>> Good afternoon. I’m Commander Ibad Khan, and I’mrepresenting the Clinician Outreach and Communication Activity, COCA, withthe Emergency Risk Communication Branch at the Center for DiseaseControl and Prevention. I would like to welcome you to today’s COCACall: Molecular Comings for Clinical and Public Health Applications toDetect Influenza and SARS-CoV-2 Viruses. All members affiliating ustoday are in listen-only mode. Next slide delight. Free continuing educationis offered for this webinar.Instructions on how to earn continuing educationwill be provided at the end of the summon. In compliance with continuing educationrequirements, CDC, our planners, our presenters, and their spouses/ partners wish todisclose they have no financial interests or other relationships with themanufacturers of commercial-grade commodities, the providers of commercial servicesor commercial backers. Planners have reviewed contentto ensure there is no bias. The presentations is not include anydiscussion of the unlabeled use of a product or a make under investigational help. CDC did not accept busines supportfor this continuing education undertaking. At the conclusion of today’s session, participants will be ableto accomplish the following: Explain the gist and possible usecases of Ct values for SARS-CoV-2 testing; discuss the value of SARS-CoV-2 sequencing inpublic health compared to clinical rule; and describe clinical experiment orderingand used for seasonal influenza in the context of SARS-CoV-2 co-circulation. After these performances, there will be a Q& A session.You required to submit questions at anytime during today’s production. To ask a question using Zoom, sound theQ& A button at the lower end of your screen, then sort your questions in the Q& A casket. Please note we receive many more questionsthan we can answer during our webinars. If you’re a patient, please refer yourquestions to your healthcare provider. If you’re a member of the media, pleasecontact CDC Media Relations at 404 -6 39 -3 286 or send an email to media @CDC. gov.We have introduced self-knowledgechecks throughout this presentation. We hope you enjoy these opportunities toassess your understanding of today’s session. Please do not type your answersinto the Q& A box, as this may disrupt the Q& Aportion at the end of the session. I would now like to welcome ourpresenters for today’s COCA Call. We are pleased to have with us Dr.Manish Patel, who is the Team Lead for the Influenza Prevention and ControlTeam with CDC’s Influenza Division. Dr. John Barnes who is the Team Lead for theStrain Surveillance and Emerging Variants Team as part of CDC’s COVID-1 9 response.And Commander Alison Halpin who’s the TaskforceLead for the Laboratory and Testing Task Force as part of CDC’s COVID-1 9 response. It is now my pleasure toturn it over to Dr. Patel. Dr. Patel, please proceed. >> Thanks, Ibad. Quick mic check. >> Dr. Patel, if you canspeak a little bit louder. That is somewhat on the low-spirited outcome. >> Can you hear me okay? >> Yes, that’s much better. >> Much better. >> Thank you. >> Thanks very much. So I was going to speak today about the2 021 -2 022 influenza season, which is now, and testing issues specificallyrelated to influenza in different contexts, SARS-CoV-2 co-circulation.And my goal was really to give youall very much a high-level overview of the CDC clinical guidance that’s availableon our websites on issues related to testing for influenza, taking into accountSARS-CoV-2 co-circulation with influenza. And I’ll basically march you through theseavailable resources and the hyperlinks on these topics on our CDC website. And you should have those linksavailable in the presentation. The recommendations in general arecategorized by three patient lays. One is outpatients and emergency departmentpatients that are likely to be accomplished. Second will be hospitalized cases, and third will be nursing home residents. Keep in thought the differenttests and the issues related to the tests themselves will not be covered, thoughthose links are available on the CDC websites. The website gives you all of the moredetails on those different diagnostic tests that are available and thevalidity of those tests. And then lastly, I’ll focus mainly oninfluenza and not SARS-CoV-2 itself today in the presentation, as thoseissues have been covered previously.Next slide. And so you see in this slither thatinfluenza task certainly, as you well know, has a history of unpredictability. You know, last year or lastseason, genuinely the past 18 months, we have had no influenza activity in theUnited Country, and minimum task globally in the southern hemisphereor the northern hemisphere. And this really has not happened beforesince we’ve had surveillance for influenza. The jury is still out onreasons why that hasn’t happened. That said, we do know influenza is going tocome back and previously has started to reappear in countless places available in the United Government, mainly in young adults. And recently, CDC has secreted HANs, Health Alert Notifications, as well as an MMWR to outline the viruses that have beendetected recently in the United Position. So I think that suffice it to say, it realizes gumption for us to be prepared and maintain vigilance for influenza. And so that really is the impetus forthis presentation, is required to provide you some of the recommendations on testing for influenza, as well as picture you the links available for the implications for increasing influenzaactivity in terms of testing and MPIs.So in terms of monitoring forinfluenza viruses in the United Mood, we use laboratory surveillance structures. And what that means is we do surveillancefor both influenza and SARS-CoV-2 in the US through numerous differentapproaches in two broad containers. We use public health surveillance networksthat are established at the local level within a district, at the mood stage, and then too at the national level. And then we also have a network of clinicallabs where testing is conducted in outpatient or disaster district or hospitalsettings or nursing home settings. And these clinical test results are submittedto the states and subsequently nationally. And so we use this to monitor forboth influenza and SARS-CoV-2. And so I think expending these data, we believe that preparing for — it will allow us to prepare forco-circulation of these two viruses. And I think it’s relevant because ithelps us mitigate the possible impact on healthcare strain this winter should theseviruses continue to co-circulate together.And with regard to influenza, as you all know, vaccination really is our besttool to reduce healthcare burden. We likewise have adjunctive treatments andprevention approaches with antivirals and nonpharmaceutical interventions. But at root causes of that, wereally need a testing plan. Because testing itself can help usidentify these viruses specifically in the rectify of co-circulation. So for that reason, navigating clinicians towardsthese testing algorithms is really the primary aim of the presentation today. Next slide. And so could co-infection of influenzaand SARS-CoV-2 occur in the same patient? And what are the implications of that? As I mentioned, we really have had minimalactivity of influenza in the context of SARS-CoV-2 for the past two years. And so we haven’t seen much co-circulationtogether more, up until very recently. And so we’ve had very few cases of co-infectionsof the two viruses in any payed patient. However, you know, it is possible to see that, specially when you start seeing both virusesco-circulating together, we will have more cases.Currently because the data are limited, we’re not sure what the implications of co-infection would be orthe risk factors for patients that is likely to get co-infections, or the potential severity. However, this is something we’regoing to continue to monitor through our surveillance structures. Suffice it to say, influenza antivirals canstill be applicable to a rectify for illnes. In expressions of the differences between clinicalpresentation and some of the epidemiology and transmission of the two viruses, the two viruses are clinicallyquite different, as you well know.The incubation span forinfluenza is much shorter. It’s about one to three days from theonset of infection to clinical indications. For COVID, it can be much longer, anywhere from two up to 14 dates. The viral shed or the period of detectionof viral RNA is typically much shorter for influenza than for COVID-1 9or SARS-CoV-2 infection. And then of course, loss of taste or smell isquite common with COVID-1 9 and hasn’t been is evident that customarily in the past with influenza. Lastly, the timing of onslaught ofthe severe ailment that we discover with COVID is much more delayedwith COVID than influenza.COVID frequently portrays in the second week, eight, nine eras after initial infection, whereas influenza tends to present muchsooner, within the first few days of infection. Now, that said, at a patient level, it really is clinically challenging to differentiate the two viruses inpatients with acute respiratory symptoms. And so what that symbolizes is that we reallyneed to rely on more laboratory testing to distinguish those two viruses. Next slide. And “were having” several web pages.In this webpage right here, you recognize thehyperlink on the bottom of this slither. This basically are provided by a summary of allof the adapted guidelines for influenza testing in the context of SARS-CoV-2 co-circulation. On the left box in the red, you ascertain thegeneral proposed algorithms for testing. And mostly, the testing strategiesvary by the three clinical positions — outpatients and ED, inpatientsor rest home occupants. And on the right, “youve had” some more information on the various diagnostictests that have existed. And there’s lots of them for influenza. I will not comment on those as I mentioned. It’s outside the scope of this presentation. Nonetheless, the links are very nice andprovide you some more up-to-date information that are available for youto review at your leisure.I will accompany you through all four ofthose hyperlinks you picture on the left box. Next slide. And then this slide right here basicallygives you the punch line up front on testing. As I mentioned, the general summary ofthese algorithms is that the testing varies by clinical train, whether the patientsare outpatients or ED cases likely to be exhausted residence, whetherthey’re hospitalized cases or whether they’re rest home residents.In outpatients or ED patients, testing alternatives could alternate. There’s a lot more flexibility there. Character of this will depend on localtesting availability to those clinicians. So clinicians do have theoption to test for SARS-CoV-2 and then simply use their clinical assessment fortesting of influenza, for diagnosing influenza and treating influenza shouldthe patient require it. But if testing is available for influenza, whichis more and more the situation in recent years, it will help with clinicaldifferentiation of individual patients, whether it’s SARS-CoV-2 or influenza. And so if testing is available, you could test for influenza.In hospitalized patients and nursinghome citizens, the recommendation is to test all believed patientsfor influenza and for SARS-CoV-2. And the reason is really thereare treatment inferences, and possibly other illnes controlimplications for these two groups of patients. I think it goes without saying that viralculture and serology are not almost handy for clinical diagnosis of influenza. And you accompany the above reasons outlined here forthose two modalities that were used in the past and are still currently used under researchsettings that are not clinically supportive. Next slide. In now, you can see a couple ofthese algorithms at a very high level. First, you meet on the left the outpatientsand emergency department patients.Actually both of these refer to outpatientclinic or disaster department cases. On the left you meet patientswho are hospitalized, and on the right you seepatients who are not hospitalized. Again, the general difference is that if thepatient is hospitalized, the recommendation is to test for both SARS-CoV-2 and influenza. And as I mentioned, the reason to test is thatpatients are to enjoy antiviral therapies and there’s connections for infection dominance. Next slide. And then the second web link you seeup on the bottom right of this slip, you click on that, you will come to this page. And this algorithm here basicallyhelps you drill down on the patients. I’m sorry, one second. It is contributing to drill down on the patients by hospitalization status, and an algorithm for testing. On the left box over there, you have thedifferent steps, including specimen accumulation, that process for SARS-CoV-2and influenza testing and then algorithm for treatmentswith antivirals. On the liberty slide–side, you havepatients if they’re not hospitalized, an algorithm for SARS-CoV-2 testing andthen influenza testing and treatment.Next slide. And then the basic summary of those–that webpagefor outpatients and ED patients who are likely to be removed is that forinfluenza, these patients, again, clinicians have opennes in testing. And testing is simply recommendedif it converts clinical handling. And this might be in various different forms, such as it might abbreviate further diagnostictesting, X-rays, antibiotic managements, and it is likely to help guideantiviral treatment. If testing is available, it is a nice thing todo, and it does uncitral secured transactions guide clinical therapy. The assays that could be used herecould be single-plexes or multiplexes. If it is a single-plex assay, then you would probably need to collect two different samples, onefor SARS-CoV-2 and one for influenza. If rapid influenza molecular assay isnot available in outpatient places, it is okay to use a rapidantigen assay for influenza. Nonetheless, keep in mind thesensitivity for those assays are lower. So rapid influenza molecular assays arethe preferred assays if they are accessible. Next slide. And then same to the page for outpatientsand ED, this page with the hyperlink on the bottom makes you the testingguidance for hospitalized patients.Next slide. And here’s the general summary of that webpage. There are four specific detailsthe webpage embraces. First, among these hospitalized cases, as I mentioned, the recommendation is to test all suspected patients forinfluenza to help guide antiviral care, help reduce antibiotic practice and alsohelp with infection control measures. Clinicians here in the hospital settingshould use multiplex or single-plex assays, but they should be molecular assays. Antigen assays, rapid antigen assays arenot as useful to hospitalized patients because the sensitivity is much lower, and largely they have fallen out of favor.For immunocompromised cases, multiplexassay, you are familiar with, with a broader body of respiratory pathogensis typically recommended. Next slide. And then lastly, the fourth webpage –the hyperlink again is on the bottom — takes you to the testingconsiderations for nursing home occupants. And each one of these web pages gives youmore details than I’m presenting here. But basically, the guidance fornursing home residents is quite similar to inpatients, hospital cases. For influenza, same thing asfor hospitalized patients, the preferred assay is a rapid influenza nucleicacid detection assay or molecular assays. And then if they’re not available, rapid antigen assays are allowed, however keep in mind sensitivityis lower for those latter assays. Next slide. And here’s the general details presented — overview of the details presentedon those webpages.First and prime for rest home citizens, state districts should be notified for both SARS-CoV-2 and influenzainfections in either occupants or healthcare personnel workingwithin the nursing homes. And then with regard to testing, as I mentioned, “the panels recommendations” are precisely thesame as the hospitalized patients. And basically, if patientsare positive for influenza, they should be treated with antivirals. I will not go through all the details becausethey’re rolled out there, and they’re the same as the ones I exactly coveredfor hospitalized cases. Next slide. So in summary, testing for both influenzaand SARS-CoV-2 is recommended in all patients who have acute respiratory illness inhospital or nursing home set settleds, nursing home residents, or outpatients or EDpatients who are likely to be accomplished home. As I mentioned, influenza testing canreally depend on the clinical judgment, and it feigns clinical management. For example, it could be used toreduce further diagnostic tests or to guide antiviral care, or perhapseven reduce redundant antibiotic use.The rapid molecular assays, they’rebecoming more widely available, are preferred for influenza because of thelower sensitivity of the antigen assays. And then lastly, bearing in mind, we are just seeing an uptick of influenza pleasure nationally. And “its certainly true it is” some of the first influenceactivity in the context of SARS-CoV-2, co-circulation, and so we’re not surewhat that’s going to look like in terms of healthcare responsibility or co-infections. And so we will continue to monitor this andreassess and add modernized advice on testing or medication, should thatarise as the season progresses. Flexibility does exist to modifyall of this locally as needed, depending on the activity and additional burdens. And administrative guidelines itself might also evolveas well as the somewhat different data at the government level, dependingon what’s happening locally. Next slide. So that raises us to the knowledge check here. I’m going to read the questionand the answers real quick.What influenza assays are not recommendedfor diagnosis of influenza infection in hospitalized cases withacute respiratory illness? A, viral culture. B, antigen assays. C, serology. D, A and B merely. And E, all of the above. I’ll give you a second. Next slide. And the remedy react hereis E, all of the above. Viral culture, as I mentioned, is not practicalor feelings for notice influenza viruses. Antigen assays, they have lowersensitivity compared to RT-PCR. And then serology assays necessary bothacute and convalescent sera four weeks after the initial blood extort, which is notpractical for diagnosing acute illnes. Next slide. Now you investigate a series ofreferences that you could revert to.And then next slither. That brings me to the end of the presentation. Thank you for your attention, and delight feel free to reach out to me, should there be any questions. And thank you for all yourefforts during the course of its pandemic. Thanks. >> Thank you very much. Next slide, delight. Now I’d like to turn it over to Dr.Barnes. Dr. Barnes, delight continued. >> Hi. Thank you for having me today. Today I’m going to talk about a numberthat has been widely used and talked about in the SARS Coronavirus outbreak andpandemic and some of its further consideration that you have to think about when — about reallytalking about cycle doorstep lists and and where we may be inducingerror into our process. Next slide, delight. So I kept this slide in there to to really kind ofgo through where we are when we’re doing a test, where we may pick up variability andwhere we may actually have implicit bias. And there are certain areas inwhich we have — have potential for both. There’s a lot of steps — we think we’reordering like a test order for PCR or something is relativelysimple, but there’s a lot of steps involved in theactual testing procedure. And some of these things can actually drivebias in the test names that we are looking at, that we may utilize Ct values on.And then others may actuallyinduce quite a bit of variability that may not be apparentwhen this testing is is done. And really you can see that throughmany, many, many steps in the pathway. There are individuals that aredifferent in our testing constants. So whether we’re testing symptomatic peopleor asymptomatic parties, vaccinated people, or whatever, these may bias some of our results. Specimen quality — the qualityof specimen, the characteristics of specimen that we make, specimen storage and transport.Reverse — technical things like make transcriptionefficiency, stage, and evaluation that we’re utilizing. Assay performance interpretation, the whole way through to really do the RT-PCRdynamics in this cycle threshold. Next slide. So Ct values. Ct values are are are a value that we get — if you lookat the bottom panel of this of this diagram that we see in the bottom, they’re a appreciate we getthrough a arrange of a threshold line, this red line that you see through thatpanel, that is essentially the — where we start to get divergence from the backgroundfluorescence of a particular PCR amplification. And this can utterly berelated to genome fakes. What we’re mostly doing is amplifying a smallpiece of that genome, and we are amplifying it up in a awfully, very specific way thatcan be related to genome replicas. And in fact, one of the things that my laboratory does is actuallymanufacture and develop diagnostic tests. And so when we go through a process like this, we actually look at that as, look at our ability to relate to genome fakes as one of the reason — one of the factors that we use to tell how well that evaluation is actually working.So if you experience the top committee of this syntheticRNA that we have, that we’re apply to make this panel, we know wehave a certain amount of that RNA, and a certain amount of totalcopies per action. And our Ct values roughly move in a threefoldmanner, which means that we have three — roughly a jump in three Ct per logchange in nucleic acid concentration. And this is something that we want to maintain. The slope of this order should be good and true, even when we get down to a very low, low level. And this is actually indicative of a good test. I will say that this isn’t the –isn’t a requirement, though. And so this should ever be borne in mind. But when we’re running it in these ways, we’re doing a great deal of authorities around this. We’re using the same instrument, the samerun status and assay, the same operator, excellence, material, analysisand everything like that.And it shapes it this this relationshipvery, particularly standard. And we uh — but what often happens is thereare assumptions made to the Ct data that this test maintains thislinear tie-in in all cases. And then the the assay area that we’reusing — utilizing, implying the articles of DNA that we’re actually enlarging, there is nomutation in that that may change our ability to efficiently amplify that special target. Next slide. So one of the things that uh numerous people donot know when they’re looking at Ct regulates and how they may impact — Ct — thresholdsettings and how they may impact Ct value is that the threshold line that I was showingyou back on the on the blood-red cable in the previous graph and now in a light-green direction now, canin some experiments are truly be set by the person running the test, by the operator.And what you can see as in this curve, this amplification curve that shows as this PCR is being amplified from a signal offrom a detection, that depending on where you named that threshold line, you getvery, very different Ct values. Those Ct values, if you go back to that samerule of approximately three Ct equals a record change in nucleic acid concentration, it basicallygives you a variety of 0.2 enters of divergence. So if you were talking about 100, you goup to 1,000, to 10, 000 photocopies, at the top, you could only detect at 10,000 replicas, oryou could detect at 100 facsimiles at the bottom. And so this this really shows thatthere’s variability time in the way that it can be set on a purelyarbitrary arrange. This is not the case for alltests, but it is the case — these are are are studies when you’reactually looking at utilizing these values.Next slide. And likewise, Ct values on the same amount ofstarting substance can run differently based on the test and based on the assay performance. So the — if we look at — my laboratory induced aa multiplex measure called Flu SC2 Multiplex, and if we look at that target and then welook at a business assay that we have, and that has two different targets, you can see what I make by this. If we utilize a standard amount of materialand decline again through a dilution streak, you can see that you get widely differing valuesbetween the multiplex target that we have testing for the SARS-Coronavirus-2 andthe commercial-grade targets for both N and RdRp. And what is also you can might be able to see inthis is that the distri — the difference between the mounts in those targets are quite different.Whereas we have a approximately three Ct jump between every on themultiplex target, 23 to 27, 23 and a half to 27 as we go on — we have over over six Ctjumps between the commercial tip target. And then the RdRp target seemsto roughly fell out of a face. Meaning that what you havethere is nonlinearity in the way that the actual target is progressing througha defined number of emulates per reaction. Meaning that it is very, very difficult then tocorrelate the amount of Ct to the amount of genome transcripts actually detected. Next slide. So self-knowledge check. Which of the following factors can changeassay performance and persuade variability in Ct values of a molecular evaluation? A, specimen site of collection.B, specimen aspect. C, enzyme used in assay. D, lab or technician preferencefor defining threshold line. Or E, all of the above. Next slide. The actual redres answeris E, all of the above. The ground is because all of thesefactors can have a very profound effect on the realized sensitivityof a molecular assay, and can serve as sources ofvariability in Ct values. Next slide. So, viral mutants within a probe or primerregion can impact Ct value quite a bit.And as we have a situation likewe have with influenza or SARS, where the virus moves end-to-end very quicklyand mutates very quickly, these are not — we tend to try to leant — good good assays tend totry to be put in biologically restricted expanses. So they don’t actually move very many times, or we don’t pick up mutations very frequently. But, but they can occur. You are truly get mutants that occur inprimers and probes of these individual assays. And those can affect theefficiency of that assay into actually producing a Ct value or a upshot. It does not mean that those are less likelyto necessarily be positive or negative on an individual patient, but it can have that impression. And it could actually cause what is calleda delay in the Ct value actually come through here. And if you look at this, this is aparticular mutation that we found in uh between two different probes, both in thenucleocapsid sphere in the SARS-Coronavirus.So if we look at the nucleo — firstly probe for thenucleocapsid, N1, there is no mutation. And so, and the Ct values of these two targetsusually guided really, really close together, mostly right on top of each other. So there is a requirement to approximately equivalent. And that when you construe the number of mutants thatwe have in the first three samples as being one, mostly, we don’t get much discerniblechange between the N1 Ct and the N2 Ct. But when we look at a second mutation thatwould be introduced in the N2 target, induced by the red and the blue arrow, thenwe can actually see that we start to affect the sensitivity of the overall assay. That we are getting that as a lessefficient amplification and detecting, and therefore a delay in that Ct.So you can see a battle log worth ofdifference, or three Ct change, again, or a log merit of difference between thenumber of potential genome forgeries detected by that assay with that mutation. This is just an example, and simply a fairlyminor example, but others can happen and have much more detrimental effects. Next slide. So besides use and just looking atthe individual things that can happen with a Ct value and the actual abilityof that Ct value to detect genome replicas, we also need to look at the use of Ct valuesto try to actually — try to actually look at infectiousness of individual patients and/ or transmissibility. Often, because Ct values can be correlatedto the number of genome fakes detected in an individual, we try to make this jump inwhich we utilize the number of genome copies of the virus there to estimateviral load, and then therefore, acquire infectiousness orassume transmissibility.And this can have a lot of troubles. In this particular study, which isdone from Dutch healthcare workers, there were two populations in whichthey were kind of appear through. One was a very much unvaccinated person. And they were testing these peoplebetween January and April of 2020. And this is really when the — when we hadbasically Alpha going through, or the first kind of variant of the Coronavirus. So “when hes” — excuse me — wehave Wuhan and Alpha going through. So when we had — when the first of these things, we onlyhad this this D6 14 G population, if you are able to. The inoculated beings reallywere looking at a movement on which we had the Delta Coronavirusgoing, mostly a so much better infectious — known much more infectious virus.And what they found was even thoughthey have a terribly, very close correlation between the two prices — Ct values on the same on thesepopulations, that those from Delta intent up being uh having a much less replication-competentvirus. And this — so even though these populationswith the Ct value, as you ensure right here, we didn’t get actually goodviral specks from that. And those viruses were not as infectious, eventhough this virus was — were assumed to be similar through the Ct values of those two populations. Next slide. Likewise, this is a a study that we’ve done byBen Joe in the lab, in which, if we look at and liken RNA replicas, which iswhat we detect with a Ct value on that nucleic acid elaboration experiment, anddetermine with a standard curve and infectivity under conditions, we can see that we have the samenumber of RNA photocopies left at four degrees or chamber temperature or 37 degrees.Those are very, very similar at daythree, period seven and simply start to diverge at the 37 -degree mark at daylight 14 and 21. But virulent virus titer held at infectiousvirus, actual viral molecules there — if we hold those at the same — to the same tiers withseven, if you look at the blue arrow here, you can see at daytime three, you getvast aberration of those viruses held at room temperature and at 37 measures than you do the RNA mimics. What this basically tells you isthat although you would have a terribly, very similar Ct at period — at four degreesand 37 unit at era seven, you would have 100,000 fewer infectiousviral corpuscles at 37 degrees. So you cannot consequently utilize — you cannotutilize Ct to — as a measure of infectiousness.A same phenomenon was also identifiedby this preprint by Eyre et al ., and the effects of SARS-CoV-2 vaccinationon Alpha and Delta transmission. They to be recognised that viral onus determined by Ct were not representativeof viral consignments at transmitting. Next slide. So Ct’s can be used at estimating genome emulates. A standard can be used to actually help youimprove the correlation between Ct and genome follows. NIBSC, which is the National Institute forBiological Standards and Control manufactures such a standard, and these can beused to help standardize assays between two different assays, and to each other.Standard curves for theseshould be run regularly. And these genuinely should berun on a prospective basis. It’s not something that you can now run astandard curve and claim all of your good data in the past, that you know how manygenome copies you inevitably spied. That’s probably not the best practice. It is not eliminate all thecaveats associated with this, though. And these still cannot be linked toinfectiousness or transmiss — transmissibility without something like additional data. An illustration would be culture. Next slide.So how can Ct values be used? They can be used prospectivelyin a quantitative assay. And there are ways to do that. I use a molecular standard with standard curves, monitoring of reproducibility of how per layer, per instrument, per adventurer, et cetera. These certainly should be used in conjunctionwith sequencing so that you actually look at the viral — piece of target of amplificationthat you’re use to make sure that you don’t have systematicchanges in the assay website. And they can also be used as with otherconfirmatory lab data like culture that helps your confidencein the use of Ct values. Or they can be used in groups, as an estimate of viral load. The same assay actually shouldbe used for this to compare this, or you should use a analogy standard. And standardization improves of populationsimproves the correlation, sample category, evidence onslaught, asymptomatic, or symptomatic. And as “youre seeing”, I gave an arrow hereand actually kind of saying that the top end of this slide is really the most thebest use of these this data. And the bottom is really the various kinds of the not quite as good.But Ct values, again, should never beused as an estimate of infectiousness without added patronizing data. Next slide. So the takeaways, Ct values are nota exhaustive measure of infectiousness. Ct values can correlate with genome forgery. The studies that are designedprospectively to minimize variability, and for instance can be strengthened byapplying a standard and a standard curve, especially at smaller sample sizes. Ct values can be used to comparedata from populations or radicals to extrapolate general assumptions on viral loading. They can be used — Ct comparings from the same test or standardizedfor cites are preferable in this method. Language exercised here should be moresuggestive and not definitive.Typical — also, ordinary diagnostic and clinical reporting of Ct values are very difficultto administer and interpret. One quantity without a great deal of background on how that count was actually descended isreally, really hard to understand. Substantial technical railings in diagnosticlabs, in the major diagnostic labs, to actually getting thesenumbers out in any, in any real space. Assay kit result capture is positive generally for these labs, there’s generally positive, negative, inconclusive, or invalid. And actually coming Ct valuesis not necessarily easy. And then likewise these labs a lotof the time use multiple assays which can introduce substantial variability, and the values can be generallygreatly exceedingly construed. Next slide. Thank you for your attention. >> Thank you very much, Dr. Barnes. Next slide, satisfy. Now, I would like to turnit over to Commander Halpin. Commander Halpin, delight started. >> Thank you very much. Hello, everyone. Thank you for joining today. Next slide, satisfy. So in the past few years, the pandemic hasreally only further demo the appraise that sequencing and string data arecritical factors driving our ability to track, check, and analyze pathogens, including SARS-CoV-2. Based on the system that we’ve setup, you want to target something that is both representative and sensitive. And based on the system that we haveset up across the country, both CDC, financings across the nation, as wellas other academic and foundations who are working really hard to advanceand improve our sequencing ability, we estimate that there’s a very highprobability — probably as much as 95% — that our national baseline surveillance systemwould be able to detect something circulate at highly, very low levels in the population. Something as low-toned as even. 05 or. 03 percent.Next slide, satisfy. So why do we do genomic surveillancesequencing for public health intents? Sequencing as a public healthsurveillance tool allows us to do population-level molecular epidemiology. And what does that mean? That means we can detect, track, andanalyze any pathogens flowing in specific populations at a extremely granular grade. We can watch over time as theproportions of certain discrepancies modify. And beyond discrepancies, each of which hasa particular constellation of mutations or genetic varies, we can zoom in onspecific mutants of interest as well. And lastly, another concentration of thegenomic surveillance structure and approaching is the fact that it focuses on collecting and sequencingprimary specimens that are SARS-CoV-2 positive that can be selected for culture. And house a comprehensiverepository of cultured viruses acts as a really important resource forthe scientific community at large. And this — these mortals, these laboratories, they’re working certainly aggressively to characterize these specimens and these viralisolates as quickly as they can with regard to natural immunity, theimpact on natural immunity, inoculations, therapeutics and diagnostics.For example, shortly after Omicron wasreported to the World Health Organization in late November, CDC turnedon heightened surveillance through its national SARS-CoV-2strain surveillance system. And the enhanced surveillance isreally meant to target sprains in the best interests or variances of interest. In this case, we were targeting a mutationin the Omicron lineage as a screen, which has enabled us to prioritizespecimens for sequencing is established that if a specimen was indeed Omicron or not. And if it was indeed Omicron, then movingforward towards subsequent isolation. And states rapidly specified usspecimens that fit this description, countenancing CDC to start this process. And then once we’re able to start thisprocess, anything that’s isolated can be shared with partners who are working to phenotypicallycharacterize SARS-CoV-2 variances, and it can also be used for phenotypiccharacterization in-house at CDC as well.Next slide, delight. I’m sure many of you have seenthe CDC COVID data tracker. And this is actually a relatively oldscreenshot, but I wanted to pick something that wasn’t all Delta all the time. And you can see on the left panel howDelta was really successful at edging out the other variants that werecirculating across the country at the time. You see from week to week the changes thatwere happening with Alpha in the teal, and Gamma in the olive green, shrinkingproportions in the string data week over week over week until it became virtuallyall Delta, that burnt orange dye. And it’s been that mode ever since. However, we are watching closely tosee how these ratios will change with the introductions of Omicron into theUnited Nation in the next few weeks and months.Next slide, delight. Now, genomic sequencing in general isstill not what we would call rapid. Certain approaches, many approachescan require days to weeks to complete from specimen collecting, to shipping, allthe style through sequencing and analysis. Therefore, the results arenot available fast enough to direct patient-level therapeutic selects. However, as I mentioned, we can usepublic health’s genomic surveillance to monitor specific modifies or mutants inthe cycle data, including mutants that are indicative of therapeutic resistancefor medications or preventative roles. This includes both the monoclonalantibodies and the small amount of molecular antivirals that have existed. Our sequencing surveillance system can provideinformation at the regional and perhaps even at the nation tier to help guideappropriate distribution of therapeutics, based on the prevalence of specificmutations that are associated with resistance to therapeutics used in COVIDprevention and treatment.And we’ve included a few links to additionalinformation on therapeutics themselves and how to lineup and administer them, ifthat is something you’re interested in. Next slide, delight. Okay, so precisely to make sure you’ve beenfollowing along, our self-knowledge test check is that genomic sequencing shouldbe ordered for persons diagnosed with SARS-CoV-2 infectionfor the following reasons: A, to determine which monoclonalantibody might be appropriate. B, to determine which big moleculeantiviral might be appropriate. C, to inform recommendationsfor the length of isolation. D, to assess the need for high-level care. E, A, B and D. Or F , none of the above. Next slide, please. And the answer, of course, is F , nothing of the above. Next slide satisfy. And the reason this is F, as I mentioned, the time required between specimen collection and accessibility of cycle dataobviates the benefit of genomic sequencing for diagnostic purposes or clinicalmanagement at the patient level. We simply aren’t there yet inmany cases in terms of speed.Furthermore, the outcome of that genomic sequencingof SARS-CoV-2 are not frequently CLI-Avalidated or authorized by FDA, meaningthey’re not meant to be used for — on human samples in terms of patient management. They’re not meant to diagnose, impede, or consider infection or assess human health. If you’re interested in more informationabout that, there’s some information at the lower end of the slither note. CDC and other public healthlaboratories across the country and globally are performing genomicsequencing for the following purposes.Surveillance, as we’ve discussedat length in this presentation. Investigations, and this includes, forexample, outbreaks or superspreader incidents. And of course research purposes. Programmes for near real-time characterizationof variances are under investigation, and hopefully as the science continues toadvance, we will see improvements in this area. Next slide delight. Thank you very much for your time and attending. >> Thank you very much. Presenters, I would like to thank you for adding our audiencewith this timely information.We will now go into our Q& A hearing. Please remember that in order to ask aquestion using Zoom, click on the Q& A button at the lower end of your screen, then form your question. So our first issue invites, are you aware ofeither the existence of or the development of any testing kits that test for bothSARS-CoV-2 and influenza simultaneously? >> Yeah. >> Do you want to do that? >> Sure, sure. Yes, there is only various out there. There are actually a couple of rapid testseven that do SARS-Coronavirus-2 and influenza. And there is only nucleic acidtests that are available for SARS-Coronavirus, flu, and RSV as well. Like I said during my presentation, we actuallycreated a B-influenza and SARS test .>> Thank you very much. Our next question questions, is there Ct valuedata available for the Omicron variant? And if not, do you have an anticipatedtimeframe having the data available and analyzed same to the others? >> So that’s a really good question. And there were various in hereabout Ct values and use of those. And this is exactly what we’retrying to discourage a bit.The assessments that we have in largepart, and there may be actually a — I haven’t checked in a little while, but theremay be actually a test that is approved for — that is actually approved for actually lookingat the number of genomes or quantitative technique. But most of the tests that we actuallyhave out there are not quantitative. They are just for a positive or negative result. And doing that can come witha lot of different a lot of different troubles. So I has not been able to seen any data like that yet, butI wanted to make sure that we handled that. >> Thank you very much. Our next question invites, do you anticipatethat genomic sequencing will be used in acute clinical care in the near future, if the methods that you were discussing for near real-time characterization methodsare available and authorized in time? >> This is Alison. That’s a great question. I think there is great promisein the sequencing engineering. I think it’s also important to remember thatone of the key components is that there needs to be a defined use for clinical care.You know, knowing the variance that apatient is harboring or newly infected may or may not impact their, you are familiar with, infection avoidance decisionsbeing made with respect to that. And some of the mutations mayimpact medication in the future. But I imagine part of it is recognizing that it’sreally important that we are very confident in the performance of the testbefore it’s used for patient care. >> Thank you very much. Our next question is specificto a patient population. I know, Dr.Patel, you talkedabout outpatient clinics, emergency bureaux, hospitalsand rest home. The question expects, do you have recommendationssimilarly for incarcerated people? Would you be taken into account similarto nursing homes or would you have different or variedrecommendations for incarcerated people? >> That’s an excellent question. So recently, CDC questioned a HAN, whichI’m sure we can add as a tie-up if it’s not already accessible to participants.And in the past, there are 2018 CID guidelinesthat are affixed in the reference list, which consider long-term care facilitiesand nursing homes as institutions. Confinements — there’s no specific guidance onprisons or other congregate installs. However, in the context of SARS-CoV-2, I think there’s a lot of flexibility for considering those institutions — those congregantsettings as institutions. So I judge the HAN does layout thatflexibility for purposes of testing, purposes of treatment with antivirals andpossibly prophylaxis with the two antivirals which is presently, oseltamivir and baloxavir. So that’s be dealt with the HANreleased by CDC on December — November 14 th.Thank you. >> Thank you, Dr. Patel. And for our gathering who are interested inlooking at the HAN, you can direct your browsers to emergency.CDC.gov/ HAN, and you’ll be ableto find the HAN in question in the archives. Okay, we have time for one last-place question. And our question countries, in lightof co-circulation with SARS-CoV-2, does CDC have different or updatedantiviral recommendations for influenza? Or do those recommend — recommendationsstay unchanged? >> I’ll give that question likewise. It’s very similar to the previous question. And the HAN itself does address those. I think there is more flexibilitythat is necessary. And CDC recognizes that. There are no specific guidelinesor recommendations that are made specificallyto co-circulation SARS-CoV-2. So two things. One, in the train of co-infections, antivirals for influenza can be used if there’s no contraindications orlimitations or regulations for employment. The operation of antivirals baloxavir or oseltamivir could certainly help mitigate localise outbreaks with care and/ or prophylaxis. And that can help reducehealthcare strain in the context of co-circulation of two viruses this winter. So there is a lot of flexibility, and the HANcovers those issues, but no specific guidelines or recommendations that are changingfor influenza and antiviral help. >> Thank you very much. This concludes today’s show. I want to take a moment to thank the presentersfor sharing their epoch and expertise with us. All continuing training for COCA Callsare issued online through the CDC training and continuing education onlinesystem at https :// TCEOLS.cdc.gov. 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