Live from San Francisco. It's the Cube. Covering Oracle OpenWorld 2016. Brought to you by Oracle. Now here's your host, John Furrier and Peter Burris. I'm here in San Francisco for Oracle OpenWorld 2016. This is SiliconANGLE Media's The Cube. The flagship program will go out to the events and instruct the signal from those. I'm John Furrier, my co-host Peter Burris. I've had two great guests here from a century. Pat Sullivan, Global Oracle Technology Lead and Terry Straus, Managing Director, Global Oracle. Practice lead for Accenture. Welcome to the Cube. Thank you. So Terry, tell us the big announcement today. Not off the reservation. It's kind of predicted. You can connect the dots. The business practice of the Oracle Business Group for Accenture. Now taking on infrastructure service. It's a serious validation now because it's kind of the final piece of the puzzle for Oracle. Absolutely. Looking good off the tee so far. Middle of the fairway, as they say. But now people were questioning the infrastructure as a service. And now you think it's ready? Tell us. I think it's ready. Well, we're very excited about Oracle's announcement and particularly about their managed service program at the MSB. What we announced today is that we are the first global systems integrator to be part of that program. And we have also announced that we're adding infrastructure as a service to our Accenture Oracle Business Group. Which is a strategic go to market with Oracle. All about accelerating our clients to the cloud faster at less risk. So it's not new. Take a minute to explain. When was it founded? And what is it in tail specific? What's the charter? It was not new this year. No, it's definitely not new. Take a minute to explain that. Exactly. The Accenture Oracle Business Group was actually launched April of 2015. And it was launched again as a strategic go to market with Oracle. Committed investments and resources all about what our clients wanted. Which was acceleration to the cloud, lower risk, and again, very fast. So that was again 2015 in April. But it was launched with just SaaS and pass. So what we're really happy about is we could extend AOBG, which we affectionately call the Accenture Oracle Business Group. We now can add infrastructure as a service to that offering. And the acceleration with customers. What's the uptake? What's the vibe? Feedback? I'm sure you've beta tested this and got some AB testing going on. You guys are Accenture. I'm sure there's analytics behind it. What's the results of the before the announcement? What made you go here? Well, sure. First off, the Accenture Oracle Business Group has been pretty successful in its inaugural year. So we've added 70 clients across the globe to this new partnership with Oracle. All cloud based, which is great. And so with infrastructure as a service, you bet. We did take a look at it pretty deeply and tested out and we were very impressed with the performance, the price for performance, as well as the speed that it came with. So that we're building into our portfolio now and building some solutions around it. The infrastructure serves. We had a little debate earlier. Juan was just talking about the database, but others like Chuck Hollis was on earlier. Some analysts say, oh, it was a reboot of infrastructure service. Some would say, no, it's in realignment with the bare metal. So there's a lot of moving parts when you start to get into the enterprise. I mean, public cloud is pretty straightforward. You know, rack and stack and some cloud somewhere and just provision stuff. Negative elastic. But in the enterprise, what was the key thing that Oracle had to do to get this milestone completed? Was it the bare metal component? What was specifically about it now that made you guys go, okay, we're ready to bring it to the Accenture fold and take it to market? I think if you look at it, John, just in terms of data, there's Oracle owns more of the world's data running on their databases. And just from that piece alone, the question we were looking at is, did we think Oracle would make their cloud to run their database the best? And they did. So when you look at it from that segment and how their database... You mean their hardware's up to snuff. They had the right stuff. Absolutely. ...before much was good. It took a lot of what they did in Exadata and they're now applying that to their infrastructure and compute cloud. Historically Accenture has gone to a client to help them pick the application and implement it to the application on-premise. So is this, in many respects, about going to the client, helping them pick the application, but then giving them the option of whether or not they want to do it on-premise in the cloud? Is that a big part of it? Frankly, we take a cloud-first mentality to our clients. We feel that going to the cloud provides both the price that they're looking for in many ways, as well as the functionality. And so we go with the cloud-first mentality. Now, many of our clients also... They may not be ready, so we will help them to get to the landing spot that they feel most comfortable with. But we lead with cloud. These are still very, very complex applications when I think a lot of people forget sometimes they associate the cloud with simple. And it's not that we can't make the applications more simple, but really you're still bringing the domain and application expertise to bear whatever the implementation style. Are you also then looking at how clients that have historically been on-premise can start moving their stuff to the clouds with you and modernize along the way? I was going to say the keyword is modernized, as opposed to lift and shift. So as you move to the cloud, what can you do to improve your enterprise? You know, to automate more and actually, like I said, rationalize and modernize your applications as you move them. I think modernize is the right word. So John's been asking, virtually everybody that's come on, a really excellent question. Namely, is Oracle going to take a sweet mentality and close it down, or is Oracle going to take some other type of mentality, APIs, and allow the ecosystem to continue to add value? From Accenture's standpoint, how do you think clients are looking at the modernization problem? Are they moving with new technologies and hoping that it stays available, or a lot of partners can add value to it, or are you seeing them looking to simplify and start to close it down? Well, that's why we launched the business group in the first place. It's because we wanted to give our clients the choice, but most importantly, we knew that we had to help our clients create the industry solutions that they need that's not available from the cloud. So the ability for us to actually purpose-build those and then repeat those across the industry to other-like clients, I think that's the key in terms of the choice that's available and what we can do with it. So you're a risk factor, but also you're also, I used the word major D before we came on, but in reality, they want someone to walk them down the path, if you will, because I think there's still some unknown questions, right? Am I getting that right? I don't want to oversimplify it, but I'm a big enterprise. I don't want to shoot myself in the foot by overplaying my hand or getting ahead of my skis or whatever metaphor we use. I mean, is that consistent with what you're seeing? Absolutely. And I think the part of the service we provide that Accenture could provide is really providing that journey, that roadmap to the cloud. What do you do first? What do you do second? It is complex. You know, and actually, you know, I think as Accenture, we flourish where there's complexity, right? Because we help our clients sort of simplify all that complexity and help them, you know, march forward again in this case to the cloud and do things in the right order in the right way. I want to get your thoughts as Peter made an observation on our opening segment today. You know, the acceleration with cloud native, certainly we had an Asia Pacific panel earlier on and mobile, especially mobile and cloud native, there's really is no complex bare method environment in mostly in China and other areas. But they put the pressure on the speed of the customer themselves, not so much the vendors and the suppliers in the space who may have great technology now. It really comes back down to the customer ability to move culturally and or inertia. Absolutely. Can you add some color around that? It's a little nuanced conversation, but it speaks to kind of the self assessment of the customer CXO or whoever and saying, are we ready? Can you share any insight and color around that dynamic? Laura, is that true? It is true. There's a lot of things that go into it, right? So there's still a lot of requirements that our clients have, whether that be around security or we talk about data sovereignty and things like it. But the adoption piece is big as well. So there's a starting point. What our interest is is working with the clients to figure out where that starting point is. But I think the big thing that we've been doing a lot of is assessing how ready are you to move to the cloud? What do you have today? And is that available in the cloud? Yeah. So you have to answer those questions first before you can have that comfort to start to move. So you had 70 customers. I saw the press release about 70 customers in your overall year. Is that customers overall? Is that Oracle customers? That's Oracle? Those are Oracle customers that are taking advantage of the Accenture Oracle business group. So migrating their legacy applications to one or more of Oracle's cloud applications. How would you put the buckets of distribution of kinds of apps in those 70 customers? Tire kicking, full deployments, rollouts, shift over. Definitely beyond tire kicking. I'd say maybe half our single pillar and the other half are multiple pillar. HCM and ERP, ERP and CX. So multiples and a large number of those also include the past components as well. Fortune 500, 10 billion in size kind of companies. That's our typical target base with Accenture but also I'd say upper, mid to certainly the enterprise level. Absolutely. That's so sizable so we heard earlier that Oracle's got 430,000 clients, 15 million users for at least one of the silos. They have 52,000 Oracle certified, I think. 52,000 Oracle's practitioners and another 20,000 Java practitioners as well. I made Java's? About 20,000. Yeah, pretty much everybody. Hey, I heard JSON and Java's pretty hot, huh? With 70 clients, that can probably, that's pretty close to representing maybe 3 to 6% of the big, big, big Oracle shops out there. That's pretty good. Yeah, we're very pleased. I've been trying to understand the Oracle Partner Network because it's been always a moving train because it's so big and it has a lot of things but one of the things that we've been seeing with the Partner Network is on the global partners you start to see these swim lanes develop within Accenture, Deloitte, your competition. What's the one thing that Accenture does well that's unique now because I'm not trying to pin you against competition but you start to see the huge, it's so much beach head. There's plenty of fruit for everyone out in those trees and there's the cloud land out there so it doesn't seem as competitive as it used to be.  Like, is there a specialism that you guys see develop in Accenture that's unique, that makes you different than everybody else? Absolutely, right? Oh, yeah, I was just saying. Oh, no, we ain't just one. Really, I'm going to give you a list and then I'll probably add to it. Well, Deloitte will say they do this better than you. I'm looking for the one thing that makes you different. Well, I don't know that there's one. There isn't one, but at Accenture, first of all, our client's always first, right? So whatever, what our client values, so client number one, but we lead through our industries, right? So our industry acumen, you know, we believe our clients desperately want from their systems integrator and then we couple it with, I believe, the deepest technology capabilities, in this case, Oracle's cloud and the two combined. Additionally, we have a very large delivery engine, our offshore organization, you know, so that we can, which actually does much of our innovation for us, so that we can take that delivery engine, combine it with the likes of AOBG and our industry skills, and deliver to our clients, again, lower risk and with acceleration and with that automation and innovation that they're looking for. Pat, what did I say? Well, I would kind of summarize a lot of it because our product at Accenture is our people and we take great pride in bringing the best people that we can in this space and we've been doing that pretty well and so as Oracle continues to evolve and move to the cloud, we're bringing the best people or training our people to make sure that we can answer the market. Accenture is very customer-focused, too, I noticed. I would say that you vary customer and you have the biggest parties, that's for sure. All the events I go to, we go to all the events. Accenture has always been the best. You always have the best parties. And that's something you put on the literature, but how would you sum up Oracle Open World so far this year for folks who couldn't make it who are watching the live stream? What's the vibe? What's the big news here? Well, to me, the big news is that they've rounded out their cloud with infrastructure, the service. I couldn't be more excited, not just for my business but for what now we can bring to our clients. And what you can support now, too, the support side. Absolutely right, absolutely. Thanks so much for taking the time to share the announcement news, congratulations and we're looking forward to seeing it at the big Accenture parties maybe later tonight or next event. Absolutely, absolutely. See you at the partner network conference. Thanks for sharing. This is theCUBE here live in San Francisco inside the show floor. Big booth, theCUBE. Oracle Open, we'll be right back.


The Akiti State Governor, Dr. Kaya Defame, has revealed that the nation must take advantage of its cultural diversity to foster unity and economic development. The governor noted that the nation is blessed with vast cultural values and endowment, which he said with innovation could replace dependency on oil and chart a pathway for economic growth and youth empowerment. The report is presented from our studio. The 34th National Festival of Art and Culture is currently holding in Akiti State. Contingents from 36 states of the Federation arrived at the state to showcase the rich cultural values of their different states. This is just as the state governor, Kaya Defame, promised the continuous support for the cultural development of Akiti State and Nigeria at large. Defame declared the event open in Ado, Akiti. He also stressed that the cultural festival will provide them an opportunity to learn and enjoy the rich cultural, hospitality and goodwill this state is endowed with. The body of our national commitment, which has rested solely on the performance of our food oil in the international market, has continued to render the nation immobile. This calls for innovative and creative solutions. Investing in culture is crucial to the general development of any society. Culture impacts on economic growth by strengthening social values, creating trust which facilitates relationship and inspiring motivation that simulates entrepreneurship. The Director General, National Council for Art and Culture and President, World Crafts Council, African Region, Olusiagun Runsewa explained that NAFEST provides a platform for Nigerians from different ethnic backgrounds to showcase their unique cultural manifestation. Nigerian is one entity where unity and nothing can suppress us. NAFEST is a brand that came up after the civil war in 1970. And today, the civil society in Akiti is telling the story of the people united and being together. For me, it's a platform to embrace what unites us, that works for us. NAFEST is a brand that has changed the narrative of this country. Some people have told you some stories about Akiti, about Nassarawa, about Ogbe. But all of them are here. That's to tell the story to the world that this country, we are together. It added that it also brings to fore the rule of culture in national peace and harmony, as well as the vast opportunity in the cultural sector for job creation and economic empowerment. It called on the participants in all the competitive events to go into them, in the spirit of sportsmanship, adding that the essence of the events was to build friendship as brothers of the same nation. Subscribe to the channel and don't forget to hit the notification button so you get notified about fresh news updates.


It's been a week full of headlines in the media industry with AT&T closing its purchase of Time Warner and Comcast topping Walt Disney's bid to acquire entertainment assets from 21st Century Fox, of course the parent company of Fox Business Network. Moody's, though, says Comcast Foxdeal could make Comcast the second most indebted company on the planet that's behind AT&T. We have Melissa Armo of Stockswish.com joining us right now. Good morning, Melissa. Thank you for coming on this morning. Good morning. So we got to talk about the debt load of Comcast potentially could be up to $164 billion. Do you think that's the problem for the company? Well, right now they're trading down. The stock hasn't looked that great considering the way the market rallied in 2017, so sure it could be a problem, but these companies are used to taking on debt. Obviously, they're trying to grow. Maybe they're trying to grow a little bit too fast, too quickly. It remains to be seen. We don't even know if Fox is going to accept their bid or not. I'm sure Disney is going to come back with something. But isn't that almost a change of strategy for Comcast because they're known to be quite conservative just in their finances and now going forward with this amount of debt?  Yes, it has been, but the problem is that everybody is so worried now about competing. These companies are worried that they're not going to be able to compete with Netflix. Everyone's consolidating. I'm not saying that's good. In fact, for the consumer, I think that that's not good. I think it's bad. It's going to mean less companies, less choice, less creativity in the market producing content, but these companies want to control content. They want to produce content. They want to charge for it, and Comcast has kind of just seen the writing on the wall thinking probably feeling that they have to do this in order to grow and expand or survive in the long term. They're not just looking at the next year. They're looking at the next 10 years, next 20 years. Right. So then almost it's inevitable. As a Comcast, if I was running Comcast, I would think, how else am I going to compete with all of the new content that's constantly coming out with Netflix? It makes sense for me to go after Fox's asset. So I feel like you're talking about it's going to cost more for consumers, unfortunately. I agree with that. But isn't that something maybe long term, five, 10 years from now, and possibly the landscape can change from here? Well, the landscape is changing. It's already been changing. I mean, that's why everybody's so afraid of Netflix. People are watching more content streaming, because if you're on your phone and you're walking around during the day, you can watch your phone. When you're watching television, you only have to be sitting in your apartment or in your home to watch TV. Also costs of getting something like Netflix or streaming is either free or cheap, like the Hulu. And that's another big reason why everybody's going after Fox. Whoever ends up buying Fox is going to end up owning 60% of Hulu. That's big time. That's one of the reasons why Disney wanted to buy Fox 2. That's huge. So I don't know what Disney's going to do, but to be a part of Disney, it'll be interesting to see what Fox does and what offer Disney comes back with. Because to be a part of Disney is so much more. So much more than just the television or movie aspect of it. It's at Disney parks. And just very, very quickly, do you think the share price of all these companies, let's say Comcast, they're going to climb up higher? Would you get in? Would you buy? I would not buy Comcast right now. I would not buy AT&T right now. I love Fox. Thank you. Thank you very much, Melissa. I appreciate that. Have a great morning. I answered that sentiment. Yeah. All right. Well, we've still got a lot more coming up. Fox are garing up for a DACA fight as Republicans released their new immigration plan. We're going to break all of it down coming up. And if you've ever had a chance to visit Fox, you can visit Fox. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks. Thanks.


My job, really, is where are all these variants coming from and what's the clinician's attitude or what do we need to interpret them? And I just want to make a couple of disclosures because I'm going to talk about some guidelines for our medical professional group. And also, I've been on the External Advisory Board for the mouse genome informatics database and at the very end, trying to integrate these two, I think, is partly what we need to do. So currently, if we look at clinical utility of precision medicine, whatever we want to call it, I think it's really been in the diagnosis of real rare Mendelian disorders, which is what I deal with, as well as in cancer diagnostics and personalized therapeutics. We're beginning to make some headway and pharmacogenomics, and I think we all hope that eventually we will understand better multifactorial disorders. So for those who are not clinicians, clinical exome sequencing has really revolutionized the way I practice clinical genetics. It has a very high diagnostic yield higher than anything we've ever had in the past. At least in pediatrics, we know it's important to study trios. If we study a child in both parents, the yield is going to be much higher than just studying the child alone, and that's because a lot of the pathogenic variants we're finding turn out to be de novo mutations. What we're here to talk about today is how do we deal with variants of unknown significance, and there's a new class of them that we are dealing with in genomic sequencing, and that's secondary findings, which I want to just spend a couple of minutes on. So actionable secondary findings can be defined as damaging variants in disease genes that are unrelated to the reason that the testing was ordered, for which there is significant morbidity or mortality, and where early diagnosis can ameliorate or prevent the disease. And there's a unique opportunity when one does either exome or genome sequencing to identify these variants, which can have implications for the patient or the family. And so, in 2013, ACMG, as well as the President's Commission on Bioethics, came out with policy statements to search for and report selected of these variants. ACMG came out with a minimum list of 56 actionable genes. Some of the authors of that document are in the room here. They're mostly hereditary cancer genes, Marfan-related syndromes, cardiomyopathies, arrhythmias, familial hypercholesterolemia, and malignant hyperthermia. So high penetrance, and there is something one can do to prevent or ameliorate the disorder. The pathogenic variants, and I'll stress that these should be known pathogenic variants, should be reported regardless of the indication when a clinical exomer genome is analyzed. Some labs do additional genes. The minimal list should be reported regardless of patient age, i.e., those reported in children. And while originally our recommendation was to do this and not have an opt out, that position was updated due to a firestorm, if you want to call that, from everywhere, so that parents and patients can opt out at the time of consent, though, at least in our experience, maybe 5% do. Labs should seek and report only pathogenic or likely pathogenic variants, and this is because there's a very low likelihood of disease. It's different than when someone already has had a cardiac arrhythmia or has a strong family history of sudden death from arrhythmia. When you're looking in healthy people, you need to be sure. Labs are supposed to list the quality of the data. They don't have to cover every exon in every one of the genes listed, but they ought to report what their coverage is. And the clinician, whether it's a geneticist or a family practice doc, it has the responsibility to tell patients about this and to interpret the findings. Our organization, as well as the QuinGen project, are refining and updating this list, and I believe at the present time there is still no consensus about reporting these findings in the research setting. So if we look then at clinical exome sequencing, who are the best candidates? And again, I'm talking from the pediatric standpoint. So when you have a specific phenotype, you ought to order the most specific tests possible. So if a child has an abnormal sweat test, you sequence the cystic fibrosis gene. If you think a child has Noonan syndrome, there's now a very good gene panel that covers all of the known Noonan genes, 85 to 90 percent, and the chance you're going to find another Noonan gene in the next week is very low. They're probably a couple out there, but they're rare and they're not coming along all the time. Whereas when you look at intellectual disability and other similar kinds of conditions, they're new genes all the time. They're probably at least 500, and so exome sequencing, in my opinion, becomes the best way to cover the spectrum. There is a longer turnaround time, and right now, though we're not going to talk about it, there may be lower reimbursement than doing specific panels. Again in pediatrics, we almost always recommend a microarray before doing an exome. Not only will you find copy number variation that may be responsible, but you may uncover consanguinity that you didn't know was there, and that, as we've just heard, can help point you to specific regions where a causative gene may lie. And compared to before exome sequencing, we still do some relatively cheap screening tests, but I certainly move to exome sequencing much quicker than we would have in the past. Oops. Oh, my God. Now what did I do? I think it's important to talk about utility of a genetic diagnosis, and even if it's not going to change management, it can make a dramatic effect on a child and a family's life. First of all, it's going to prevent additional unnecessary testing, and kids and families go through this long odyssey, and both the financial but the emotional impact to have a diagnosis is really important. As we learn more about disorders that may help prevent or recognize future medical complications, it may help predict function as an adult. For sure it's going to provide better guidance concerning recurrence risks, and some insurers are actually beginning to accept this information as a cause for doing the test. Rarely it will prevent, permit specific medical therapies, although we always tell our families this is rare, at least in the pediatric field that I deal with, and they shouldn't get their hopes up. So what's the experience that we've had clinically? We're a large children's hospital, but we don't have a huge genome center, and so this is really a clinical perspective. So at our institution, all exome sequencing must be ordered or approved by a clinical geneticist. We feel that this is a bit of a gatekeeper. A lot of our physicians don't understand all the nuances involved. This can happen in different ways, referrals to genetics, which is the standard way. I've been involved in starting some case conferences with different disciplines, where, particularly with neurology, we've been doing this a year and a half now, they present cases they think are important for exome sequencing. We discuss them, and it's worked incredibly well. We're beginning to understand them, and they're understanding us. We move from is this case good to do an exome to how do I interpret this variant of unknown significance? And I think this is one way where we're talking with them, and we can present our feelings and use some of the basic model organism data to help sort out what might be actually disease causing. And then we are planning, or I am planning, a genomics clinic starting small, and then we hope to expand. So how have we done? Our exomes now go to Baylor, America. We're starting in-house, hopefully by the end of the summer. But through the end of August, on 160 clinical exomes done, we had a 44 percent positive yield, which I think is fantastic. It wavers a little. And it's all across the board, different kinds of disorders. And then we had 2.5 percent or four secondary findings that were positive, BRCA1, MEN2, BRCA2, and a calcium channel gene that we've had to deal with. I've gone through the records and analyzed the first 100 cases. This takes a fair amount of time. But for the positive cases there, 46 percent, with a positive result, had a change in management beyond the reproductive risk. Now most of these were changes in surveillance that you were worried about a disorder. You didn't find it. So you could stop surveillance, or in some cases you had to do surveillance. Three of them were specific for a medication or a diet change, including a patient that had a seizure movement disorder, and based on the gene found they could change to a drug that was actually helping the movement disorder much better. The other thing is that 20 out of the 41 were de novo, which results in a dramatic reduction in recurrence risk. So we just don't know it. We had assumed it was probably 25 percent. And now it's almost certainly less than 1 percent. And that is really important to families. And I think something that we need to push going forward. And there was some novel gene identification, like in many sites. So where do I think clinical sequencing is going? Well, it's rapidly expanding to carrier and population screening. Some of the companies that are now doing carrier screening prior to pregnancy will do panels of known mutations, but a couple hundred bucks more you can do a whole exome. And those need to be interpreted. And as we're moving into population screening, again, we're looking at healthy people, and when we find variants, the bar has to be set fairly high. This whole meeting is moving from gene identification to variant pathogenicity, and there's a need for tools to validate these, particularly the missense variants. And as research is moving to whole genome sequencing and clinical will follow, in one test you'll be able to look for chromosomery arrangements, which I think will be very powerful. But there will also be the complexity of assessing non-coding variants, which right now I don't even want to think of from the clinical side. So ACMG has put out standards and guidelines for a good while now on variant calling from our Laboratory Quality Assurance Committee. And in 2013, there was an update to this to try to assess how to call variants from whole exome and genome sequencing, to try to standardize the process, make it transparent, and to have similar results across labs. The work group consisted of lab directors and some clinicians from our organization, the Association of Molecular Pathology and the College of American Pathology. The classification terminology is complicated like CNVs, there's pathogenic, likely pathogenic, VUS, likely benign and benign, and there's a very complicated scheme of how labs are supposed to grade evidence. And I thought the best way would be to give an example, Howard gave a similar kind of thing. So this was actually a case that we talked about in our neurology conference, and I think one of the lab fellows for the slides. So this was an 18-month-old with severe progressive epilepsy, they did a seizure panel, there were no pathogenic variants, but they had a variant of unknown significance in a potassium channel gene. The gene was known to cause dominant seizure disorders originally benign neonatal seizures you have as a newborn and then they go away, but it's also now been found that it will cause later onset seizures as well. There were three publications with some functional data, and so how do you grade evidence for this? So looking at the population frequency, if you look in the exact and other databases, it looks like it's about 1 in 250, which is much too frequent for a disease that maybe is 1 in 50,000. A case control study, if you look at the bottom there, shows that it is enriched in disease. The variant in this region is highly conserved. And while the functional prediction programs are mostly that it would be deleterious, it's not 100% like that. And then you could look in ClinVar where variants are reported by laboratories with their interpretation. And again, there weren't many here, but one said it was benign, one said it was unknown significance, and one said it was pathogenic, which doesn't really help you very much. So you could plug this into the checklist that ACMG had, and our lab has modified that. Hopefully you can see this, oops, I got to go back one, I think. So there's strong and supporting evidence, and in this case, there was evidence that the allele frequency for the disorder was too high, and also that you saw it in healthy individuals, which would go against this being pathogenic. But you could look on the other side, and there was some established in vitro functional data saying it was damaging, and there was also tracking through families and effecteds that it associated with disease. And what we're looking for here is to look at these in vitro or functional data and how can that help us sort these out, these kinds of things. And so when you get this conflicting data, what the guideline says and what the lab says is, you need to call it a variant of uncertain significance. And I will just say here that I think the lab has to be very conservative, but this is where the clinician's input, I think, is valuable. And so while I wouldn't have been convinced near the beginning of Howard's example, by the end, I would have been willing to say to that family, I think this is involved, and I think that the clinician has to be informed and has a responsibility to take all of the data and put it in context. And so what can model organisms do? They can demonstrate a role for the protein in the biological process. I don't think they can demonstrate pathogenicity, but they certainly can help, which is what we're trying to do here. Hopefully in the future, we can use model organisms to demonstrate gene-gene interactions and eventually to test possible therapies. The model depends on the gene and the phenotype. This is too simplistic, but there are lots of models at the disposal that we have, and I think one of the challenges is understanding the advantages and the limitations of each model and that you're not going to have an autistic mouse, but if you see CNS expression and behavioral abnormalities, that may tell you that this gene or variant may be involved in a human disorder. So to just do a couple of examples, one can use yeast to study conserved metabolic pathways. And so for much of my career in the old days, I studied X-linked mouse models that turned out to be defects in cholesterol synthesis. And this was the major mouse I studied, the bear patches mouse, X-linked male lethal, and I spent years trying to clone this the old-fashioned way with genetic mapping, physical mapping, and eventually we found that it was a disorder of cholesterol synthesis. Now we did one thing smart through all of these years, and that was that there's another mouse model called Tattered, also X-linked male lethal, looked very much like bear patches. We mapped that to a completely different region of the X chromosome. But once we knew bear patches, we looked in that region and were able to find another gene that was the next step in cholesterol synthesis and very rapidly found out that that was the gene for Tattered and a human X-linked male lethal disorder. So I think this is one example where we used yeast way back when and it helped. Certain types of disorders I think are only going to be able to be studied in mammals. You can't study placental disorders in zebrafish. I think also as we get to higher neural function behavior, the mouse and other higher mammals may be very important. And so again, from some of our autism work, we found damaging de novo variants in novel genes in two of our human autism patients that I think are likely pathogenic based on behavioral phenotypes and knockout mice. Now those are total gene knockouts we're in our human patient. It's a de novo heterozygous variant. But again, to look at where it's expressed, when it's expressed in some relation to phenotype to me means it's probably pathogenic. I have not told these two families as yet that this is the likely cause, however I will say that. And finally, I just want to finish. I think that one of the best places to focus who we're going to direct understanding how models help is the clinical molecular geneticist who runs a diagnostic lab. And that slide's gone. But through my work with JAX and then the American College, I was able to facilitate a webinar that the outreach coordinator at JAX did on how to use the mouse genome database and how a clinical lab could try to look at model organism data to inform some of their deliberations about whether a gene or a variant was pathogenic. And I think it's the laboratory directors that need to review all this data and might have the skill and the time, more than the clinician, to try to integrate that into their report. So I'll stop there. Thank you. So while people think about their questions, we'll have five minutes for you and then we'll have an open free for all. I want to come back to the question of who is the interpreter of the laboratory data? Is it the director of the genetics lab or is it the cardiomyopathy expert in cardiomyopathy clinic? It's both. And when we came out with our new standard of practice for our profession, there was some somewhat heated discussion about what is the laboratory director's role in interpretation and what is the clinician's role. So I think the laboratory director is the one who has to go through and decide was the test done right. Is this pathogenic meeting some criteria? But then I think the clinician has to put it in context. If you have a pathogenic variant clearly, but it doesn't fit the clinical disease, that's not the answer to the child or the patient's problem. And so I feel very strongly that we take the report that the laboratory generates to the best of their ability with the clinical information provided. So if the clinician doesn't provide any information or it's just intellectual disability but you don't say they have a mole or two sign or other things, it's hard for the lab to do their job. But then I think the clinician has to take that and put it in context. So you know, you could say I'm hedging, but I think our role is to take what the lab says and interpret it in the context of the patient. So let's hear from the cardiomyopathy expert. Yeah. Sorry, I wasn't really going to talk about cardiomyopathies, but I do think that we have a historical precedence of laboratories that are providing information that inform clinical care, but are being run and organized and data is interpreted by someone who's never seen the patient. And in the imaging field, of which we make extensive use, there's a very common phrase that ends many reports. Clinical correlation is advised. And I think that's a really important thing to put in the context of genetics and genomics. If we knew that A caused B and phenotype would emerge and evolve, we'd be done with this conference and we could move on to therapy. But I think we have to recognize we don't understand that, and so clinical correlation is going to be, in my opinion, where the buck stops because if it doesn't make sense or it might make sense in the future, there can be an advisory, but I would have difficulty in terms of making a diagnosis. I don't think these are diagnostic tests. I think they are informative tests, the same way that an X-ray that shows a mass in the lungs is informative of lung cancer, but not diagnostic of lung cancer. My other question to you would be actually a bit of a surprise. I'm actually in favor of having a bit of a free-for-all of letting people do genetic testing. And I think the reason for that is because clinicians are scared. They don't understand a lot of the nuances. And I think it's a see one, do one, learn one kind of approach. And so I frankly would urge you to take off the buffer of the clinical geneticists. I mean, I think it's an expensive proposition from a healthcare dollar's research utilization, but I think we can make people learn a whole lot rather than sequestering this kind of information into the really subspecialists. So I guess I'll make one comment at that. So the neurologists who've come to our conference, we don't have it over the summer. When they email me a one sentence about why they want to do an exome, it's fine. Now we still have to have a genetic counselor who can sense and all of that, but I think there's some baseline education. And I think the clinicians who really don't know anything about this get scared. But the hope is that if we can interact, get some idea, and they get some idea, yeah. Then I think having them order it. And this is again partly driven by finances, but also really by what's in the best interest and the best test for the patient. So Les, and then I'll. Yeah, listening to this and a number of the other talks, I'm struck by the fact that I think here we're talking about a number of different assertions of truth. And they're qualitatively quite a bit different. And Daniel, I think sort of your nature paper from that workshop started that conversation. These assertions of relationships of causality between disruption of a gene and a phenotype, then assertions of the relationship of a variant to that phenotype. And then as you work toward the clinic, then assertions of the human relationship of a gene to a phenotype and the relationship of a variant in a person to a phenotype. And then finally, the molecular diagnosis of the patient. And all those are different assertions of different kinds of truth. And the nature and the habits of evidence that we have for those are a bit in flux. But we have some, I think, established approaches to these. And it strikes me, I'm glad you brought up, you didn't really use the word, but you started talking about Bayesian inference. And I'm sorry to see you shudder, because I think it relates to what Howard was saying. And I think that we have a well-established tradition, especially in basic science and common disease of setting up large controlled trials with the very frequentist Fisherian approach to analyzing significance. And I think in some ways we have a bit of a tyranny of that mindset in science and medicine today, which is probably why no one raised their hand at your meeting. And I think, though, as we move, what you're actually talking about is taking a mass of evidence and using Bayesian reasoning, prior probabilities and conditional probabilities, and using that to come to an assertion or in the final decision, a diagnosis about a patient. And I think what we have to do is begin to convince our colleagues when it is appropriate to stick with Fisherian, and when we have to start thinking in a Bayesian way. And that affects a lot, I think, about how we treat functional data. Because functional data are somewhat challenging to introduce into Bayesian modes of reasoning and decision making. But I think we will have to begin to do it, because some of the data Howard and others have presented really are conditional probabilities that modify the posterior that that is the cause of the patient's disease. And we have to be very careful to separate, and I'm glad, was it, who of you, so you both I think were saying you were arguing about the separation of the assertion of pathogenicity of the variant from the diagnosis of the patient. And the former goes on in the laboratory, the latter goes on in the clinic. And we really, if we muddle those, it'll be a bad mess. No, I would agree. I just, I can't do a chi-square, and so when we get to math, it really, that's why I started mapping in the mouse years ago, because you just did a cross and counted up recombinance in the old days. But no, I think how do you weight some evidence against other evidence? And I think we will have to come to that, hopefully again in some way that I can just look at it or plug it in. But I think right now it's trying to get evidence and what are the types of evidence and then it will be how to weight it. So no, I agree. So I was actually going to extend a little bit on less is common, because I think you're absolutely right, this distinction is very important. But one of the areas where it's blurred is actually in therapeutic trials. So we have lots of therapeutic trials where we are actually supplying the post-hoc condition. And we ignore causality. There are lots of situations where this sort of limited set of preconditioning sets plus one biomarker led to a therapeutic outcome that looked beneficial, therefore for time memorial thereafter, we will use that biomarker as a surrogate and go on and treat it. And this is natural history of how therapies are introduced in medicine. I think one of the things that may be extending a little bit on that and on Gail's talk is if we move beyond diagnosis to therapy more quickly, then I believe we'll actually close the gap much more rapidly. I think one of the things that we have focused on as geneticists is diagnosis and making most patients don't care if they have LQT 10 or 13 or 19. In fact, antibodies probably go LQT more than seven as being mislabeled. What they really want is something that will actually make them live longer or feel better. And so either we supply the conditions and do the tests or else we continue this sort of introspection until we have the perfect solution, which as you point out, I don't think will ever come. I would consider that was a comment not necessarily requiring a response. And I'll move on to Elizabeth and then Bruce and then we'll let you sit down. I think it's on the same vein. So one of the things that you had mentioned was that there were a number of cases where you found novel genes which were you diagnosed the patients with deleterious variants and novel genes. And in one of the examples, it looked like it was a animal model that had been used to make that leap. So I was curious what the other cases were. But this discussion is why I was curious because I think we have examples of where we're using lots of disparate data and we're making that leap into something that couldn't be diagnosed. We've got some sort of analytics. We make a diagnosis and I was just curious what those other cases were. But mainly to highlight the ability that we're already doing this, we just need to do it faster, better and more automated. Was that in the autism example, I guess? It was in your 41 whole genomes that you had done through Baylor. You said three of them were novel gene. Oh, OK. So that was Baylor coordinated. And in all of those cases, they waited until they found at least a second unrelated case before calling it. And so I can't say because they weren't my cases, but I know at least a couple of them. It was read out as negative. And then three, six months later, you get the call that, hey, we found another case. We think this is it. And by the way, can we write it up? So again, a clinical lab often, I can't say everyone, if you have a damaging variant in a novel gene and you think it might fit until you find the second case, they're not going to call it out on a clinical report. That's why we need to do this. We have the compute to do that now. I think another way to frame the point Les was making that doesn't require the use of mathematics is to remember that medicine, the practice of medicine is fundamentally dealing with ambiguity. Most of what we do, there aren't simple black and white guaranteed to be correct answers. So we're always integrating information, taking into account history, lab findings, and so on, to make clinical decisions. So we shouldn't actually really be that uncomfortable with the idea that we're faced with variants of unknown significance. It's what we do as clinicians all the time. However, what made me uncomfortable putting the data that Howard had talked about in the medical record was two things. One, that's probably the best way to bury the information. But actually on the other side, there is a danger that it will look more solid than it really is. And although you could put all the caveats you like and you can have the lab director be the sort of interpreter and put cautions up and down, there's a real likelihood that somebody somewhere won't read them or won't understand them and will misinterpret them. And I've certainly seen that, signing out lab reports and also seeing patients that were first seen by other clinicians who were the recipient of the lab report, then they find their way to me and you're kind of aghast that they misinterpreted what was in clear black and white. So I think that the problem here isn't dealing with ambiguity. It's figuring out ways to make it clear that many of these results, in fact, are ambiguous. And how do you put that into a context where the potential for misuse is minimized? Do you want to have a, you can gavel the last word for that. I never disagree with Bruce. Okay. No, I think he's right. Howard wants to follow up for that discussion. Yeah, so. You get to step. Yeah, no, you're safe, yeah. So Bruce, just as a follow up, so I agree with you. So I think part of the discussion here is, is that, so how do we move to that level of confidence, right? So I think that is the crux of the matter, is that what is the level of evidence for which we would be willing to, I'll say, take the risk to make something that's definitive? I'm not sure I know the answer to that, but what went through my mind as I was listening to your presentation was that the piece that was missing was, so what difference does this make? What am I going to do with it? And to me, that would make a big difference. Just cementing it in the medical record so it's on the problem list is not a terribly useful thing, I don't believe. So would I talk to the family based on the evidence you presented? I think I would, and I would try to give them a balanced understanding as best I knew about what this is. But until this becomes a finding that's been verified in lots of cases, which may never happen for many of the things we're talking about, I'm not sure I would say this is black and white end of discussion, this is what it is, but I think a lot depends on what they want to do with the information. If it's to offer testing to other people so they can have surveillance, I think there's a valid use and with the caveat that there are pitfalls, why not? Would you use it for prenatal diagnosis? The answer probably depends a lot on what the phenotype is and what the impact of all this is. So I think putting it into as a question in total isolation of the clinical usefulness of this makes it a very abstract conversation. When you put it into a clinical context, I don't think there's a black and white answer. My answer is I would talk to the family, tell them what I know and what I don't know, and engage in shared decision making.


Good morning Mr. President, how are you? Good to see you. How are you? Good to see you. Yes. Good to see you. Good to see you, too. Good to see you. Good to see you. Why do you re-anything? It's the first time I'm seeing you. I can't believe it. It's all right. Anyway, as far as you're coming, I was on the floor on the horse. It's a relaxation anyway. It's a little bit of staying here in the sun. They have been in our area since past Asian. You didn't invite me to play squash. You need an invitation to come talk to me. No, no, no. We're shy. No, invitation. If you aren't available, I'll go to... You know what they didn't do. General Vessi was just there. Pardon? General Vessi came. Come on, T.T. You sure? Don't move, fellas. Don't move, fellas. Don't move, please. In Riyadh, King Fahad used the claims he's lost three kilos from using the Searle's new product. They have been honored today to welcome and confer with King Hussein and President Mubarak. Their visit highlights the friendship between the United States and the two important countries they lead. Our countries share common interests in developing practical solutions to the problems of the Middle East. The goodwill and trust between us promise a solid foundation for overcoming the formidable obstacles to peace and progress in the region. Our discussions today have reaffirmed that Egypt and Jordan will remain leaders in efforts to bring peace and security to the Middle East. King Hussein and President Mubarak have demonstrated foresight, realism, and resolve which are essential if the peace process is to succeed. We discussed in detail opportunities for progress in the Middle East. Recent events in the area make it even more urgent to keep the broader peace process moving. The tragic events in Lebanon show that the occupation of territory by outside forces does not lead to peace, but rather to continued conflict and turmoil. I wish today, therefore, to reaffirm my commitment and that of our government to the principles I set forth in September of 1982 and in particular to the principle that the Arab-Israeli conflict must be resolved through negotiations involving an exchange of territory for peace. The Egyptian-Israeli Treaty proves what can be accomplished when states have the will to take risks for peace, and I am confident that further steps toward peace in the Middle East are possible. For our part, the United States is ready to do all it can to keep the process moving forward. King Hussein, President Mubarak, the men I deeply admire, and I'm grateful to them for having come here to speak as friends and to reconfirm our common purposes in the enduring struggle for peace. Mr. President, my good brother and all-time friend, President Mubarak, I'd like to thank you, sir, for your great kindness enabling me and my brother, President Mubarak, to meet with you today and to discuss all aspects of the problems which we face in our area of the world and our common goals and objectives for a better future, for all in that area, for the establishment of a just and comprehensive peace, for better stability, and for a better life for generations to come. I'm very grateful for the opportunity to have had this chance to hear your views, sir, and the views of President Mubarak on all matters and to contribute what I could for the purpose of achieving better understanding of our respective positions as we move ahead with hope and determination and with a commitment to do our utmost for a better future in the area from which we come and for a just and comprehensive peace. I will carry back with me the impressions I gained of your determination and that of the United States to contribute its full share to help all concerned achieve their objectives. We are proud of our friendship. It is of long standing. We are hopeful that this friendship will develop and evolve and that based on trust and confidence and with determination we shall overcome what appeared and have appeared to be for a long period of time insurmountable obstacles. After all, the cause we are striving to serve is the cause of people, their future, their rights, a human dignity and at the same time their freedom and a better life, which is their right. I thank you once again, sir, for many kindnesses and I thank you, my brother, for your continued success and I would like to say that this has been a visit I shall always remember. I will treasure the memories of this visit and the wonderful opportunity it has given me to meet with you both. Thank you very, very much indeed for the many kindnesses and the warmth of your work. Thank you. I was very pleased to meet once again with our good friend President Reagan and discuss with him issues of great concern to our nations. We did so in the spirit of friendship and cooperation that dominates the relationship between Egypt and the United States. I find it most rewarding to consult regularly with President Reagan and exchange views with him on matters of mutual interest. He is a statesman of great courage and wisdom. He has a profound sense of mission and responsibility. Our bilateral relations constitute a shining model for understanding and the cooperation among nations. We are determined to strengthen the bonds of friendship that link our peoples. The talks we held today will certainly add to this ever-growing friendship and mutual understanding. I would like to seize this opportunity to thank the American people for cooperating with us in the vigorous efforts we are exerting to improve the quality of life for our masses. We are striving to reform our economic system and increase production and productivity. We are struggling to restore security and stability to the Middle East and Africa. Egypt has a pivotal role to play and a mission to fulfill. It is determined to do so with vigorous and determined dedication. We are devoted to strengthen the structure of peace in our region and throughout the world. The situation in Lebanon today is intolerable. The escalation of violence and the bloodshed is a threat to us all. Every nation is called upon to help. The peacekeeping role of the UN must be expanded and reinforced. The partition of this war-torn country should be prevented at any cost. The Lebanese people have a right to live and prosper like all other nations. The key to a viable solution is the prompt and unconditional withdrawal of Israeli forces. The Israeli invasion is the root and the cause of the present sad situation in the area. No problem can be solved through foreign intervention and the use of force. The Lebanese crisis is a stark reminder of the centrality of the Palestinian problem. That question must be addressed frontly and without delay. Our purpose is to create the necessary conditions for coexistence and the mutual recognition between the Palestinians and the Israelis. This coexistence must be based on justice and the recognition of rights. First and foremost, right of the Palestinian people to self-determination should be honored and exercised. This is the clue to peace and security for all nations, including Israel. Palestinian people are entitled to your support and understanding. There is no substitute for a direct dialogue with them through their chosen representative, the PLO. Such dialogue will immensely serve the cause of peace to which we are both committed. Mr. Arafat is a responsible leader who has demonstrated tremendous courage under the most difficult circumstances. A dialogue with him would reassure the Palestinian people and rekindle their hope for a better future. No other nation can speak for the Palestinians. No other entity has demanded to lay on their requirements for peace. Lay out their requirements for peace. And no other nation is more qualified than the American people to lend them their support and backing. War between Iran and Iraq is another sad chapter in the history of the Middle East. We should spare no effort to bring it to an end immediately. No one can possibly benefit from the continuation of bloodshed between peoples who are linked together through the strongest cultural and spiritual bonds. To restore peace between these neighbors, certain concrete steps should be taken by those who are genuinely concerned. The mere expression of goodwill is no help in the face of continued fighting and escalated tension. I came here also to plead the case for Africa. The African people need your attention and understanding. They are struggling against formidable odds. Economic crises and natural disasters are strengthening their efforts for development and social transformation. Helping them is not only a moral obligation. It is a practical necessity for building a better world in which all nations live in peace and cooperate for their common good. We are seeking your help in order to secure the unconditional independence of Namibia. The continuation of the present situation is unacceptable to all African nations. The minority regime of South Africa must know that the United States cannot support its policy of aggression and violation of human rights. It was a happy coincidence that I met here with His Majesty King of Hussain and pursued with him our ongoing consultation. We believe that Jordan has an important role to play in solidifying the structure of peace. It is an element of stability and security in the Middle East. Therefore, we support the dialogue between Jordan and the PLO. This is a positive step towards peace. A month ahead, we will be intensifying our contents with our partners in the peace process with a view of accelerating progress. I have extended an invitation to President Reagan to visit Egypt at the earliest possible date. This will give our people an opportunity to demonstrate the depth of their sentiments towards the President and every American. Thank you.