"RCTs of Cardiovascular Outcomes in Obstructive Sleep Apnea: Is it Time for an Alternative Trial Design" Ulysses J. Magalang (11.18.2020)
November 20, 2020ID5915
To CiteDCA Citation Guide
- 00:00Thank you and.
- 00:25Alright, I think we're ready
- 00:27to get started everybody.
- 00:28Hello, my name is Lauren Tobias
- 00:30and I'd like to welcome you.
- 00:32Doris Yale State Sleep seminar,
- 00:34Yale sleep seminar.
- 00:35This afternoon I have a few
- 00:36quick announcements before I
- 00:38introduce today's speaker.
- 00:39First, please take a moment
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- 00:56you will need to do that first.
- 00:59If you have any questions
- 01:00during the presentation,
- 01:01I encourage you to make use of the
- 01:03chat room throughout the hour and
- 01:06recorded versions of these lectures
- 01:07will be available on line within two
- 01:10weeks at the link provided in the chat.
- 01:12Finally,
- 01:13please feel free to share the
- 01:15announcements for our weekly lecture
- 01:16series to anyone else who may be interested,
- 01:19or contact Debbie Lovejoy to
- 01:20be added to our email list.
- 01:22So now I'm delighted to introduce Doctor
- 01:25Ulysses Magalang as our speaker today.
- 01:27Doctor Magalong is a professor of medicine.
- 01:29And neuroscience in the division
- 01:31of pulmonary critical care and
- 01:34Sleep Medicine at the Ohio State
- 01:36University and director of the
- 01:38OSU Sleep Medicine program.
- 01:40He is a member of the American
- 01:43Thoracic Society Scientific
- 01:44Advisory Committee and a founding
- 01:46member of the Sleep Apnea,
- 01:49Global Interdiscipline or
- 01:50Interdisciplinary Consortium,
- 01:51which promotes collaboration
- 01:52between international experts
- 01:54working in the field of genetics
- 01:57and genomics of sleep apnea.
- 01:59Doctor Magalong's is in an
- 02:02accomplished researcher whose work
- 02:04examines the effects of intermittent
- 02:06hypoxia on adipose tissue biology,
- 02:08particularly its effects on glucose
- 02:11control and diabetes and atherogenesis.
- 02:13His funding sources include the NIH an,
- 02:17the ASM Foundation,
- 02:18and he has projects including
- 02:21looking at the genetic,
- 02:23epigenetic,
- 02:23and metabolomic basis of different
- 02:26subtypes of OSA,
- 02:27and another project looking at.
- 02:30Transcranial direct current stimulation
- 02:32therapy for central hypersomnia.
- 02:33He regularly speaks nationally
- 02:35and internationally,
- 02:36and topics including phenotypes of
- 02:38sleep apnea and the neurobiology
- 02:41of breathing and I am delighted
- 02:43that he's here today to give a talk
- 02:46entitled RCT's of cardiovascular
- 02:48outcomes and obstructive sleep apnea.
- 02:50Is it time for an alternative trial design,
- 02:54and with that I will turn it over to you.
- 03:00Thanks,
- 03:00Lauren, good afternoon.
- 03:01Thanks for inviting me.
- 03:03So when I first received the
- 03:05invitation I thought about presenting
- 03:07some of the animal studies that
- 03:09we're doing here at Ohio State.
- 03:12However, you know,
- 03:13given the audience of this seminar series,
- 03:15I quickly changed my mind.
- 03:17So this afternoon we're going to
- 03:19talk about humans and that rodents.
- 03:24So this is my first slide.
- 03:27I have no conflict of interest to
- 03:31report in relation to this presentation.
- 03:34Let me start with this headline from 2017.
- 03:39From CNN Health stating that sleep apnea's
- 03:43CPAP machine doesn't cut heart risks.
- 03:47And of course the article is refering to.
- 03:51The now famous Safe Study,
- 03:54its largest trial so far up CPAP.
- 03:59In in cardiovascular disease that
- 04:02was published in the New England
- 04:05Journal of Medicine in late 2016,
- 04:07and the studies show that CPAP did
- 04:11not prevent cardiovascular events in
- 04:13patients with moderate to severe OSA
- 04:16and stab Lish cardiovascular disease.
- 04:19It did confirm results of prior studies
- 04:23that CPAP improve daytime sleepiness,
- 04:25health related quality of life.
- 04:29And mood.
- 04:31So in the next 40 minutes or So
- 04:34what I'm going to talk about?
- 04:37RCT's cardiovascular outcomes in
- 04:39OSA and biases in this RCT's.
- 04:42However, before before that,
- 04:45I'm gonna that's on a little
- 04:48bit about OSA disease,
- 04:50heterogeneity as well as some
- 04:53of the preclinical and large
- 04:56epidemiological studies that have
- 04:59been done and published that you're.
- 05:03All familiar with just as a
- 05:06review to put the.
- 05:08Results of the RCT's in
- 05:11the proper perspective.
- 05:13And then finally we will discuss
- 05:15alternative designs for future studies.
- 05:18In particular,
- 05:19we're going to touch on
- 05:22propensity score matching.
- 05:24So this is the famous Sir Bradford Hill
- 05:28who in the 60s published the criteria
- 05:32for the assessment of causation.
- 05:35What I have listed here are some of the
- 05:38criteria as well as the corresponding
- 05:41types of studies in the right side to
- 05:45fulfill the criteria for causation.
- 05:47So mechanistic and preclinical
- 05:50experiments both in animals.
- 05:52In humans are typically done to explore
- 05:56the biologic plausibility of causation.
- 05:59Epidemiological cross sectional
- 06:01studies showed the strength.
- 06:04Consistency and dose response of the
- 06:08Association while longitudinal studies.
- 06:11Show that the timing is right,
- 06:14you know the chronology is right,
- 06:16and then finally you have.
- 06:18Of course interventional studies
- 06:20which can be observation,
- 06:21ull or in the form of RCT.
- 06:24So randomized control trials that are
- 06:26used to evaluate the treatment effects.
- 06:31As far as treatment trials are concerned,
- 06:34you know proponents, of course of evidence
- 06:37based medicine state that there is a
- 06:40hierarchy of evidence with RCT's and
- 06:43systematic reviews and meta analysis
- 06:45occupying the top of the triangle.
- 06:47And the reason for that is indeed
- 06:51the quality of evidence shown with
- 06:55the error on the right hand side is
- 06:59higher from the bottom to the top.
- 07:02And mainly because of the effects
- 07:07of confounding.
- 07:08As shown on the left,
- 07:10the increasing arrows on the left hand side.
- 07:15However, there are situations where
- 07:18randomization is not possible or ethical.
- 07:22So for example,
- 07:24it would be unethical to randomize to
- 07:27no smoking versus versus versus smoking.
- 07:31And this is to illustrate this point.
- 07:34This is an article published in
- 07:36the Christmas edition of The BMJ.
- 07:38You know there they are known to publish
- 07:41this kind of articles around Christmas time.
- 07:45And this manuscript addresses the issue
- 07:48that parachutes reduces the risk of
- 07:51injury after gravitational challenge,
- 07:53but their effectiveness has
- 07:56not been proven by RCT's.
- 08:00So they perform a systematic review
- 08:02and found of course that know
- 08:04our cities have been performed,
- 08:06and they conclude that the basis for
- 08:09power should use is purely observation.
- 08:12ULL and it's apparent efficacy
- 08:14could potentially be explained
- 08:15by a healthy cohort effect.
- 08:18That is,
- 08:18those individuals who jumped from an
- 08:21airplane without without a parachute
- 08:24are likely to be mentally unhealthy.
- 08:27And that individuals.
- 08:29Who insist that all intervention
- 08:31interventions need to be validated by
- 08:33our CPS? Need to come down to earth.
- 08:36With a bomb.
- 08:39Of course they could have answered
- 08:42your question had they included all
- 08:45observational data and not only are cities,
- 08:48so it turns out that the US
- 08:51Parachute Association registers
- 08:52every single jump from an airplane.
- 08:57Of course, with the parachute.
- 09:00And in 2007 there were over 2 million jumps,
- 09:04resulting in 821 injuries and 18 deaths,
- 09:08so that's a relative risk
- 09:10reduction of about 99.9%.
- 09:13A huge can argue so.
- 09:15Huge effect size that cannot be ignored.
- 09:18So I have to be honest,
- 09:20I hesitated to use example
- 09:22because now it's probably the
- 09:24only the only slide that you
- 09:26will remember from this talk.
- 09:31But observation ULL study set value,
- 09:34but they still have to be.
- 09:36The methods should be rigorous.
- 09:40And I I would present argument that
- 09:43perhaps propensity score matching
- 09:46provides as meta methodology to robustly
- 09:50assess the cardiovascular benefit.
- 09:52Of CPAP in in real world patients.
- 09:57So let's talk about OSA disease heterogen.
- 10:00Nyati we've been at Ohio State.
- 10:05We've been actively participating in an
- 10:07international consortium called Sajik.
- 10:09As Lauren alluded to.
- 10:12You know there's there's.
- 10:14There's two sides in the US.
- 10:16There's two in Australia,
- 10:17a couple in Europe,
- 10:19and then the rest in in Asia.
- 10:22And one of the object objectives of Sajik
- 10:25is to establish a large multinational
- 10:28cohort with detailed phenotyping.
- 10:31To understand common and ethnicity specific
- 10:35always say presentations and risk profiles.
- 10:39So sleep apnea, of course,
- 10:41is a heterogeneous disease that's that.
- 10:44Is 2 patients with the same severity
- 10:47of the condition may present
- 10:49with totally different symptoms.
- 10:51And using cluster analysis we published
- 10:55an article about two years ago showing
- 11:00that indeed there are different
- 11:03symptom clusters of sleep apnea.
- 11:06And they are the consist of
- 11:10obstructive sleep apnea patients with
- 11:14predominantly insomnia symptoms.
- 11:17The typical OSA with excessive
- 11:20sleepiness as well as the third class
- 11:24are composed of relatively asymptomatic.
- 11:27Always say patience.
- 11:31So what is clustering?
- 11:32I probably don't need to.
- 11:35Tell this group about this since.
- 11:40Claire and doctors in truck.
- 11:43Actually at Publix up articles about
- 11:47clustering cluster analysis begins with
- 11:50a predefined set of input variables
- 11:54targeted to a specific question.
- 11:57Example other symptom based subtypes of OSA.
- 12:02You then apply a clustering algorithm
- 12:05and an many are available to group the
- 12:09patients such that within a cluster.
- 12:13Patients are as similar as possible
- 12:16and then between clastres they
- 12:18are as dissimilar as possible.
- 12:21The clustering method is unbiased,
- 12:24meaning it is unsupervised
- 12:27and typically uses the lowest.
- 12:30Value of the so-called BICR valuation
- 12:34information criteria to define the
- 12:37optimal number of number of clusters.
- 12:41So this table is is busy,
- 12:43but it's just meant to simply show the
- 12:47symptom questions and there's a variety.
- 12:50To define the clusters that
- 12:53was used in our study.
- 12:55Shows the characteristic's of the
- 12:57three clusters with the value side
- 13:00light that that helped define.
- 13:02You know this this clusters
- 13:04in different colors there.
- 13:09So the first clustering study was actually
- 13:12done in a clinical population in Iceland,
- 13:15and the results are shown here
- 13:18in the on the left hand side.
- 13:21What is known as the Ice Axe study?
- 13:26Showing indeed that there are three clusters
- 13:29and that that's shown on the left side.
- 13:33And what is not known after that article,
- 13:36as Publius is that if the classes
- 13:39are unique to Iceland with its
- 13:42relatively homogeneous population?
- 13:45We did find in our paper that the
- 13:47same 3 classers generalize in an
- 13:51international sample of clinic patients,
- 13:54although with some what you know,
- 13:57different prevalence of the insomnia
- 14:01and minimally symptomatic groups
- 14:03as shown in the figure here.
- 14:07The sleeping group remained
- 14:08constant at about 40%,
- 14:10and by the way,
- 14:11I just want to point out that
- 14:13the responses that defined the
- 14:15sleepy group was not solely on the
- 14:18basis of the Epworth score score,
- 14:20but that was all that was that
- 14:23was part of it.
- 14:27So this three symptoms sub
- 14:29subtypes are found in both.
- 14:32In both clinical and community
- 14:36based samples worldwide.
- 14:38So that's the original
- 14:40I sax study in Iceland.
- 14:42This is our study in Sajik
- 14:45which we compared to.
- 14:47Up the the nine Iceland,
- 14:50we also have a in the paper.
- 14:54There was a second group of Iceland
- 14:57patients that basically reproduced
- 14:59their their their original finding.
- 15:03And this is been shown also in a
- 15:07population based cohort in South Korea
- 15:10as well as in Europe and most recently,
- 15:15although this is not published yet,
- 15:18but it's been.
- 15:21Found and generalized,
- 15:23the three subtypes generalized
- 15:26to the Canadian biobank samples.
- 15:33And most importantly, so this is a.
- 15:38A study that was published
- 15:40in the Blue Journal by Diego
- 15:42Mazzotti out of the pen group.
- 15:45In 2019, recent analysis.
- 15:47So this is a re analysis of
- 15:50the Sleep Heart Health study.
- 15:53And this indicates that the
- 15:58increased cardiovascular risk.
- 16:01Would always say is driven by patients
- 16:04in the excessively sleepy subtype.
- 16:07So these are survival plots of knew,
- 16:11incident.
- 16:11Coronary heart disease,
- 16:13knew incident cardiovascular disease,
- 16:16and knew incident heart failure
- 16:19and after adjusting for covariates
- 16:23in the in the adjusted analysis,
- 16:26it's only this excessively sleepy
- 16:29subtype that predicted the occurrence
- 16:32of cardiovascular disease,
- 16:34and that's perhaps shown better here.
- 16:38In this figure.
- 16:40In the sleep part field study there was a.
- 16:45Another group called moderately sleepy,
- 16:48but it's the excessively sleepy
- 16:51subgroup where that had the increased
- 16:55cardiovascular risk, Interestingly.
- 16:58Sleepy patients or subjects without OSA?
- 17:06That wasn't there,
- 17:07not at risk for future garbage.
- 17:10Cardiovascular events.
- 17:12So, just to summarize,
- 17:14there are three symptom clusters
- 17:17that generalize the moderate severe
- 17:20OSA patients in both community
- 17:22and clinical samples.
- 17:24The OSA cardiovascular risk comes from
- 17:27only the excessively sleepy subtype.
- 17:30And sleepiness in those without OSA
- 17:33did not increase cardiovascular risk.
- 17:36Anne Anne it's conceivable that
- 17:38distinct molecular responses to OSA
- 17:41result in sleepiness and increased
- 17:44risk of cardiovascular disease in.
- 17:47And in certain patients,
- 17:49to this end,
- 17:51this was actually the basis of a.
- 17:56Dot Med grant application between Penn,
- 17:59Ohio State and University of British
- 18:02Columbia with innogy bias and Alan
- 18:05Pack that's looking at the molecular
- 18:07basis for differences between or say
- 18:10subtypes because that's not known right,
- 18:14we just this.
- 18:16This just got funded.
- 18:18And we got funded for 3000
- 18:21samples from patients with OSA.
- 18:23So basically the idea is a thousands
- 18:26of samples in its three subtypes,
- 18:29and the top Med program
- 18:32doesn't give you resources.
- 18:35For collection that they collecting
- 18:37the samples but it does give you
- 18:40resources for the following whole
- 18:43whole genome sequencing DNA methylation
- 18:45patterns as well as metabolomics,
- 18:48so they'll do that.
- 18:51Those three things in in
- 18:55all the 3000 samples.
- 18:58I believe this is going to be a good
- 19:01resource because you know that that
- 19:03Med program releases the data for
- 19:05two other two other investigators.
- 19:10So just quickly I'm going to touch on
- 19:13preclinical and epidemiological studies.
- 19:16You guys all know this.
- 19:20Numerous studies looking at biological
- 19:23plausibility of obstructive sleep
- 19:25apnea and cardiovascular disease,
- 19:28just to name a few increased
- 19:31oxidative stress through impaired
- 19:33vasoreactivity increase catecholamines.
- 19:36Increase platelet aggregation and
- 19:40increase inflammation and this
- 19:44been shown in many animals and.
- 19:48And human studies.
- 19:50They are small, but it does show
- 19:54a biological plausibility of the.
- 19:57Of obstructive sleep apnea
- 19:59causing cardiovascular.
- 20:01Events just to give you an example,
- 20:05you guys are very familiar with Seabass.
- 20:08Apollo skis.
- 20:09A paper that was published in the Blue
- 20:14Journal many years ago where he exposed.
- 20:18C57 Black 6 mice.
- 20:21Two chronic intermittent hypoxia and found.
- 20:26In panel D here that if you
- 20:29combine intermittent hypoxia,
- 20:31exposure with high cholesterol
- 20:33diet that the this is sections
- 20:36of the order that you will find
- 20:40atherosclerotic plaques or as
- 20:42all the other groups did not.
- 20:45This is our own metaanalysis
- 20:47also from out of the Sajik group,
- 20:50showing that the effects of CPAP
- 20:53on blood pressure in patients with
- 20:56resistant hypertension and the forest
- 20:58flat shown here shows the results
- 21:01of the randomized control trials.
- 21:04On 24 hour systolic blood pressure.
- 21:08And in this analysis we found that
- 21:11there is a large decreases in systolic
- 21:15blood pressure after CPAP use in the
- 21:19order about 7 millimeters Mercury.
- 21:25Just to summarize, in the interest of time.
- 21:30See you all know that large epidemiological
- 21:33studies consistently find that OSA is an
- 21:37independent risk factor for hypertension,
- 21:39coronary artery disease, heart failure,
- 21:41stroke and death, and death due to CBT.
- 21:47And that individuals effectively
- 21:49treated with CPAP have the same rate
- 21:52of cardiovascular events as age,
- 21:55sex and weight match controls
- 21:57with no apnea or snoring.
- 22:00I'm referring, of course,
- 22:02to the very famous study of Doctor Marin.
- 22:07Where he showed that severe always saying
- 22:11Christmas trees of cardiovascular events
- 22:13and that CPAP use reduces this risk
- 22:17because those patients and always say
- 22:20we'd always say on C pap have the same
- 22:24cardiovascular event rate as controls,
- 22:26an inflamed snores,
- 22:28and the more important thing is
- 22:31that I believe this is in a follow
- 22:34up paper where they showed that.
- 22:37Medication refill rates are similar
- 22:41in users and nonusers subsea of CPAP.
- 22:45Suggesting that healthy user bias,
- 22:47which is of course a big confounder
- 22:50in observation.
- 22:51ULL studies does not explain
- 22:54the observed benefit of CPAP.
- 22:57So if you then look at Sir Bradford
- 23:01Hill's criteria, you'll find that.
- 23:05All of this things had been have been shown.
- 23:11And except for our cities.
- 23:13So.
- 23:16Why is it that the three major are
- 23:19cities that have been published so
- 23:22far have been have been negative,
- 23:24and I'm talking about course the SAFE study,
- 23:28which is the largest?
- 23:29There's the re courage to study
- 23:32and then there's a dissect study
- 23:35that was published in Lancet
- 23:37respiratory medicine just this year.
- 23:40So I'm going to send a review
- 23:42real real quick.
- 23:43This three RCP's and we're going
- 23:45to discuss some of the biases.
- 23:47That we believe are present.
- 23:50So the same, of course,
- 23:53very briefly,
- 23:54is a study multicenter study of roughly
- 23:582700 adults with moderate to severe OSA.
- 24:02And it's they have coronary or
- 24:06cerebral cerebral vascular disease.
- 24:09They were randomized to see Pap less use,
- 24:13less useful care versus usual care alone.
- 24:16And of course the primacy of the
- 24:20primary composite endpoint scuse me
- 24:23was death from cardiovascular causes.
- 24:26Am I stroke?
- 24:29Or hospitalization for unstable angina.
- 24:34Heart failure ortie The mean follow-up
- 24:37was 3.7 years and the incidence of
- 24:41the primary endpoint did not differ
- 24:44significantly in patients who did
- 24:47versus those that did not receive C
- 24:50Pap with a hard hazard ratio of 1.1.
- 24:55And I mentioned earlier CPAP
- 24:57did improve daytime sleepiness,
- 24:59health related quality of life and and mood.
- 25:04The records study was published in the
- 25:07Blue Journal about four years ago.
- 25:09The single center RCT.
- 25:13There's it's a smaller study.
- 25:15Of course,
- 25:16there's 244 patients with newly
- 25:18revascularized coronary artery
- 25:20disease and moderate to severe
- 25:22OSA without daytime sleepiness.
- 25:24So this this patient also had stab Lish,
- 25:28coronary artery disease,
- 25:29and obviously they were randomized
- 25:32to sipat versus no see bat and the
- 25:35primary endpoint is listed there.
- 25:38It's again,
- 25:39it's a composite endpoint endpoint.
- 25:41Little bit longer follow up of.
- 25:444.75 years and again,
- 25:46the incidence of the primary endpoint
- 25:49did not differ significantly in patients
- 25:52who did versus those who did not receive
- 25:55a seat back with a hazard ratio of a .8.
- 26:02And in the third study,
- 26:05is that uh, is the Isak study
- 26:08that was published this year.
- 26:11It's a multi center RCT.
- 26:13This patients have were admitted
- 26:16for acute coronary syndrome.
- 26:18They were found to have moderate severe OSA,
- 26:22diagnosed during the first 24 to
- 26:2572 hours after admission and we
- 26:28without daytime sleepiness. Um?
- 26:31Of course you can question you know
- 26:34there's some data that says that.
- 26:38When you follow patients where
- 26:40admitted for acute coronary syndrome
- 26:43that perhaps there hi changes
- 26:45but nonetheless that was there.
- 26:50Entry criteria. Again,
- 26:53randomized to see that versus know
- 26:56Steve at about 600 in each arm.
- 26:59Again, it composite endpoint
- 27:01that's listed there with a
- 27:04median follow up of 3.3 years.
- 27:08And again, the primary endpoint
- 27:10did not differ significantly
- 27:12in patients who did versus
- 27:14those who did not receive.
- 27:17C pap therapy.
- 27:20So what are the biases in the in this
- 27:23published RCT's of cardiovascular outcomes?
- 27:26In no essay I I'm just going to
- 27:30touch on a couple. We believe that
- 27:34there is a sample selection bias.
- 27:37And and and there are a few things to
- 27:41consider here. But first thing is,
- 27:45are they recruited participants
- 27:47representative of real world and patients?
- 27:51And we believe the answer to this is no.
- 27:57Based on the data that I presented to you,
- 28:00they included.
- 28:02Non sleepy patients and excluded.
- 28:06The sleepy patients who are.
- 28:10The ones.
- 28:11That are primarily at risk of
- 28:16developing cardiovascular events.
- 28:18All these prior our cities were secondary
- 28:22prevention studies and and really that
- 28:24was done deliberately because she,
- 28:27you know they wanted a
- 28:29higher event rates force.
- 28:31But one of the downside of that
- 28:34would be that you know a lot of this
- 28:38patients were already being managed
- 28:40actively and they they are on statins
- 28:44and and perhaps the effect of.
- 28:47Uh, partly the reason why it's
- 28:50negative is that the effect of.
- 28:53Of C PAP may have invented.
- 28:57The largest issue, we believe,
- 29:00is that you know where and how
- 29:04this participants were recruited.
- 29:07So all these RCT's focus and diagnosing OSA.
- 29:13Among relatively asymptomatic individuals
- 29:16with stab Lish cardiovascular disease.
- 29:19As opposed to identifying adults
- 29:23with clinically diagnose.
- 29:25Always saying, then randomizing them.
- 29:28So there they are not from the sleep clinics.
- 29:34And we believe that symptomatic the bias
- 29:38occurs because symptomatic patients are
- 29:40less willing to be randomized to a study
- 29:43arm that receives no treatment for an
- 29:45extended period of time of follow-up,
- 29:48which is what you need for a
- 29:51study of cardiovascular events.
- 29:53Or their providers are less
- 29:56likely to recommend participation
- 29:58and such was the expiry.
- 30:00As in some NH sponsored trials.
- 30:02So for example, the Apple study had.
- 30:07You know, according to clip, Kushida had.
- 30:10Terrible time with recruitment in
- 30:13the sleep clinics and they had to
- 30:17resort to really large advertising.
- 30:20The other trial that comes to mind is
- 30:24nalaka Gooneratne's memories trial.
- 30:27Were he actually?
- 30:29You know providers were not
- 30:32willing to randomize.
- 30:34Their subjects with cognitive
- 30:37impairment if they have they
- 30:40were found to have sleep apnea.
- 30:43So we believe that these are
- 30:45not our patients.
- 30:46If you look at the exclusion criteria
- 30:50there that's listed and then the
- 30:52average on the right hand side.
- 30:54The. The average effort,
- 30:59sleepiness,
- 30:59scale score that all the recent RCT
- 31:04sub C Pap on cardiovascular events
- 31:07had had had had the same bias.
- 31:11And of course,
- 31:12you know they had to exclude this
- 31:14patients because it's unethical
- 31:16to randomize sleepy OSA patients
- 31:18to no treatment in cardiovascular
- 31:21trials of seed Bab,
- 31:22basically because of fear of automobile.
- 31:26Accidents as well as workplace accidents.
- 31:32But but the sample bias likely
- 31:35led to the very low adherence
- 31:38to CPAP that was reported.
- 31:41So that's another bias,
- 31:43because low adherence to therapy would
- 31:46tend to underestimate the effect size.
- 31:49And this is the summary.
- 31:53Of the adherence data.
- 31:57In in the three trials in the
- 32:00records actually separated their
- 32:02users and all patients here,
- 32:04so all patients here,
- 32:06these are the CPAP users in
- 32:09the regards the trial.
- 32:11The bottom line is after 20 four
- 32:15months roughly in the range of.
- 32:192.8 to 3 hours per nine.
- 32:25And you'd say, well, that's what
- 32:27you're going to get with C pap,
- 32:29but but there's some.
- 32:31Evidence that they may not
- 32:33be in our patients so.
- 32:36This is Peter's studies study that
- 32:39was published in 2019 using big data
- 32:44looking at CPAP usage in clinic patients.
- 32:48.6 million patients and and you can
- 32:52see that that indeed the device usage
- 32:55is roughly in the area of about 62.
- 32:59To 70% now, I mean this this study
- 33:02of course is limited because.
- 33:05You know these are they didn't.
- 33:07They didn't include those who did
- 33:10not drop up or return their seat
- 33:13that because that's going to be.
- 33:16They won't have the data and then.
- 33:20And and and it is.
- 33:22In addition, this was only the 90 days so.
- 33:26Off of therapy. But still some some evidence.
- 33:30Not great that perhaps our clinic patients.
- 33:33If you if you enroll them in
- 33:37a in a in a trial of C pap.
- 33:43Would perhaps use? Their seat belt
- 33:49more and then you know as I mentioned,
- 33:52likely some of the selection bias that accord
- 33:57resulted in the lowest seat belt usage.
- 34:01The two of these studies in fact did
- 34:04a propensity score matching in those
- 34:07who are adherent versus non adherent.
- 34:10Um? So the Save and Isaac did this
- 34:15and they got a point estimate of a .8.
- 34:19I would just point out and this is.
- 34:23This was I think it was Dan Gottlieb who,
- 34:26in an editorial in JAMA pointed
- 34:28this out at this point,
- 34:30estimates similar to the meta analysis of.
- 34:34That that's that's off of
- 34:36our cities Anstatt in trials.
- 34:41And but at the end of the day, you know this.
- 34:46This post hoc analysis using
- 34:48propensity score matching.
- 34:50Where or underpowered because of
- 34:53the event rate, the recuts a study
- 34:58did show that they if you separate
- 35:03out the users versus non users that.
- 35:08There was a difference in in
- 35:11cardiovascular events in a different
- 35:14versus non adherent subjects.
- 35:17So the question is.
- 35:20What are the alternative
- 35:23designs for future studies?
- 35:25If you think about,
- 35:26we believe there are three three
- 35:29ways of doing this. One is.
- 35:31We can include the excessive
- 35:34sleep patients in the trials,
- 35:37include them in the useful
- 35:39RCT you know the question is,
- 35:42is this ethical?
- 35:44And then there's also the question
- 35:46of whether symptomatic patients
- 35:48and their providers agreed to
- 35:51not being treated for years.
- 35:53The second one was actually published
- 35:56and was written by a doctor,
- 35:59Javaherian colleagues in,
- 36:01and they suggested that.
- 36:03Let's do the RCT with pharmacological
- 36:06management of sleepiness using using
- 36:10Modafinil. We don't think this to wait.
- 36:13Wait, are the way to go.
- 36:16It's probably we.
- 36:17We believe that using a study design
- 36:20using propensity score matching that
- 36:23allows the inclusion of excessively
- 36:26sleepy or Safeway patients.
- 36:28Most likely to show a cardiovascular
- 36:31benefit from CPAP and not only
- 36:33that because you're in a propensity
- 36:36score design and real world patient,
- 36:39you're going to compare users
- 36:41versus non users.
- 36:42You could examine the true benefit
- 36:45of C pap therapy on cardiovascular
- 36:48outcomes within real world clinical patients.
- 36:52And this is the the paper that I
- 36:55was alluding to that was published.
- 36:58They estimate that they would
- 37:00need a sample size,
- 37:02about 24,000 with 12,000 in each arm.
- 37:05Using pharmacological management of.
- 37:07Of sleepiness.
- 37:10This is the way we think that
- 37:14this the using propensity score.
- 37:17Should be done.
- 37:19You know you have include.
- 37:21Subjects who are seen in the clinic.
- 37:24So you have the inclusion criteria there.
- 37:27Of course there will be sleepy subjects
- 37:29based on the sleepy subtype and they will
- 37:32be treated with CPAP in all the patients.
- 37:35But the most important thing there
- 37:38in any propensity score design is to
- 37:41obtain the covariates and I'll explain
- 37:43that in a little bit and then you can.
- 37:46You can then compare those who are adherents.
- 37:50Versus those who declined
- 37:52therapy or non users.
- 37:53You could define this as less than
- 37:56two hours per night or you could say
- 37:59less than one hour per night without
- 38:01using the without CPAP you states
- 38:04in the last 30 days and then you
- 38:07can do a propensity score design.
- 38:11With an annual follow up of CPAP adherence,
- 38:15an major adverse cardiovascular events.
- 38:19For for a number of years.
- 38:22So this is crucial for any PS design study.
- 38:26You need to include a rich
- 38:28set of clinical relevant,
- 38:30clinically relevant covariates.
- 38:32Associated with.
- 38:33Basically we do things,
- 38:35the CPAP adherence and the outcome,
- 38:38and this reduces the bias associated
- 38:41with observed and unobserved covariates.
- 38:45And just in the interest of time,
- 38:47I'll you know these are the useful things.
- 38:52That we would think would be important
- 38:55as predictors of CPAP adherence.
- 38:57Including educational attainment.
- 39:01Social economic factors.
- 39:04Insoft,
- 39:05presence of insomnia and psychological
- 39:09problems but also include measures of.
- 39:14Self efficacy as well
- 39:16as medication adherence.
- 39:21The predictors of the events obviously
- 39:24are the useful things that we consider.
- 39:29Gender, obesity, prevalence, CVD, smoking.
- 39:34Lipids, family history and
- 39:37physical activity as well as Dyett.
- 39:41Assessment so what's propensity score?
- 39:47So the definition,
- 39:49the PS is the probability.
- 39:52Or being in the treated group conditional
- 39:56on all relevant baseline covariates.
- 39:59And at here's the.
- 40:00Is the formula there and basically
- 40:03it says that given two subjects with
- 40:06identical values of your propensity score,
- 40:09one from the treated group and
- 40:12one from the control group.
- 40:14If it's the same then analysis may proceed
- 40:17as if the subjects were randomized.
- 40:20And of course the key assumption is that no,
- 40:24there are no observed confounders.
- 40:27There's three types of PS design.
- 40:30She used stratification by PSR
- 40:32subclasses at one to one matching or
- 40:35there's a technique called inverse
- 40:38probability of treatment waiting,
- 40:40but the fondle fundamental considerations
- 40:43of this science is that the outcome days
- 40:48that data is not used in the PS design.
- 40:51So in regulatory studies.
- 40:55So FDA actually uses these two.
- 40:59To make a decision whether to
- 41:02approve surgeries or devices.
- 41:05It must be documented that the PS design.
- 41:09Start decision had no access to the
- 41:13outcome data and therefore the PS
- 41:16design faces a second design phase.
- 41:19Very briefly, this is just a schematic.
- 41:23You perform a observation,
- 41:25ULL study and you have the developed
- 41:29propensity scores using this
- 41:31techniques and then at the end of the
- 41:36day you got PS based matched pairs.
- 41:39So this is nothing new.
- 41:42Independent group has used this to assess
- 41:45CPAP treatment and fasting lipids.
- 41:48For example,
- 41:48and you'll see this is known as the lab plot,
- 41:53and here are the cold marriage
- 41:56and the PS design sample.
- 41:59As you can see,
- 42:01simulates that of us if you've
- 42:04done a randomized control trial.
- 42:07So we believe that the benefits
- 42:10of a PS assign.
- 42:13And obtain valid estimates of causal
- 42:15treatment effects in observation.
- 42:17ULL Data Bay creating covariate
- 42:19balance similar to or even better
- 42:22than under randomization.
- 42:24You can use real world patient data
- 42:27that is often not well represented in
- 42:31those that you choose to be randomized.
- 42:35You can include patients that cannot be
- 42:38otherwise ethically be randomized in RCT's,
- 42:40and you can evaluate benefits of
- 42:43treatment efficiently in larger samples.
- 42:45Because this is a pragmatic
- 42:47trial so you can just, you know,
- 42:50you can easily insert this within
- 42:53the context of clinical practice.
- 42:56And so,
- 42:57while an RCT provides the preferred
- 43:00level of evidence in ideal world,
- 43:03PS designs can achieve the same
- 43:06level of evidence.
- 43:08For treatment effects in the real world.
- 43:12And you know,
- 43:13I,
- 43:14I certainly am not an expert on the
- 43:16propensity score matching at the sign.
- 43:19Greg Maislin in our group is the one that.
- 43:24That that has worked with Donald Rubin,
- 43:27who is the inventor of the
- 43:30propensity score matching,
- 43:31and this this manuscript.
- 43:33He did a good job in explaining this.
- 43:37If you're interested, there's a
- 43:39recently accepted paper in sleep.
- 43:44That was accepted just.
- 43:47Last last week I believe,
- 43:50where he explained in detail more
- 43:54the propensity score matching.
- 43:57So the proposed clinical trial would
- 43:59be a multi center RCT of patients
- 44:02with moderate to severe severe OSA.
- 44:05We believe we can do this with
- 44:08either 10 or 1310 to 13 sites you
- 44:12offer seat up to all patients.
- 44:16The primary would be similar to the
- 44:18same a composet endpoint follow up of.
- 44:21Two to five years.
- 44:24And we believe that we with 11,000 subjects,
- 44:27and that includes additional 10% to
- 44:29maintain power after loss to follow
- 44:32up or trimming of patients in the
- 44:35PS design that you could do this.
- 44:37Now you say, well, that's a lot of subjects.
- 44:41We actually did a.
- 44:42So if you look at the number of subjects.
- 44:47We included this data in in a
- 44:50recent grant that we submitted.
- 44:52The total here is like this is the
- 44:55annual number of subjects in the centers
- 44:58and you have 7 to 6000 potentially.
- 45:04And rollable patients.
- 45:05So we believe that we could
- 45:08we could do this study.
- 45:10It's going to be a heavy lift. We we, we,
- 45:15we we think but but it's worth trying.
- 45:18So to summarize.
- 45:21Get few minutes for questions.
- 45:24Sleep apnea is heterogeneous disease symptom
- 45:28clusters of those with daytime sleepiness,
- 45:32insomnia, and asymptomatic groups.
- 45:34Are consistently shown in community
- 45:38and clinical samples worldwide.
- 45:41It's important because EDS we
- 45:43believe is a marker of cardiovascular
- 45:45risk in in those with OSA,
- 45:48but not in those without always say.
- 45:52And Publix are cities of cardio
- 45:55cardiovascular outcomes in OSA
- 45:57have been negative and inconsistent
- 46:01with the large epidemiological
- 46:03data because of major biases.
- 46:06That's primarily the sample selection bias
- 46:10and bias due to adherence to therapy.
- 46:14In future studies need to include
- 46:17and focus on sleepy subjects.
- 46:20Ethical lamp limitations,
- 46:22including this patients can
- 46:24be overcome with observation.
- 46:26ULL designs using propensity scores an
- 46:29to obtain a robust treatment effect.
- 46:33This designs need to directly
- 46:35ensure balance of covariates related
- 46:38to cardiovascular events,
- 46:40including measures of healthy
- 46:42used userin healthy adhere bias.
- 46:45In patients who are very compliant
- 46:48seat back compared to non users
- 46:50and I'm going to stop there.
- 46:53Thank you.
- 46:55Thank you so much Doctor Magalong,
- 46:58that was really a fantastic talk
- 47:00and I think really help to clarify
- 47:03some of the the residual questions
- 47:06that a lot of us had about how we
- 47:09should be characterizing the benefit.
- 47:12The cardiovascular benefit of CPAP
- 47:14for patients after these these recent
- 47:16trials I want to invite people to
- 47:19unmute themselves and ask questions.
- 47:21I expect there probably are some. Not
- 47:25really, I was going to say I'm not
- 47:27sure I have access to the chat room,
- 47:30but you could just tell us up, Garth. How
- 47:33are you? Thank you so much.
- 47:36That was a really thoughtful presentation.
- 47:38I'm so sorry we can't
- 47:40have you here in person,
- 47:42but we really appreciate you making
- 47:45the time and congratulations on the
- 47:47top Med project and I, you know,
- 47:49I agree with with so much of what
- 47:52you were saying and I think the
- 47:56propensity score matched approach
- 47:57is a great is a great idea and I
- 48:00I think I also want to emphasize.
- 48:03A point that you made which is you know,
- 48:07the trials that have been the three
- 48:10trials that you referenced that
- 48:12would really have been done to date,
- 48:15and I think we're really in the
- 48:18the infancy of doing randomized
- 48:20control trials in our field compared
- 48:22to the size of the trials that
- 48:26typically occur in cardiovascular
- 48:28disease are tiny and with so many
- 48:32pharmacological treatments available.
- 48:34That that actually reflects some of the
- 48:36biologic pathways by which sleep apnea
- 48:39can lead to cardiovascular disease.
- 48:41You really need so those large sample
- 48:43sizes to to demonstrate an additional
- 48:46benefit associated with CPAP therapy.
- 48:48But I think one point I would add
- 48:51is that I think the outcomes may
- 48:54be also different depending on the
- 48:56cardiovascular event that is chosen,
- 48:59and I think save may have pointed
- 49:02to this a little bit.
- 49:04Some of our studies and stroke have
- 49:07suggested this as well that there
- 49:09there may be a more robust affect in
- 49:12stroke for some reason compared to MI,
- 49:15and I think some of the observation.
- 49:18ULL data support that but.
- 49:21Another another approach I think to
- 49:24doing a randomized controlled trial.
- 49:27We've done is is more of a
- 49:30comparative effectiveness approach,
- 49:32and so you're not randomizing a
- 49:34patient that you have diagnosed
- 49:36with sleep apnea and not treated,
- 49:39but but rather randomizing to a diagnosis
- 49:42and treatment intervention strategy,
- 49:44trial versus the usual care approach,
- 49:47and I think that that might help
- 49:49to get through some of the ethical
- 49:52challenges and could be a potentially
- 49:55useful strategy in a very high
- 49:58pretest probability population.
- 50:01Thank you Clark.
- 50:02With it, you know I just didn't have
- 50:04the time to to go into those details,
- 50:07but that was those points.
- 50:09Your point about Cerebro
- 50:11vascular disease versus.
- 50:12You know, ameisen all those
- 50:15those kind of events?
- 50:17Certainly there is data to suggest
- 50:20that you'll have probably a greater
- 50:23effect on cerebral vascular effect
- 50:26events and and and the other issue
- 50:29of doing a comparative effectiveness.
- 50:32I didn't list it here,
- 50:35it was actually in the paper.
- 50:39Potentially you could say,
- 50:41well, let's do an enhance.
- 50:43Add CPAP adherence so that that way you can
- 50:48have a separation between with usage right.
- 50:52We believe that they may.
- 50:54That might actually affect the sample size,
- 50:57and you're going to because
- 50:58it's you're going to.
- 51:00You're probably going to need.
- 51:03A very large sample size,
- 51:04if that's the approach that you're going to.
- 51:08That you are going to take.
- 51:12But but those are very good points.
- 51:19Can I hire
- 51:20lease is high
- 51:21High made Nelson? How are
- 51:23you good? Thanks oh that was
- 51:25a great insightful talk.
- 51:27I'm just going to ask
- 51:29it kind of
- 51:30a different question.
- 51:31We're going to treat all patients with OSA
- 51:34that are sleepy because we have no
- 51:37other better treatment than CPAP.
- 51:40If that's a statement,
- 51:41then who cares about whether
- 51:43CPAP is going to reduce or not
- 51:46reduce cardiovascular events? OK,
- 51:48so the question is the
- 51:50non sleeping group that we
- 51:51don't really have the full
- 51:53confidence that whether they do or
- 51:56they do not have that
- 51:58increase risk. And that's the
- 52:01tough rope to trade with something
- 52:03like super, which lends itself to
- 52:06suboptimal adherence on
- 52:07a long term
- 52:08basis. How we gonna actually.
- 52:11Answered that question.
- 52:14Well, to the point of so the the first
- 52:16point or question is where are you
- 52:19going to treat this patient's anyway?
- 52:21Because they're sleepy is that is that,
- 52:23is that correct? Well, you know,
- 52:26we believe that there is a reason
- 52:29and one of them there are other.
- 52:31You know. There are several reasons,
- 52:33but the major one is that.
- 52:37You know right now I should know.
- 52:42Screening for or identifying.
- 52:46UH, patients, for example,
- 52:48a large scale in primary practice
- 52:51is is not recommended, right?
- 52:54So we believe that showing
- 52:57that sifat indeed impacts.
- 53:00On whether sudrow basket
- 53:03or or cardiovascular event
- 53:05would would sway you know.
- 53:08A people too.
- 53:13To identify more cases of sleep apnea and
- 53:17perhaps towards towards screening, although
- 53:20that's a different entirely different topic.
- 53:24The other thing is, as in other studies.
- 53:29That show that you know physician
- 53:32advocacy of treatment. For example,
- 53:35if if if they know that the treatment
- 53:40makes a difference, they would indeed.
- 53:44Outside of the excessive daytime sleepiness,
- 53:48they would indeed encourage identification of
- 53:51patients as well as US treatment of patients,
- 53:55in that I think that's well known in
- 53:59the in the cardiovascular literature.
- 54:03Your second point is about the non sleepy.
- 54:09Patients out how we're going to,
- 54:11how we're going to treat them. I.
- 54:16It's. I mean, that's as far as there
- 54:21are others who will argue with you.
- 54:23That if they are asymptomatic.
- 54:29Up at the present time,
- 54:31there is no rationale to treat them.
- 54:35I mean, I know,
- 54:37I know that's probably a very controversial
- 54:41statement given some of the guidelines.
- 54:46About at least the data that we have.
- 54:52In the Sleep,
- 54:53Heart tells Saudi and of course
- 54:55that needs to be replicated.
- 54:57It's it's.
- 54:58It's actually only the sleepy
- 55:00group that was that was at risk,
- 55:03or at least that was what
- 55:05was shown by the panel group.
- 55:08Yeah, the problem with the Epworth,
- 55:10which we use all of us use for assessing
- 55:14subjective sleepiness is very,
- 55:15very susceptible to
- 55:17false negative scores.
- 55:18Yeah, I pointed that out.
- 55:20I specifically said that actually
- 55:22that the subtype of sleep apnea is
- 55:26not only does that only include.
- 55:28The The Epworth Sleepiness Scale score.
- 55:31So determining those subtypes is actually
- 55:34there are other questions that were included
- 55:37that although it's it's the F word,
- 55:40was a component of defining the
- 55:42sleepy subtype. But it's it's not.
- 55:45It's not the F word. Alone.
- 55:50That defines the sleepy subtype.
- 55:52At least you know in, in, in,
- 55:55in the papers that we have
- 55:58established what we have popped. It
- 56:00have worked their real world situation.
- 56:03We use Epworth Aurora comperable type
- 56:05of a self administered questionnaire
- 56:07as opposed in
- 56:09a research based type of tools.
- 56:11So identifying those people with or without
- 56:14sleepiness is going to be
- 56:16prone to bias against or in favor of
- 56:20selecting people for
- 56:21treatments. Right after that,
- 56:24and then we actually so Brendan
- 56:28Keenan at Penn actually has created
- 56:32a so based on the on the studies
- 56:36that we publish it is there is a an
- 56:41app Web type app that you could.
- 56:46Plug in the answers to the
- 56:48questions and it will give you.
- 56:51The answer whether that patient
- 56:53belongs to a sleepy subtype,
- 56:55but you know whether that lends itself
- 56:57to the usual busy clinical practice.
- 57:00I I I agree with you. Yes,
- 57:05so why aren't we using objective
- 57:07measures of sleepiness?
- 57:09I mean, there's a big literature showing
- 57:12that subjective measures are terrible.
- 57:14An an an an so that's like, uh,
- 57:18that's that's a real problem and
- 57:20I think the other problem in a
- 57:22lot of these studies is that they
- 57:25are studying patients too late.
- 57:28So in the safe trial,
- 57:30the average patient was over,
- 57:32you know, 61 years old.
- 57:34By then the patient,
- 57:35already his cardiovasc he or
- 57:36her cardiovascular system,
- 57:38is already really abnormal.
- 57:40And for example,
- 57:41in in an art clinic in Canada,
- 57:44our average patient was 48 years old.
- 57:47And and and and and at the age
- 57:50of 48 they had already had
- 57:52symptoms for like 5 to 10 years.
- 57:55They already were very heavy
- 57:58users of health care resource
- 58:00is for five to 10 years,
- 58:01and that's the group that
- 58:03we ought to be studying,
- 58:05not the ones that already
- 58:07have a bunch of diseases.
- 58:10Yeah, that's certainly true.
- 58:12I mean, again, that May contributes
- 58:14to remember these are all
- 58:16secondary prevention trials, right?
- 58:19They had to have.
- 58:22CVD in order to be enrolled in in
- 58:25the in the in the Safe study and
- 58:28the other ones are they had acute
- 58:31coronary syndrome and then the
- 58:33the other study they you have to
- 58:36have a cast proven coronary artery
- 58:38disease and and I agree with that.
- 58:41Perhaps you know the the.
- 58:44Although I think the entry criteria
- 58:46of the age is about is is 18,
- 58:48but you're saying that the.
- 58:50The the the average age is there,
- 58:53they're older, they're older.
- 58:55Yeah, I mean it. It reminds me of
- 58:57the Women's Health Initiative study
- 58:59where the you know they were giving.
- 59:02They were treating women.
- 59:04You know, for menopause like 15 years
- 59:06after their menopause, Ann and Dan.
- 59:09And that's you know. In other words,
- 59:11we're treating patients way too late.
- 59:14We ought to be screening them earlier,
- 59:16and that's where I think the
- 59:19RTC should focus an in fact.
- 59:21There are several studies early,
- 59:23you know years ago that showed
- 59:25that that that the mortality
- 59:26of patients with sleep apnea,
- 59:29the older patients actually don't do so bad.
- 59:31You know it's the younger ones that have
- 59:34that seem to have the higher mortality.
- 59:37Yeah, that's because of this.
- 59:40Basically as survival effect,
- 59:42right? Yeah, yeah. Ulysses
- 59:45I have a question.
- 59:46This is Nancy Rediker High we met. I think
- 59:49that grant reviews.
- 59:50Hi, my question is about the
- 59:52mechanisms of the sleepy patients and
- 59:54CVD. So you've
- 59:56mentioned this study about the
- 59:57looking at genetics and and what
- 59:59could you let? You know there's,
- 01:00:01so there's obviously all different
- 01:00:03kind of genetic pathways,
- 01:00:04but is it
- 01:00:05possible that this is just,
- 01:00:07you know, the sleepy patient,
- 01:00:08it's just it's inflammatory or
- 01:00:10it's some other underlying process.
- 01:00:11It's causing the connections,
- 01:00:12so that's really just an
- 01:00:14epic phenomenon that there's
- 01:00:15inflammation going on anyway,
- 01:00:17or it matches what
- 01:00:18I'm guessing, but
- 01:00:19what? What kind of
- 01:00:20genetic pathways are you looking at?
- 01:00:23Well, that that that Grant is, we don't know.
- 01:00:26Basically, you see that it's it's there,
- 01:00:29but there are possible mechanisms and
- 01:00:31and the number one suspect will be.
- 01:00:34Of course what you mentioned is inflammation,
- 01:00:37right? There is some evidence of
- 01:00:40inflammation activity may cause
- 01:00:42you to be to be to be sleepy.
- 01:00:44Now to the point of.
- 01:00:48The PV, the objective evidence of sleepiness.
- 01:00:54We could potentially add results of,
- 01:00:56although it's not really sleeping
- 01:00:58as its vigilance would.
- 01:01:00That would be easy to incorporate,
- 01:01:02would be psycho motor vigilance
- 01:01:04testing for example.
- 01:01:05That might be.
- 01:01:07That that might be a that might
- 01:01:09provide really confidence on the
- 01:01:12defining the sleepy subtype.
- 01:01:14One Pvt is so easy to do now.
- 01:01:18I mean, we could do
- 01:01:20it on an iPad.
- 01:01:22We don't need a special device.
- 01:01:24Yeah, it feels like something
- 01:01:26that could readily be incorporated
- 01:01:29into clinical encounters.
- 01:01:32It is just going back to the to the
- 01:01:34top match of the the way that would
- 01:01:37that Grant was structured was that.
- 01:01:39We you know, it's basically
- 01:01:41we're going to do a whole genome.
- 01:01:44All all the mix an all the all the
- 01:01:48epigenetic things and see if there are
- 01:01:51any differences in the in the subtypes.
- 01:01:55Of course, when when the data is
- 01:01:58published in publicly available,
- 01:02:00there's a bunch of things that you
- 01:02:03could do with that with that data.
- 01:02:08Thank you so much for the accounts.
- 01:02:10I think as there are a few minutes
- 01:02:12past the hour and people hung around
- 01:02:14because this is such a compelling topic,
- 01:02:17but we should still cut it off here and thank
- 01:02:19you again. Needless yeah.
- 01:02:21Thanks for inviting me,
- 01:02:22I appreciate it. Thank you. Thanks.
- 01:02:26You like Michelle? Take care.