrix 0810228CF Coronavirus 0C43 Zeptometrix 0810024CF Coronavirus HKU1 LIJ Clinical Sample Cytomegalovirus ATCC VR 977 Enterovirus A Type 71 Zeptometrix 0810047CF Enterovirus A Coxsackievirus A2 ATCC VR 1550 Enterovirus A Coxsackievirus A10 Zeptometrix 0810106CF Enterovirus B Coxsackievirus A9 Zeptometrix 0810017CF Enterovirus B Coxsackievirus B4 ATCC VR 184 Enterovirus B Coxsackievirus B5 ATCC VR 185 Enterovirus B Echovirus 6 Zeptometrix 0810076CF Enterovirus B Echovirus 9 Zeptometrix 0810077CF Enterovirus B Echovirus 11 Zeptometrix 0810023CF Enterovirus B Echovirus 30 Zeptometrix 0810078CF Enterovirus C Coxsackievirus A21 Zeptometrix 0810235CF Enterovirus C Coxsackievirus A24 ATCC VR 1662 Enterovirus C Poliovirus 2 attenuated ATCC VR 301 Enterovirus C Poliovirus 3 attenuated ATCC VR 193 Enterovirus D Type 68 ATCC VR 561 Epstein Barr Virus Zeptometrix 0810008CF Herpes Simplex virus Type 1 Zeptometrix 0810005CF Measles ATCC VR 24 Mu
46. ctices for laboratories and specific safety practices for the instrument e Read and understood all applicable Safety Data Sheets SDS Electrical Shock Hazard WARNING Severe electrical shock can result from operating the instrument without the instrument covers or back panels in place Do not remove instrument covers or panels High voltage contacts are exposed when instrument covers or panels are removed from the instrument If service is required outside the U S contact your local Nanosphere distributor WARNINGS AND PRECAUTIONS REAGENTS AND CONSUMABLES A Toxicity of Reagents e Exposure to chemicals sealed inside the Test Cartridge is hazardous in case of skin contact respiratory inhalation or ingestion There is a very small amount of formamide lt 1 v v Protective disposable gloves laboratory coats and eye protection should be worn when handling specimens Extraction Trays Amplification Trays and Test Cartridges e See Safety Data Sheets SDS for toxicity information Safety Data Sheets SDS are available at www nanosphere us support e An SDS with more information is available for the Test Cartridge Amplification Tray and Extraction Tray at www e labeling eu and at www nanosphere us support or upon request from Nanosphere Inc Page 24 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 8
47. e re OR E Mail productsupport nanosphere us gt Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 CONTACT INFORMATION In the United States ae Nanosphere Inc 4088 Commercial Avenue Northbrook IL 60062 Customer and Technical Support Phone 1 888 837 4436 toll free E mail technicalsupport nanosphere us Outside of the United States Please contact your local Nanosphere distributor Page 55 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor CU www e labeling eu NAN024 TEST KIT LABELING The contents of a Test Kit may use EN 980 graphical symbols The symbols are defined below REF Catalog number UC Use by YYYY MM DD LOT Batch code Serial number Manufacturer Upper Limit Temperature limitation Upper and Lower Limit Temperature limitation Consult instructions for use Harmful Flammable Irritant BN SN E Toxic Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 56 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436
48. ected 516 41 41 473 475 89 0 100 99 2 100 91 4 100 98 5 99 9 100 100 Contrived 360 360 360 Contrived 360 360 360 98 9 100 98 9 100 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Page 33 of 59 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Table 11 Results Stratified by Target Analyte Adenovirus Human Metapneumovirus hMPV Rhinovirus Agreement 95 CI E Agreement 95 CI Suc pd n3 iH Positive Negative Spesimen De mE Positive Negative 91 7 98 2 100 99 5 g Fresh 1052 22 248 1009 10284 1 Fresh 1052 10 10 1037 1042 74 1 97 7 97 1 98 8 E 72 2 100 98 9 99 8 81 8 96 4 g 100 99 9 9 Frozen 1145 27 33 1072 1112 g Frozen 1145 36 36 1108 1109 i 65 6 91 4 95 1 97 3 i 90 4 100 99 5 100 i 86 0 97 2 i 10096 99 7 hi All 2197 49 57 2081 2140 s All 2197 46 46 2145 2151 74 7 92 7 96 5 97 9 92 3 100 99 4 99 9 97 4 98 3 92 6 99 8 Selected 516 38 39 469 477 Selected 516 25 279 488 489 86 8 99 5 96 7 99 1 76 6 97 9 98 8 100 99 4 99 4 Contrived 360 358 360 Contrived 360
49. ed on the Substrate These are used to determine that hybridization was performed correctly RP Flex algorithm requires that these controls be valid before decisions regarding the presence or absence of any other target on the panel can be determined If these controls are not valid a No Call result will be obtained and the test should be repeated Table 4 Internal Processing Controls Control Description Function Internal Processing Control Artificial DNA construct with detection T INT CTL 1 oligonucleotides Controls for target hybridization related issues Internal Processing Control Intact MS2 Phage along with primers and detection Controls for lysis extraction target amplification INT CTL 2 oligonucleotides Added to each test specimen amp hybridization External Controls Good laboratory practice recommends running external positive and negative controls regularly For example viral transport medium may be used as the external Negative Control and previously characterized positive samples or negative sample spiked with well characterized target organisms may be used as external Positive Controls Regardless of the choice of quality control materials external controls should be used in accordance with local state federal accrediting organizations as applicable TROUBLESHOOTING Refer to the Troubleshooting section of the Verigene System User s Manual Page 21 of 59 Verigene Respiratory Pathogens
50. edominant influenza A viruses in circulation RP Flex may not detect novel Influenza A strains If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities specimens should be collected with appropriate infection control precautions used specifically for novel virulent Influenza viruses and sent to appropriate health authorities for testing Viral culture should not be attempted in these cases unless a biosafety level BSL 3 facility is available to receive and culture specimens BACKGROUND AND CLINICAL UTILITY Respiratory tract infections can be caused by a variety of viral and bacterial organisms Viruses notably influenza A influenza B and RSV are responsible for the majority of respiratory illnesses and cause significant morbidity and mortality Influenza A and B viral infections often result in the respiratory illness commonly referred to as the flu Flu can lead to serious complications such as pneumonia bronchitis sinus infections encephalitis and a general worsening of chronic conditions Flu is highly contagious and according to the Centers for Disease Control and Prevention CDC an average of 2096 of the population contract flu each year Over 200 000 people are hospitalized and between 3 000 and 49 000 people die of complications depending on the severity of the flu season Symptoms include fever headache body aches
51. en and specific detection is performed on an oligonucleotide array housed within the Test Cartridge To prevent reagent dispensing errors all reagents are prepackaged in single use consumables Several layers of controls built into RP Flex ensure that failures at any step within RP Flex are identified during the procedure or in the end point image analysis of the Substrate Internal Processing Controls An artificial DNA construct serves as a target hybridization control and is referred to as the Internal Processing Control 1 INT CTL 1 If the INT CTL1 is not valid a No Call INT CTL 1 result will be obtained and the test should be repeated The bacteriophage MS2 serves as a specimen extraction amplification amp hybridization control and is referred to as the Internal Processing Control 2 INT CTL 2 This control is automatically added by the Processor SP to each specimen prior to the extraction step If the INT CTL 2 is not valid a No Call INT CTL 2 result will be obtained and the test should be repeated The following exception exists INT CTL 1 detection alone is sufficient for a valid call if any of the viral or bacterial targets are also detected there is no requirement for INT CTL 2 to also be detected Table 4 summarizes the two internal processing controls If both INT CTL 1 and INT CTL 2 are Not Detected a No Call INT CTL result will be obtained Additional positive and negative controls are immobiliz
52. en specimens and 361 of which were contrived frozen specimens One hundred and fifty two 152 specimens resulted in an initial RP Flex No Call for a No Call rate of 4 6 145 3299 specimens 95 Cl 3 9 5 4 Seventeen 17 specimens incurred an initial Pre Analysis Error PAE resulting in a PAE rate of 0 5 17 3299 specimens The initial total No Call and PAE rate observed during the clinical trials is 5 1 169 3299 specimens 95 Cl 4 4 5 9 Of the one hundred and fifty two 152 initial No Calls all except fifteen 15 repeated specimens yielded a valid test result upon retesting and of the seventeen 17 initial PAEs all repeated specimens yielded a valid call upon repeat The final No Call rate was 0 5 15 3299 specimens 95 Cl 0 3 0 7 and the final PAE rate was 0 0 3299 specimens for a total final valid test rate of 99 5 3284 3299 specimens 95 Cl 99 3 99 7 Table 8 below provides a summary of demographic information for the 2412 prospectively collected specimens 1082 fresh and 1330 frozen enrolled in the clinical trials Table 8 Summary of Demographic Information for the Prospectively Collected Specimens Enrolled Prospective Fresh Prospective Frozen Combined Spe Range S LG i Percentage ione 4 Percentage mae s Percentage 0 1 151 14 0 165 12 4 316 13 1 gt 1 5 176 16 3 382 28 7 558 23 1 gt 5 12 73 6 7 98 7 4 171 7 1 gt 12 21 74 6 8
53. est Cartridge cover If using opener insert to edge of Test Cartridae cover b Insert the Test Cartridge into the Hybridization Module of the Processor SP until it reaches a stopping point The image below shows the user loading a Test Cartridge into the Processor SP Note If the Test Cartridge is not inserted properly a message will appear on the Processor SP Status Display when the user attempts to close the Drawer Assembly Hybridization Module c On the Reader enter the sample ID by scanning the barcode or manually enter the sample ID using the data entry keyboard Press Yes to confirm the sample ID if manually entering Ensure the Hybridization Amplification and Extraction options are selected see image below Page 13 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a N O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor LIU www e labeling eu NAN024 FRIDAY 06 13 14 08 09 a m MENU SESSION de rs e len Assign Sample Cartridge 024113876 Test RP 8 Accept Session Setup Processing Results A d In the subsequent dialogue box on the Reader select or de select the target groupings to activate or deactivate results reporting for those targets Target groupings
54. ex provides a qualitative result for the presence Detected or absence Not Detected of the RP Flex target genes The image analysis of the Substrate provides light signal intensities from the target specific capture spots as well as the internal processing controls negative control background and imaging control spots The mean signal intensity of a target is compared to the assay s signal detection threshold to make a determination Table 2 lists the possible test results generated by RP Flex representing identification of viral and bacterial nucleic acid sequences targets their presence is verified before a valid result is provided as described below Table 2 Calls for Valid Tests Test Result Reported as Detected Target Genes Viral Targets Adenovirus Hexon h Polymerase large protein L for species A PV Nucleoprotein N for species B Influenza A Matrix protein M Influenza A H1 Hemagglutinin HA Influenza A H3 Hemagglutinin HA Influenza B Non structural protein NS Parainfluenza 1 Fusion protein F Parainfluenza 2 Polymerase large protein L Parainfluenza 3 Nucleoprotein NP Parainfluenza 4 Phosphoprotein P RSVA Polymerase large protein L RSV B Fusion protein F Rhinovirus 5 UTR Bordetella Targets Bordetella parapertussis bronchiseptica gidA B holmesii fumC B pertussis Toxin promoter region Test Result Reported as Not Detected
55. f 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 Nanosphere Viral Species and Bacterial Genus Viral Strains and Bacterial Species Source Target LoD Influenza A 3 3x10 TCIDso mL Wisconsin 67 05 H3N2 Zeptometrix 0810252CF H3 3 3x109 TCIDso mL Brisbane 60 2008 Zeptometrix 0810254CF Influenza B 1 2x101 TCIDso mL Influenza B Florida 02 2006 TriCore Influenza B 3 0x10 TCIDso mL Massachusetts 02 2012 Zeptometrix 0810239CF Influenza B 1 2x101 TCIDso mL Parainfluenza 1 TriCore Parainfluenza 1 9 0x10 TCIDso m ATCC VR 94 1 TriCore Parainfluenza 2 ATCC VR 92 Parainfluenza 2 1 0x10 TCIDso mL Parainfluenza Parainfluenza 3 Zeptometrix 0810016CF Parainfluenza 3 3 3x109 TCIDso mL TriCore 2T Parainfluenza 4a ATCC VR 1378 Parainfluenza 4 2 7x102 TCIDso mL i oot TriCore 1T A Rhinovirus 39 ATCC VR 340 Rhinovirus 1 0x10 TCIDso mL Rhinovirus B Rhinovirus 14 ATCC VR 284 Rhinovirus 9 0x10 TCIDso mL C Rhinovirus C41 UW Madison Rhinovirus 2 4x103 PFU mL RSV A A2 TriCore RSV A 3 3x100 TCIDso mL ATCC VR 1540 Respiratory Syncytial Virus RSV B Wash 18537 62 E RSVB 3 710
56. fluenza A and A H1 1 1 Rhinovirus 1 Rhinovirus Influenza A and A H3 1 0 IA Rhinovirus Parainfluenza 4 RSVB 1 0 N A Adenovirus Parainfluenza 2 1 1 Parainfluenza 2 1 Rhinovirus B pertussis 1 0 N A RSVA RSVB 1 1 RSV A 1 Total Co infections 91 Total Double Infections 86 Total Triple Infections 4 Total Quadruple Infections 1 a A discrepant co infection or discrepant analyte was defined as one that was detected by RP Flex but not detected by the comparator method s Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 36 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor LIU www e labeling eu NAN024 D Table 14 Additional Distinct Co infection Combinations Detected by the Comparator Method s but not detected by the RP Flex in the Prospective Clinical Trial Distinct Co infection Combinations Detected by the Comparator Methods I i Number of ER Discrepant Discrepant Analyte s Analyte 1 Analyte 2 Analyte 3 Analyte 4 3 Co infections Rhinovirus RSVB 9 9 Rhinovirus 9 Adenovirus Rhinovirus 3 3 Adenovirus 2 Rhinovirus 3 Rhinovirus Parainfluenza 4 3 3 Rhinovirus 2 Parainfluenza 4 2 Rhinovirus Parainfluenza 3 2 2 Parainfluenza 3
57. g damaged material may lead to No Calls or false results Handle supplies reagents and kits with powder free gloves at all times to avoid contamination and change gloves between removal of used consumables and loading of new consumables Handle specimens carefully with powder free gloves at all times Open one tube or specimen at a time to prevent specimen contamination Change gloves between specimens With PCR tests there is a possibility of obtaining false positive results due to amplicon based contamination Strict adherence to the laboratory s decontamination procedures following the Verigene Daily Maintenance protocol and careful disposal of consumables into biohazard waste containers after completion of the test are all critical for guarding against false positive results Biological specimens such as respiratory specimens stool tissues body fluids and blood of humans are potentially infectious When handling and or transporting human specimens follow all applicable regulations mandated by local state provincial and federal agencies for the handling transport of etiologic agents WARNINGS AND PRECAUTIONS INSTRUMENTS A General Instrument Safety WARNING Use this product only as specified in this document Using this instrument in a manner not specified by Nanosphere may result in personal injury or damage to the instrument Anyone who operates the instrument must have e Received instructions in both general safety pra
58. gative results are more likely to occur When prevalence is low false positive results are more likely to occur Due to the genetic similarity between human rhinovirus and enterovirus some strains of enterovirus may be detected as rhinovirus Cross reactivity with Human poliovirus 2 Human poliovirus 3 Enterovirus D68 and Coxsackievirus A24 was demonstrated through empirical testing Due to the genetic similarity across the human adenoviruses this assay is expected to be inclusive to all species Inclusivity with adenovirus G was based on in silico analysis only Influenza A subtyping is based solely on the hemagglutinin gene No subtyping is performed based on the neuraminidase gene Recent vaccination with the intranasal Influenza vaccine may produce false positive results for influenza A and or influenza B The Bordetella parapertussis bronchiseptica test is designed to detect Bordetella parapertussis and Bordetella bronchiseptica The Verigene RP Flex probes for the Bordetella parapertussis bronchiseptica Page 22 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a B O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 gene target also detect Bordetella pertussis Thus if a Bordetella pertussi
59. gle laboratory site with one 1 Verigene reader and twelve 12 Verigene Processor SPs The test panel representing all the RP Flex analytes except for B parapertussis and B bronchiseptica consisted of two 2 negative samples one negative simulated NPS matrix and one Staphylococcus aureus spiked in negative simulated NPS matrix as well as seven 7 positive mixed samples at two different concentrations for a total of sixteen 16 unique samples Samples were prepared by spiking previously characterized and quantified organism stocks into simulated NPS matrix at Moderate Positive 5x LoD and Low Positive 2x LoD concentrations The results of the precision study are summarized in Table 15 which provides the percent agreement between the expected results and the obtained results for each sample tested The Reproducibility Study of the RP Flex test evaluated the same test panel as the one used in the Precision Study The sixteen 16 unique samples were tested in triplicate by two 2 operators over five 5 non consecutive days at three 3 sites for a total of ninety 90 tests per sample The results of the Reproducibility Study are summarized in Table 16 Page 38 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S C
60. h cidofovir after bone marrow transplantation in children Bone Marrow Transplantation 27 6 621 626 Miller E K Lu X Erdman D D Poehling K A Zhu Y Griffin M R Hartert T V Anderson L J Weinberg G A Hall C B Iwane M K amp Edwards K M 2007 Rhinovirus associated hospitalizations in young children Journal of Infectious Diseases 195 6 773 781 HRV phase lla study achieves clinical proof of concept Drugs com MedNews 2009 June 1 Retrieved December 1 2014 from http www drugs com clinical trials hrv phase iia study achieves clinical proof concept 7523 html Fast Facts 2014 February 13 Retrieved December 1 2014 from http www cdc gov pertussis fast facts html Clinical Features 2014 September 4 Retrieved December 1 2014 from http www cdc gov pertussis clinical features html Disease Specifics 2013 August 28 Retrieved December 1 2014 from http www cdc gov pertussis clinical disease specifics html Page 58 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a B O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 22 Harvill E T Goodfield L L Ivanov Y Smallridge W E Meyer J A Cassiday P K Tondella M L
61. high as 47 however a recent study suggests that the prognosis may be good if the infection is diagnosed and treated early Rhinovirus is the most common cause of viral infection in the United States Rhinovirus infection is generally associated with the common cold but can also cause lower respiratory tract infections Although rhinovirus infections are generally self limiting symptoms can be more serious among immunocompromised patients and patients with underlying respiratory conditions A 2007 study estimates that the rate of hospitalization associated with rhinovirus infection is 4 8 per 1000 children under five and 25 3 per 1000 children under five with a history of asthma or wheezing The near term potential for a new drug for the treatment of rhinovirus further necessitates the need for accurate testing options Bordetella spp and Bordetella pertussis in particular cause pertussis commonly referred to as whooping cough which is a highly contagious bacterial disease marked by severe coughing fits In 2012 48 277 cases of pertussis were reported in the United States Bordetella spp are small gram negative coccobacillus that are obligate aerobe as well as a highly fastidious organism In addition to B pertussis Bordetella parapertussis and Bordetella bronchiseptica can also cause human infection however only B pertussis and occasionally B parapertussis cause pertussis whooping cough in humans Pertussis can cause serious
62. hybridization to captured amplicons Silver enhancement of the gold nanoparticle probes bound at the capture sites results in gold silver aggregates that are imaged optically with high efficiency by the Reader The Reader also serves as the user interface and central control unit for the Verigene System storing and tracking information throughout the assay process The Processor SP utilizes single use consumables to perform RP Flex including an Extraction Tray Amplification Tray and Test Cartridge A separate Tip Holder Assembly contains two pipette tips that are used to transfer and mix reagents during the assay The user tests a specimen by loading the single use consumables into the Processor SP pipetting the prepared specimen into the Extraction Tray and initiating the protocol on the Verigene Reader by scanning or entering the Test Cartridge ID and specimen information Following assay completion the user inserts the Substrate Holder portion of the Test Cartridge into the Reader for optical analysis and generation of RP Flex test results MATERIALS PROVIDED Verigene RP Flex Test Kit Catalog number 20 005 024 e 20 RP Flex Test Cartridges Each Test Cartridge comes preloaded with all required reaction reagents including wash solutions oligonucleotide probe solution and signal amplification solutions required to generate a test result The Test Cartridges are contained within a carrier labeled as RP 20 006 024 e 20 RP Flex Extraction Tray
63. ific for all Adenovirus species note the primers for the TaqMan assay are not the same primers used in the RP Flex itappears that the amplifiable genome equivalents available in these two adenovirus viral stocks are significantly reduced comparing to that of the other adenovirus stocks tested in the study Page 43 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 Table 19 Influenza A Inclusivity Results m i Influenza A A H1 or A H3 acid Strain Source i i Subtype E AMEN Multiple of LoD pa Multiples of LoD A California 07 2009pdm09 IRR 9 0x10 3x 9 0x10 9x A New Caledonia 20 99 Zeptometrix 9 0x10 3x 9 0x10 9x A New J ersey 8 76 TriCore 2 7x102 9x 3 0x10 3x AINWS 33 TriCore 3 0x10 lx 3 0x10 3x H1N1 AIP R 8 34 Charles River Labs 3 0x10 1x 3 0x10 3x A1 Denver 1 57 TriCore 3 0x10 1x 3 0x10 3x A1 FM 1 47 TriCore 3 0x10 1x 3 0x10 3x AJ Solomon Islands 3 2006 Zeptometrix 3 0x10 1x 3 0x10 3x A Hawaii 15 2001 IRR 2 7x102 9x 2 1x10 27x AJ Aichi 68 Charles River Labs 1 0x10 lt lx 1 0x10 3x H3N2 AJ Hong Kong 8 68 Charles River Labs 3 0
64. ins tested Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 44 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor L4 www e labeling eu NAN024 Table 20 Influenza B Inclusivity Results Type Strain Source Va Multiples of LoD B Allen 45 TriCore 9 0x10 3x B Florida 07 2004 TriCore 9 0x10 3x B GL 1739 54 TriCore 9 0x10 3x B Hong Kong 5 72 ATCC 9 0x10 3x Influenza B B Malaysia 2506 2004 TriCore 9 0x10 3x B Maryland 1 59 TriCore 9 0x10 3x B Taiwan 2 62 TriCore 9 0x10 3x B Wisconsin 01 2010 IRR 9 0x10 3x B Lee 40 Charles River Lab 9 0x10 3x B Florida 04 2006 Zeptometrix 9 0x10 3x Table 21 Human Metapneumovirus Inclusivity Results Subtype Strain Source A Multiples of LoD hMPV Al 16 Zeptometrix 0810161CF 9 0x10 3x hMPV A2 20 Zeptometrix 0810163CF 9 0x10 3x hMPV B1 5 Zeptometrix 0810158CF 9 0x10 3x hMPV B2 4 Zeptometrix 0810157CF 9 0x10 3x 18 Zeptometrix 0810162CF 9 0x10 3x Table 22 Parainfluenza 1 4 Inclusivity Results Type Source Strain saber Multiples of LoD Parainfluenza 1 Zeptometrix 0810014CF 2 7x102 3x Parainfluenza 2 Zeptometrix 0810015CF 3 0x101 3x ATCC VR 93 2 7x102 81x Parainfluenza 3
65. ist Influenza Vaccine Live Intranasal Additionally all potential interferents were tested in triplicate without RP Flex target organisms as negative controls No false positive was observed for the negative controls except for the Medlmmune FluMist Influenza Vaccine Live Intranasal Spray 2011 2012 Formula G Carryover Cross Contamination Study The potential for carryover and cross contamination on the Verigene system was assessed by alternately testing three 3 representative high positive respiratory pathogen samples Adenovirus 3 B Influenza A H1N1 both at 1 00x10 TCIDso mL and Bordetella pertussis at 1 00x10 CFU mL followed by testing a negative NPS sample The high titer sample was alternated with the negative sample five 5 times on six 6 unique Processor SPs No carryover or cross contamination was observed H Competitive Interference In order to assess potential competitive inhibition for RP Flex binary combinations of all test panel organisms representing all possible dual infections were evaluated Contrived samples were prepared in negative simulated NPS matrix with one panel organism present at a Low Positive titer 8x LoD and a second organism present at a High Positive titer 1 00x10 TCIDsy mL for viruses 1 00x10 CFU mL for bacteria The performance of Verigene RP Flex was evaluated with each of the one hundred and eighty two 182 unique sample combinations tested in replicates of three 3 The
66. known to be present in the human upper respiratory tract and therefore the most likely to be encountered in NPS specimens These normal flora organisms were tested at a concentration of 1 00x10 CFU mL with the exception of Mycoplasma pneumoniae which was tested at 1 00x10 CCU mL and Neisseria meningitidis which was tested at 1 00x10 genomic copies mL and cytomegalovirus which was tested at 1 00x10 PFU mL No interference was observed with the RP Flex test for any of these samples tested Exogenous and Endogenous Substances A comprehensive interfering substances study was performed to assess the potential effects of endogenous and exogenous substances that can commonly be found in clinical upper respiratory specimens Three 3 representative target organisms detected by RP Flex Adenovirus 3 B Influenza A H1N1 and Bordetella pertussis were evaluated at 3x their respective LoD for potential interference in the presence of thirty six 36 potentially interfering exogenous substances Page 51 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a n O S D a a OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Cl www e labeling eu NAN024 Table 30 Two 2 endogenous substances were also included human blood and human DNA None of
67. le wearing fresh gloves use a lint free decontaminating wipe to thoroughly wipe the Drawer Assembly of the Verigene Processor SP as well as the OPEN CLOSE button on the front of the Processor SP Do not use the same lint free decontaminating wipe to clean more than one Processor SP For the Verigene Reader use a decontaminating wipe to clean the user Touchscreen Barcode Scanner and the door of the Analysis Compartment Please refer to the Verigene System User s Manual for additional details on routine and daily maintenance Page 6 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 METHODS Note Gloves should be worn whenever handling RP Flex test components specimens and while interacting with the Verigene System Good Laboratory Practice regarding glove changing must be followed when handling test kit components and specimens and while interacting with the Verigene System in order to prevent contamination of the Verigene System and between samples A Specimen Collection amp Storage Inadequate or inappropriate specimen collection storage or transport may yield false negative results Due to the importance of specimen quality
68. lex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a n O S a re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 X Please Confirm A Reveal Target s Influenza A Influenza A H1 Influenza A H3 Influenza B i ld 15 Print results for the newly revealed target test results a Upon confirmation of the newly selected targets touch the Print button to print a Detail Report b A Summary Report is available by moving to the Results screen of the Session on the bottom Navigation Bar go to MENU then select Print Summary The Summary Report will provide results of all samples processed within the current session c Detail Reports can also be viewed and printed from the Results window First select the desired Test from the list go to MENU and then touch Print Detail Note Targets not selected for reporting will be described as results not available in the Summary Report Page 18 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a B O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 INTERPRETATION OF RESULTS RP Fl
69. lly enter in the Test Cartridge ID by selecting MENU and Enter Barcode and then keying in the Test Cartridge ID number with the Reader s keyboard b optional Scan the Test Cartridge cover s 2D barcode using a gun style Barcode Scanner to display the Test Cartridge s Reference Number Expiration Date and Lot Number on reports Note The wand style Barcode Scanner will not read 2D barcodes 7 Loading a Test Cartridge a Hold the Test Cartridge by the handle with one hand using the other hand apply pressure with the palm of the hand and remove the Test Cartridge cover by bending the cover away and over the Reagent Pack edge Ensure that the valve plate is not moved during cover removal see illustration below Note Do not remove the Test Cartridge cover until immediately prior to inserting the Test Cartridge into the Processor SP Page 12 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service Ul www e labeling eu NAN024 In the U S Phone 1 888 837 4436 toll free a O S a re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Pull here to remove Test Cartridge cover Palm of hand on cover and fingers pulling on Test Cartridge cover handle Do not move the valve plate when removing the Test Cartridge cover Pull opener up to remove T
70. luenza 3 33 33 33 33 383 33 3 3 3 3 33 33 33 33 3B i Parainfluenza 4 33 33 33 33 383 33 3 3 33 3 3 3 3 33 33 3 3 Adenovirus 33 33 33 33 383 33 3 3 33 33 33 33 33 3 3 Rhinovirus 33 33 33 33 383 33 3 3 33 33 33 33 3 3 8 9 E Bordetella pertussis 33 33 33 3 3 3 3 33 3 3 33 33 33 33 33 3 3 Bordetella holmesii 33 33 33 33 383 33 3 3 33 3 3 3 3 3 3 333 3 3 Total Detection Rate No 39 39 39 39 44 45 39 39 44 45 49 51 39 39 39 39 39 39 39 39 49 51 44 45 39 39 54 57 of Low Titer Strain 100 100 98 100 98 96 100 100 100 100 96 98 100 95 3 3 indicates that all expected targets for the low positive titer organisms as well as the high titer organisms were detected in all three replicates However in 10 cases the low titer organism was detected in 2 of the 3 replicates For each of these 10 cases an additional 6 tests were performed successfully to yield a final total of 8 9 successful tests The single discordant result in each of these 10 combinations is likely reflective of the probability for missed detection in samples at the low concentration Page 54 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a n O S
71. me Parainfluenza 4 rp ne o o o i POS n 0 1 16 0 26 0 43 Adenovirus Pos 18 65 59 53 POS n 0 0 2 1 0 1 4 NMEN Pos 08 259 26 05 Rhinovi POS n 7 16 57 1 145 5 231 iln Pos 20 6 29 1 300 250 332 132 283 Bordetella POS n 1 0 1 0 0 0 2 parapertussis bronchiseptica Pos 5 9 0 4 s 0 2 Bordetella pertussis DII T 5 5 Bordetella holmesii DI 5 o 3 a J 4 Page 26 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 Table 6 Expected Value As Determined by RP Flex Summary by Collection Site for the RP Flex Prospective Clinical Evaluation Fresh Prospective Specimens February 2015 March 2015 Geographic Region Division Region Northeast Midwest US State NY Wi otal Target Site 2 7 Total n 147 107 254 POS n 9 0 9 nfluenza A Pos 6 2 3 5 POS n 0 0 0 Influenza A subtype H1 Pos POS n 9 0 9 Influenza A subtype H3 Pos 6 2 3 5 POS n 31 13 44 nfluenza B 96 Pos 212 121 173 POS n 8 4 12 RSVA Pos 5 5 3 7 47 POS n 6 3 9 RSVB Pos 3 8 2 8 3 5 POS n 0 0 0 Parainfluenza 1 P
72. mps virus ATCC VR 106 Varicella Zoster virus Zeptometrix 0810026CF Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 49 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Li www e labeling eu NAN024 Table 29 In Panel RP Flex Organisms Viruses and Bacteria and Additional Influenza A Virus Strains with Other Hemagglutinin HA Types Tested for Analytical Specificity Bacteria Virus Name Type Source Strain Number Adenovirus A Type 31 Zeptometrix x810073CF Adenovirus D Type 26 Zeptometrix 0810117CF Adenovirus D Type 37 Zeptometrix 0810119CF Adenovirus F Type 40 Zeptometrix 0810084C F Adenovirus F Type 41 Zeptometrix 0810085CF Adenovirus E Type 4 Zeptometrix 0810070CF Bordetella holmesii ATCC 51541 Bordetella pertussis ATCC 9797 nfluenza A Brisbane 59 2007 HINI TriCore nfluenza A Wisconsin 67 05 H3N2 Zeptometrix N A nenza H1N1 pandemic TriCore A California 04 2009pdm09 p nfluenza A Victoria 361 2011 H3N2 Zeptometrix 0810240CF nfluenza A H2N22 J apan 305 1957 nfluenza A H5N1 A Duck Hunan 795 02 nfluenza A H5N1 A Chicken Korea IS 2006 Scaly breasted nfluenza A Mal unie MongKong
73. ontact your local Nanosphere distributor C www e labeling eu NAN024 Table 15 Precision Study Results Negative Percent Agreemen analyte Verigene RP Flex Target Positive Percent Agreement 95 CI Negative Pour Ride Low Moderate 10096 10096 10096 Parainfluenza 1 48 48 48 48 671 671 92 6 100 92 6 100 99 4 100 100 100 100 Parainfluenza 2 48 48 48 48 671 671 92 6 100 92 6 100 99 4 100 100 95 8 100 Parainfluenza 3 48 48 46 48 671 671 92 6 100 86 0 98 8 99 4 100 100 100 99 9 Parainfluenza 4 48 48 48 48 670 671 92 6 100 92 6 100 99 2 100 100 100 100 RSVA 48 48 48 48 671 671 92 6 100 92 6 100 99 4 100 93 8 100 100 RSVB 45 48 48 48 671 671 83 2 97 9 92 6 100 99 4 100 100 100 100 nfluenza A 96 96 96 96 575 575 96 2 100 96 2 100 99 3 100 100 100 100 Influenza A H1 48 48 48 48 671 671 92 6 100 92 6 100 92 4 100 100 100 100 Influenza A H3 48 48 48 48 671 671 92 6 100 92 6 100 92 4 100 100 100 100 nfluenza B 48 48 48 48 671 671 92 6 100 92 6 100 92 4 100 97 9 100 99 9 Rhinovirus 47 48 48 48 670 671 89 1 99 6 92 6 100 99 2 100 100 100 100 hMPV 48 48 48 48 671 671 92 6 100 92 6 100 92 4 100 100 100 99 7 Adenovirus 48 48 48 48 669 671 92 6 100 92 6 100 98 9 99 9 100 97 9 100 B pertussis 48 48 46 47 672 672 92 6 100 88 9 99 6 99 4 100 100 100 10
74. os POS n 1 0 1 Parainfluenza 2 Pos 0 7 0 4 POS n 1 4 5 Parainfluenza 3 Pos 0 7 3 7 2 0 POS n 2 0 2 Parainfluenza 4 Pos 14 0 8 POS n 1 3 4 Adenovirus Pos 0 7 2 8 1 6 POS n 7 4 11 hMPV Pos 4 8 3 7 43 POS n 8 7 15 Rhinovirus Pos 5 5 6 5 5 9 Bordetella parapertussis POS n 0 0 0 bronchiseptica Pos POS n 0 0 0 Bordetella pertussis Pos 7 POS n 0 0 0 Bordetella holmesii Pos Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex Page 27 of 59 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Table 7 Expected Value As Determined by RP Flex Summary by Collection Site for the RP Flex Prospective Clinical Evaluation Frozen Prospective Specimens October 2013 March 2014 Midwest Site 3 Target Total n 1317 POS n 52 POS n 4 nfluenza A y arinflunza3 9 ___ Pos 3 9 Pos 0 3 POS n 49 POS n 20 Influenza A subtype H1 Parainfluenza 4 Pos 3 7 Pos 15 POS n 1 POS n 68 Influenza A subtype H3 Adenovirus Pos 0 1 Pos 5 2 POS n 1 POS n 37 nfluenza B hMPV Pos 0 1 Pos 2 8 POS n 7 2 POS n 207 R
75. osphere distributor Ci www e labeling eu NAN024 10 11 12 13 18 19 20 21 Thompson W W Shay D K Weintraub E Brammer L Cox N Anderson L J amp Fukuda K 2003 Mortality associated with influenza and respiratory syncytial virus in the United States JAMA 289 2 179 186 Jansen A G Sanders E A Hoes A W Van Loon A M amp Hak E 2007 Influenza and respiratory synoytial virus associated mortality and hospitalisations European Respiratory Journal Falsey A R Hennessey P A Formica M A Cox C amp Walsh E E 2005 Respiratory syncytial virus infection in elderly and high risk adults New England Journal of Medicine 352 17 1749 1759 Mahony J B 2008 Detection of respiratory viruses by molecular methods Clinical Microbiology Reviews 21 4 716 747 Key Facts about Influenza Flu amp Flu Vaccine 2014 September 9 Retrieved December 1 2014 from http www cdc gov flu keyfacts htm The 2009 H1N1 Pandemic Summary Highlights April 2009 April 2010 2010 August 10 Retrieved December 1 2014 from http www cdc gov h1n1flu cderesponse htm CDC Estimates of 2009 H1N1 Influenza Cases Hospitalizations and Deaths in the United States 2010 May 14 Retrieved December 1 2014 from http www cdc gov h1n1flu estimates_2009_h1n1 htm Antiviral Drug Resistance among Influenza Viruses 2014 December 1 Retrieved December 4 2014 from http
76. p additional tests on other Processor SP instruments follow the same procedure To avoid contamination and sample mix ups set up one test at a time 11 Upon completion of processing a The Reader will generate a ring to notify the user when processing is complete and the Status Display on the Processor SP will flash a message indicating Procedure Done Ready to Open Drawer b Open the Drawer Assembly by pressing the OPEN CLOSE button c Cap the Amplification Tube for disposal d Remove the Test Cartridge upon completion or within 12 hours of test completion and immediately orient to its side e While keeping the Test Cartridge on its side separate the Reagent Pack see illustration below Substrate Holder 12 Analyzing results a Remove the protective tape from the back of the Substrate in the Substrate Holder see illustration below Note Use precaution not to touch the surface of the Substrate Page 15 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ci www e labeling eu NAN024 b Use the Barcode Scanner to scan the barcode on the Substrate When the barcode is accepted a prompt to load the Substrate Holder into the Reader will be
77. ratory infection if used in conjunction with other clinical and laboratory findings The results of this test should not be used as the sole basis for diagnosis treatment or patient management decisions Negative results in the presence of a respiratory illness do not preclude respiratory infection and may be due to infection with pathogens that are not detected by this test or lower respiratory tract infection that is not detected by an NPS specimen Conversely positive results do not rule out infection or co infection with organisms not detected by RP Flex The agent s detected may not be the definite cause of disease The use of additional laboratory testing and clinical presentation may be necessary to establish a final diagnosis of respiratory infection Clinical evaluation indicates a lower sensitivity specific to RP Flex for the detection of Rhinovirus If infection with Rhinovirus is suspected negative samples should be confirmed using an alternative method Page 1 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Performance characteristics for influenza A were established when influenza A H1 2009 Pandemic and A H3 were the pr
78. rted as N A upon a Detected result for Bordetella pertussis Page 19 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us _ Outside the U S Contact your local Nanosphere distributor LIU www e labeling eu NAN024 Calls related to an invalid RP Flex test are listed in Table 3 below together with the appropriate recourse which should be taken by the user Table 3 RP Flex Invalid Calls and Recourse Call Reason Recourse Ensure Substrate is seated properly in the Substrate Holder Repeat image analysis by selecting Menu and Enter Barcode and then scanning the Substrate Holder barcode If the No Call persists repeat RP Flex No Call NO GRID Reader unable to image Substrate No Call INT CTL 1 Internal Control 1 not detected indicating a target hybridization issue Internal Control 2 not detected indicating lysis No Call INT CTL 2 extraction amplification issue or target hybridization issue INT CTL 1 and INT CTL 2 not detected indicating Repeat RP Flex No Call INT CTL lysis extraction amplification or target hybridization issue No Call VARIATION No Call BKGD Reader unable to obtain result because of high variability in the target specific signals No Call NEG
79. s a Remove one Sample Well Cap from the strip and place inside the BSC b Place the Extraction Tray in the Extraction Tray Holder inside the BSC Refer to image below for Extraction Tray Holder c Gently vortex the sample for 10 15 seconds and pipette 200 uL of the sample into the bottom of the Sample Loading Well in the Extraction Tray Refer to image below for Sample Loading Well location Extraction Tray Holder Extraction Tray Loading Well d After sample loading place the Sample Well Cap over the Sample Loading Well Take precaution to handle only the edges of the Cap and firmly press down until the Cap is fully inserted into the Sample Loading Well Page 8 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Cl www e labeling eu NAN024 l Customer Service or Technical Service N n In the U S Phone 1 888 837 4436 toll free m Sample Well Cap in Packaging Pressing down on edge of Cap Extraction Tray with Cap inserted e Keep the Extraction Tray in the BSC until ready to be inserted into the Extraction Tray Module on the Processor SP 3 Loading the Extraction Tray onto the Processor SP a The Extraction Tray can only be loaded in one location and orientation in the Drawer Assembly When the Extraction Tray is loaded correctly
80. s Detected result is obtained no determination regarding the presence of Bordetella parapertussis or Bordetella bronchiseptica can be made as the results for Bordetella parapertussis bronchiseptica are not considered or provided Due to the small number of positive specimens collected during the prospective study performance characteristics of the following targets were established using mainly selected retrospective and contrived samples influenza A H3 RSV A parainfluenza virus 1 parainfluenza virus 2 parainfluenza virus 3 parainfluenza virus 4 Bordetella pertussis Bordetella holmesii and Bordetella parapertussis bronchiseptica e Cross reactivity with organisms not tested in the Analytical Specificity section may lead to erroneous results Page 23 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 WARNINGS AND PRECAUTIONS GENERAL RP Flex is for in vitro diagnostic use Caution Federal law restricts this device to sale by or on the order of a physician or to a clinical laboratory Never use any Tips Trays Tubes or Test Cartridges which have been broken cracked punctured previously used or visibly damaged usin
81. s with Tip Holder Assemblies Each Extraction Tray comes preloaded with all required reagents including lysis binding buffer wash solutions and buffer solutions necessary to extract nucleic acids and generate a test result The Extraction Trays with Tip Holder Assemblies are contained within a carrier labeled as RP 20 009 024 e 20 Sample Well Caps The Caps come packaged in strips of 5 Caps The Sample Well Caps are contained within a plastic bag labeled as 40 001 001 Page 4 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Uil www e labeling eu NAN024 Verigene RP Flex Amplification Kit Catalog number 20 012 024 e 20 RP Flex Amplification Trays Each Amplification Tray comes preloaded with all required reagents including enzymes and buffers necessary to amplify nucleic acids and generate a test result as well as an amplification tube The Amplification Trays are contained within a carrier labeled as RP 20 011 024 MATERIALS NEEDED BUT NOT PROVIDED Instruments and Equipment e Verigene Reader Catalog number 10 0000 02 e Verigene Processor SP Catalog number 10 0000 07 e Barcode Scanner e 2 8 C Refrigerator e lt 20 Freezer e lt 70 C Freezer Op
82. tected results in some of the replicates Based on in silico analyses a number of Enterovirus strains have a relatively high homology to RP Flex Rhinovirus oligos with some percent identities to Rhinovirus RP Flex oligos of 84 As a result some cross reactivity at high titer was expected In silico analysis also determined that Pneumocystis jirovecii sequences have a maximum Oligo Identity to RP Flex targets of 67 and therefore Pneumocystis jirovecii was not predicted to be cross reactive to RP Flex Rhinovirus probes Extracted nucleic acids from all Rhinovirus positive tests of the Pneumocystis jirovecii positive clinical sample were evaluated with an analytically validated PCR BDS Rhinovirus assay PCR BDS test results confirmed the presence of Rhinovirus in all samples indicating that the Pneumocystis jirovecii positive clinical sample also contains Rhinovirus nucleic acids F Interference Microbial Interference Three 3 representative target organisms detected by RP Flex Adenovirus 3 B Influenza A H1N1 and Bordetella pertussis were evaluated at 3x their respective LoD for potential interference in the presence of seven 7 potentially interfering microorganisms not detected by RP Flex Staphylococcus aureus Neisseria meningitidis Corynebacterium diphtheria Haemophilus influenza Streptococcus pneumoniae Mycoplasma pneumoniae and cytomegalovirus These seven 7 microorganisms represent the most prevalent microorganisms
83. th the RP Flex in triplicate at an initial concentration 3 fold higher than the LoD determined for each analyte In cases where the expected targets were not detected in one or more replicates concentrations at a 3 fold higher level were evaluated RP Flex demonstrated analytical reactivity to all one hundred and eight 108 strains tested with some strains requiring higher titers for detection The individual strains and concentrations at which positive test results were obtained for all three 3 replicates are presented by target organism in Table 18 though Table 26 below Table 18 Adenovirus Inclusivity Results ei Serotype Strain Source op uppis pr A 31 0810073CF Zeptometrix 1 1x100 1x 7 VR 7 ATCC 3 3x100 3x is 21 VR 1099 ATCC 3 3x100 3x 11 VR 12 ATCC 3 3x10 3x 14 0810108CF Zeptometrix 3 3x100 3x e 34 VR 716 ATCC 3 3x100 3x 35 VR 718 ATCC 1 0x10 9x 2 111010 TriCore 3 3x10 3x C 5 0810020CF Zeptometrix 8 1x102 729x 6 0810111CF Zeptometrix 2 7x102 243x D 26 0810117CF Zeptometrix 1 1x100 1x 37 0810119CF Zeptometrix 1 1x100 1x 40 0810084CF Zeptometrix 1 1x100 1x 41 0810085CF Zeptometrix 1 1x100 lx Based on in silico analysis the oligonucleotide identities of all the tested Adenovirus C subtypes have very similar ranges Based on the investigation of viral stocks titers using a quantitative TaqMan real time PCR developed at Nanosphere that is spec
84. tinct Co infection Combinations Detected by the RP Flex in the Prospective Clinical Trial Distinct Co infection Combinations Detected by the RP Flex Number of E Discrepant Discrepant Analyte s j Co Analyte 1 Analyte 2 Analyte3 Analyte4 3 PRA Adenovirus Rhinovirus 27 18 Adenovirus 16 Rhinovirus 3 Rhinovirus RSV B 22 7 Rhinovirus 4 RSV B 4 Adenovirus RSVB 5 1 Adenovirus 1 RSV B 1 Adenovirus Rhinovirus RSV B 3 3 Adenovirus 3 RSV B 1 Adenovirus hMPV 3 1 Adenovirus 1 Rhinovirus Parainfluenza 1 3 1 Rhinovirus 1 Rhinovirus Parainfluenza 4 3 1 Parainfluenza 4 1 Rhinovirus RSVA 3 2 Rhinovirus 2 Rhinovirus Parainfluenza 3 2 1 Rhinovirus 1 Parainfluenza 3 1 Rhinovirus hMPV 2 1 hMPV 1 Adenovirus Influenza A and A H1 Influenza B RSV B 1 1 Adenovirus 1 ib dd 1 Influenza B 1 Adenovirus Rhinovirus Parainfluenza 1 1 0 N A Adenovirus Rhinovirus B pertussis 1 0 N A Rhinovirus Parainfluenza 2 1 1 Rhinovirus 1 Adenovirus Parainfluenza 4 1 0 N A Adenovirus RSVA 1 1 Adenovirus 1 RSV A 1 Influenza A and A H1 Parainfluenza 3 1 1 Influenza A and A H1 1 Influenza A and A H3 Parainfluenza 2 1 1 Influenza A and A H1 1 Parainfluenza 2 Influenza B RSVB 1 1 RSV 1 Parainfluenza 1 RSVB 1 1 RSV B 1 B parapertussis Parainfluenza 2 prone niseptis 1 0 IA Parainfluenza 3 RSV B 1 0 IA Rhinovirus In
85. tion Tray Tip Holder Assembly and Test Cartridge from the refrigerator Remove the Amplification Tray from the freezer and begin test run within 30 minutes Note Do not refreeze the Amplification Tray once it has been thawed Note For Amplification Trays stored at temperatures 20 C thaw the tray at room temperature for at least 10 minutes prior to beginning test run b Open the Drawer Assembly by pressing the black OPEN CLOSE button located on the front of the Processor SP C Open the Drawer Clamp by pressing in the silver latch and lifting the Drawer Clamp prior to loading the consumables The following image shows an empty Processor SP Page 7 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a n O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor Ul www e labeling eu NAN024 Press to open the Drawer Assembly Press to lift Drawer Clamp 2 Adding Sample to the Sample Loading Well in the Extraction Tray Note Samples should be loaded inside a biosafety cabinet BSC If a BSC is not used a dead air box splash shield face shield or other personal protective equipment should be used when handling samples in accordance with the lab s own procedures for handling potentially infectious material
86. tional e Micro pipettors amp filtered tips e Vortex e Decontamination wipes spray or comparable sanitizer e Biological Safety Cabinet BSC e Verigene Extraction Tray Holder Catalog number 421 00019 01 e Test Cartridge cover opener Optional STORAGE HANDLING STABILITY Table 1 Consumable Storage and Handling Verigene RP Flex Storage e Comments Test Components Conditions Sample Well Caps Tip Holder Assemblies 2 30 C Do not freeze Extraction Trays Test Cartridges 2 80 Shipped frozen Upon receipt store frozen Ampimgatign Trays Do not re freeze after thawing Page 5 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C U www e labeling eu NAN024 VERIGENE DAILY MAINTENANCE A Work Area Preparation Each day of testing and before and after sample preparation prepare the testing work area by sanitizing the BSC countertops vortex mixers pipettes and any other equipment used for sample processing with a lint free decontaminating wipe B Verigene System Cleaning Prior to the start of testing each day and after completing a run perform the following steps for each instrument used for testing Whi
87. trived in Simulated NPS at high concentrations 1 00x10 TCIDsy ML for viral targets and at 1 0x10 CFU mL for bacterial and fungal targets except for Mumps virus which was tested at the highest available concentration of 1 6x10 TCIDso mL Four 4 organisms which were not available as titered stocks were evaluated using genomic DNA at 1 0x10 copies mL All samples were tested in triplicate with the RP Flex Page 47 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 e Nanosphere Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C www e labeling eu NAN024 Table 27 Bacterial and Fungal Organisms Tested for RP F ex Analytical Specificity Genus Species Strain Number Acinetobacter baumannii ATCC 19606 Bordetella avium ATCC 35086 Bordetella hinz i ATCC 51784 Bordetella petrii ATCC BAA 461 Bordetella trematum ATCC 700309 Candida albicans ATCC 18804 Candida glabrata ATCC 38326 Chlamydophila pneumoniae ATCC VR 1360 Chlamydia trachomatis Serovar D ATCC VR 885 Corynebacterium pseudodiphtheriticum ATCC 10700 Corynebacterium diphtheriae ATCC 14779 Corynebacterium striatum ATCC BA
88. ve LoD confirmed with twenty 20 replicates To ensure the accuracy of the LoD determination if the initial detection rate was 100 a further twenty 20 replicates were performed at the next lower concentration until lt 95 was achieved The confirmed LoDs for the twenty eight 28 strains tested and the corresponding LoDs for the RP Flex test reportable targets are shown in Table 17 below Table 17 Verigene RP Flex Limit of Detections Viral Species and Bacterial Genus Viral Strains and Bacterial Species Source Target LoD C AdV 1 Zeptometrix 0810050CF Adenovirus 1 2x101 TCIDso mL Adenovirus B AdV 3 Zeptometrix 0810062CF Adenovirus 1 1x10 TCIDso mL E AdV 4 Zeptometrix 0810070CF Adenovirus 4 1x10 TCIDso mL Metapneumovirus 9 A1 TriCore hMPV 3 0x10 TCIDso mL Metapneumovirus 27 A2 Zeptometrix 0810164CF hMPV 1 1Xx10 TCIDso mL Human Metapneumovirus Metapneumovirus 3 B1 Zeptometrix 0810156CF hMPV 1 0xX101 TCIDso mL Metapneumovirus 8 B2 TriCore hMPV 3 3x10 TCIDso mL Brishane 59 2007 Influenza A 3 0x101 TCIDso mL risbane i HIN1 TriCore H1 1 0x10 TCIDso mL Influenza A 3 0x10 TCIDso mL California 04 2009pdm09 H1N1 TriCore Hl 1 0x10 TCIDso mL Influenza A Influenza A 3 3x109 TCIDso mL Port Chalmers 1 73 H3N2 TriCore H3 3 3x10 TCIDso mL Influenza A 3 7x101 TCIDso mL OL Zeptometrix 0810240CF H3 1 2Xx10 1 TCIDso mL Page 41 o
89. wer Clamp f Page 11 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nanosphere distributor C U www e labeling eu NAN024 6 Ordering a Test a All tests must be ordered through the Verigene Reader No tests can be processed on the Processor SP without the user entering the Test Cartridge ID and Sample ID through the Reader i Logintothe Reader i To start a new Session proceed to the next step iii To order a test in a previously created session select the desired Session from the drop down SESSION menu then proceed to step v Note Up to 60 Test Cartridges can be entered into a single session iii From the Menu Bar SESSION tab select Start New Session where the Session Setup window will appear iv Touch the Please Enter button next to Session ID and enter information by using the data entry keyboard The Session ID can be any unique identifier in a format defined by the laboratory The operator ID is automatically entered as the currently logged in user v Touch the Processing option on the Navigation Bar at the bottom of the screen a Enter the Test Cartridge ID by scanning the barcode using the Barcode Scanner attached to the Reader The user may manua
90. x10 lx 1 0x10 3x Al Victoria 3 75 Charles River Labs 24x10 81x 2 4x103 129x A Ohio 02 2012 RR 2 7x102 9x 2x10 81x A Indiana 08 2011 RR 1 0x10 lt lx 1 0x10 3x H3N2v A Minnesota 11 2010 RR 2 4x103 81x 9 0x10 27x A Indiana 10 2011 RR 1 0x10 lt lx 3 0x10 9x H2N2 J apan 305 1957 R 9 0x10 3x H2N3 Mallard Albert79 03 R 9 0x10 3x A Duck Hunan 795 02 R 9 0x10 3x H5N1 A Chicken Korea l5 2006 R 9 0x10 3x A Scaly breasted Munia HongKong 2006 R 9 0x10 3x H5N3 A Duck Singapore 645 1997 R 8 1x10 27x H7N2 A New Y ork 107 2003 R 9 0x10 3x HINT A Netherlands 219 2003 R 2 7x102 9x E quine 1 P rague 1956 R 9 0x10 3x H7N9 Anhui 01 2013 R 9 0x10 3x H9N2 Hong Kong 1073 09 R 9 0x10 3x Chicken Hong Kong G 9 97 R 9 0x10 3x H10N7 Chick Germany n 1949 R 9 0x10 3x Based on in silico analysis the oligonucleotide identities of all the tested Influenza A H3N2 strains have very similar ranges Based on the investigation of viral stocks titers using a quantitative TaqMan real time PCR developed at Nanosphere that is specific for Influenza A H3 strains note the primers for the TaqMan assay are not the same primers used in the RP Flex itappears that the amplifiable genome equivalents available in this Influenza A H3N2 viral stock are significantly reduced comparing to that of the other Influenza A H3N2 stocks tested in the study Based on in silico analysis the oligonucleotide identities to this strain have slightly lower ranges than the other two H3N2v stra
91. y provided in this paragraph no other license is granted expressly impliedly or by estoppel LIMITED PRODUCT WARRANTY Nanosphere Inc warrants that this product will meet the specifications stated on the product information sheet If any component of this product does not conform to these specifications Nanosphere Inc will at its sole discretion as its sole and exclusive liability and as the users sole and exclusive remedy replace the product at no charge or refund the cost of the product provided that notice of nonconformance is given to Nanosphere Inc within sixty 60 days of receipt of the product This warranty limits Nanosphere Inc liability to the replacement of this product or refund of the cost of the product NO OTHER WARRANTIES OF ANY KIND EXPRESS OR IMPLIED INCLUDING WITHOUT LIMITATION IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR NON INFRINGMENT ARE PROVIDED BY NANOSPHERE INC Nanosphere Inc shall have no liability for any direct indirect consequential or incidental damages arising out of the use the results of use or the inability to use this product and its components REFERENCES Page 57 of 59 Verigene Respiratory Pathogens Flex Nucleic Acid Test RP Flex 027 00050 01 Rev B September 2015 Customer Service or Technical Service In the U S Phone 1 888 837 4436 toll free a O S e re OR E Mail productsupport nanosphere us Outside the U S Contact your local Nan
92. y refer back to a previously completed RP Flex test and reveal testing results for targets not initially selected for reporting by the Reader Note This option is only available for valid Verigene RP Flex tests To do this 0 2 OF 2 DA On the Reader touch the SESSION tab Select Fast Results After the pop up window appears touch the Please Enter button Scan the sample barcode sample ID for the sample of interest or manually enter the sample ID All results attached to the entered sample ID will be displayed If multiple tests have been performed on the same sample ID select the test of interest from the list If only one test has been performed on the entered sample ID results will automatically be displayed Touch the More button Sample sample1 Test RP Cartridge 0241 More Consumables Info Influenza A Influenza A H1 result not e result not available Influenza A H3 Influenza B result not a e result not available Rhinovirus Adenovirus result not e result not available v Any targets not previously selected for result reporting are available to reveal testing results Select the additional target grouping s or target s that you would like to reveal Within each target grouping select or de select targets to reveal results Confirm the targets for which you wish to reveal results by selecting Yes Page 17 of 59 Verigene Respiratory Pathogens F ex Nucleic Acid Test RP F

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