And a presidential candidate of the all-progressive Congress, as Shuwa Jopola Ahmed Tunibu, has promised to serve Nigeria tirelessly, faithfully and honestly, if he clinches office in the February 25 election. And while promising security agencies and personnel that they will be properly trained, compensated and managed, he called on the youth to vote him into office, saying they would not regret it. Tunibu said he purposefully surrounded himself with brilliant youth because he believed in a democracy of ideas, teamwork and collaboration. Hello, hope you enjoyed the news. Please do subscribe to our YouTube channel and don't forget to hit the notification button so you get notified about fresh news updates.


Over the last 30 years. Over the last 30 years? In the last 30 years. Over the last 30 years. A lot of the approach we've taken as economists and statisticians to measuring poverty has kind of missed or put little weight on what's happening to the poorest of the poor. We're seeing dramatic reduction in poverty globally in the incidence of poverty and the numbers of poor. And this is fantastic. It's accelerated since the new millennium. But what we're not seeing is a lifting of the floor. In other words, the poorest are being left behind. We're seeing fewer people living near the floor. The floor, the lowest level of living in society, but people are still living at that level. If you go back to the mid-19th century, you found poverty levels in today's rich world, including in Finland today, which was similar to say Africa today. It was just as poor as Africa is today. It's the best of our knowledge. But the process of escaping poverty in today's rich world was quite different to what we're seeing in the developing world. And this is one of the important differences. The pace of reducing numbers of poor was actually slower in the rich world that we're seeing in the developing world. The developing world is accelerating in terms of numbers of poor is falling rapidly. But a big difference is in the today's rich world that we're more successful at raising the floor through social policies in particular. The developing world has still got a big challenge going forward in developing social policies that are fully inclusive, including reaching the poorest. Poverty is not just about nicely targeted cash transfer programs. They can be an important part of the story, but there's a broad set of policies. China, for example, has made enormous progress in reducing poverty. In human history, we've not seen anything comparable. But China didn't just do it through targeted cash transfers. In fact, they've played very little role. It did it through a broad sweep of economy-wide reforms, openness in the economy, policies that encouraged investment, policies that made markets work better, including for poor people. That's crucial, giving them better access to land, credit, making the labour markets more efficient from the point of view of access to jobs for poor people. These things are crucial. Social protection and transfers are definitely part of the story. Don't ever neglect that, but there are many parts of the story. And better understanding of all of those dimensions of policy must be the highest priority. Over the next 30 years. Over the next 30 years. Over the next 80 years. Over the next 30 years, a big challenge for the developing world is going to assure that the state has the capacity to fight poverty. The ability to implement effective policies is a huge constraint on effective anti-poverty policies. One of the cruel ironies of fighting poverty is harder to do it in poor places. That's why they're poor. It's both capabilities of administrations and it's political will. But it's both of these things. Political will in the absence of state capacity is symbolic interventionism. You need that state capacity and that's the thing that's lacking the most across the developing world today.


Hi, this is Dr. Dine. I have a problem out of Chapter 10 on Kaya Square. This problem is a goodness of fit test and we know that because we're asked to test the claim of this social service organization that the distribution of educational attainment of mothers is uniformly distributed. So we need to test to see if the distribution of the data that we get matches that uniform distribution. And our alpha, our significance level is .05. They first want us to state the null and the alternative and in the Kaya Square goodness of fit, the claim is that the distribution is uniform and that is the null. The null is always that the distribution observed does meet the expected distribution. So the alternative is the complement which is that it's not uniform. And again the null is the claim. We need to find the Kaya Square critical value, the rejection region. We need to find the test statistic, the standardized test statistic if you will, and then make a decision. So we're going to do that using stat crunch. Remember if you're in my stat lab you can click on the little rectangle there and open up this data directly in stat crunch and I'm going to do that now. Okay I have stat crunch open and we have the data, the response categories, there's three of them, and then the frequencies in each of those categories. So we're going to get the critical value first and we do that by going to stat calculators Chi Square and it brings up the calculator. We need to enter the degrees of freedom and that's just a number of categories minus one. So we've got three K is equal to three so three minus one would be two. We need to enter our alpha which is point zero five and remember for our goodness of fit test the distribution we're interested is always a right tail so we make it point to the right and there's our rejection region beyond five point nine nine one which I think is the answer they wanted. So that's the first part. Then we're going to do the Chi Square test itself. As usual we go back to stat. Now we look down and if you look down toward the bottom you'll see there is a goodness of fit test there and we want the Chi Square test and it brings up this dialog box and we need to get the observed data. Now I'm going to click on that and that's our frequency column. The expected we don't have a column with the expected frequencies but we know that all cells are equal proportion which is a uniform distribution and I'm going to go ahead and get the expected values because I think they're always interested and we just click compute and we get our results here. We get our standardized test statistic of five point six seven eight. We got a p-value of point oh five eight which is greater than our significance level point oh five so that would tell us to re excuse me fail to reject the null and we get our expected distribution which is uniform which is what we wanted. So that tells us what we need. Now if we look over here with our critical area critical value in rejection region five point nine nine is the start of that. The five point six eight is close but it's not quite in there. It's just outside of the rejection region which matches with our p-value which is just over point oh five. So if we go back into the problem we see that we got the answers correctly five point nine nine one for the critical value. The rejection region is to the right of that critical value. The standardized test statistic is five point six eight eight and then we need to make a decision which was fail to reject and we always need to include the significance level. In this case it's at the five percent significance level. There's not enough evidence to reject the claim. Remember the null was the claim. So you need to remember that when you look at your conclusion. So there's not enough evidence to reject the claim that the distribution of educational attainment responses is uniform. So I hope this helps.


The paper reviews the mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discusses how impairments in these mechanisms can contribute to muscle atrophy. It also highlights the importance of understanding how protein synthesis and degradation are co-ordinately regulated by signalling pathways influenced by mechanical stress, physical activity, and nutrient availability for the prevention and treatment of muscle atrophy in various diseases. This article was authored by Paulo Bonoldo and Marcos André.


Having a balance between analytical skills and creative skills is really important because I see these as being like different muscle sets inside the brain. And if you want to avoid fatigue, then what you need to do is switch from one to another. If you try and do one for too long, it becomes hard to sustain a high level of creativity for a long period of time, and then it becomes hard to sustain a high level of analytical quantitative thinking for a long period of time. So by mixing the two, by jumping from one to the other, it's easier for our brains to remain fresh. What I try and do in class is to get them to associate ideas that they wouldn't normally associate. And some of that, again, is going to feel silly, it's going to feel weird, and that's great. You want them to be confident enough in their approach to innovation that they're not afraid to throw out an idea that seems really off the wall. But the way that you get them there to start with is by encouraging them, helping them to associate things that have never been associated before. The other thing that I like even more is to have them in groups interview each other and really take the time to get beyond what's your name, where you're from, what's your favorite sports team, but really get into some things that are personal about each one of them, some things that they really care about, because everybody really cares about something. And if you can talk with someone long enough, you can start to identify what those things are. And when you get to that point and you understand what is special about each one of these people, then you can take those things that are special and start talking about how you might combine two of them. So the example I always come back to that I just love is the student who really liked camping and the other student who really liked Japanese food. And they came up with an idea of bento boxes for camping that would be a way to sort of have everything prepackaged for a camping excursion and it could just grab and go. I love that idea. And the way that they got there was combining two things that have nothing to do with one another. But there were two things that two people really cared about. In order to do this, they need to have skills around questioning. They need to be able to understand not just how to interview, but how to think about questions that are going to take someone away from what they might just assume, whatever the status quo in their lives is, whatever social norms we might set up about, what an appropriate conversation to have between two people who don't know each other that well would be. And then we've also got to encourage them to network with people that are not the same as them. You don't get any benefit from networking as an innovator if you're networking with people who are just like you. You know, I really try and push students to expose themselves to a diverse group of other people. And if there's a type of person that you don't know, if there's a type of person who has a set of beliefs that you don't subscribe to, it can be really helpful for you to get to know those kinds of people. And it also helps them to start to experiment with lots of different ideas that are unusual to them or hobbies that they maybe didn't grow up with to ideally travel to other places where they put themselves in a radically different kind of environment where they see people solving problems in different ways from the ways that they're used to solving those same problems. When they do that, they can then harvest those ideas that they have been exposed to and combine them with things that they already know and come up with something new. And so that's where we're really trying to get them. So they're asking questions, they're networking, they're experimenting, and then they're combining these things together.


Storytelling. Research results. You already know how effective and attractive storytelling is as a method. Unfortunately, the research conducted this year in seven European countries revealed that one-third of teachers, trainers, and educators didn't know what storytelling was. Knowledge of digital storytelling was even worse. Two-third admitted they had never even heard of digital storytelling. As you can see for now, storytelling isn't popular in Europe, but the majority of the study sample expressed their high interest in this method. More than 90% wants to learn how to use digital storytelling. This means that there is a great demand for training in this area.


Hey guys, Mark Bridge here just with a few of the comments that you've put on social media So I'll read them out and give a quick answer just to give you my thank you Maurice Storm So many memories. I remember how approachable and friendly a person mark is Must have caught me on a good day, Maurice Enjoyed our chats and we'll miss seeing him at the games all the best for Mark and his family for the future Thank you very much, Maurice. I'm terrible with names. I guarantee I know who you are if I speak to you So I'm sorry if I pull that weird face there Natalie Calder Thank you for giving us the highest of highs with the ACL Thank you for being red and black We will miss you, but wish you all the best The originals will always have a special place in our hearts Thank you very much for that Natalie. I mean referring to the originals. It's very good to see the club getting people like Dean Heffernan and Michael Beach and back involved coaching a W League team So that's a big thing. So let's try and get out there to support these guys as well Jason Sanderson Thanks for the memories mark and for being part of the Wanderers family Congratulations on your 250th game last week and good luck in the future always red and black Thanks very much Jason that 250 games. Thank you very much as well. I mean especially actually while I'm here Thank you for everyone for the The kind words for the 250 games last week even the the Central Coast Fans and the stretcher bearers. It's the first time you've actually been nice to me. We're not been up there Usually it's abuse. So thank you for those kind words Shannen King when Topper introduced him to the dignitaries in the ACL final as fat head First goal first hat trick absolute club legend will miss your bridgey Yeah, Nikolai Top of Stanley to everyone it doesn't know that story before the I think every finals game of the ACL The dignitaries and like the the Royals and that come out to shake hands and the captains introduce each player To the dignitary thing was King in Saudi Arabia and Nikolai Being the joker he is thought it was funny to introduce me as Sir fat head. So I don't think the King had any idea what was going on and just nodded But yeah, it was hard for me to keep a straight face. So cheers Shannon and cheers Nikolai because I keep hearing that So, yeah, they're all the comments guys. I heard there was tens of thousands more So thank you for those kind words and it's something that I'll cherish


And the Katana state government says, contrary to certain reports by some sections of the media, the bond between the governor of the state Nasser Arafai and the parents of the abducted students of the federal college of forestry mechanization and other citizens in captivity is a deep empathy. In a statement on Friday, the commissioner for internal security and home affairs, Samuel Irwin, said the governor will continue to work hard until banditry is contained without succumbing to emotional blackmail citing an instance that one noted that some sections of the media have been reporting the parents responses to the purported threats by the governor to prosecute them, which according to him is simply false and deeply mischievous. According to the commissioner, the statement of the governor warning importers who have been presenting themselves as government appointed emissaries to negotiate with the bandits across the state has nothing to do with the parents or relatives of the abducted students or any person in captivity. He said the state government will not join issues with the parents whose pain is understandable and with whom the Katana state government shares the common goal of the return of the abducted students.


As Pikeville and Pike County ramp up for trick-or-treating this Thursday, Pike County health director Tammy Riley spoke with Mountaintop about some simple safety tips that you should take before going out this year. So inspect all candy when you get home. So have a nice meal or some warm food for the child before going out and that does help eliminate the temptation of snacking or nibbling on the treats before they can be inspected. And very important are choking hazards for the very young children, so ensure that you remove like hard candies, gums, small toys and treats that are placed in the Halloween bags for the very young children. So you want to be careful with that and throw anything away that would be a choking hazard. Other safety tips include checking the visibility of your child's costume and testing the effects of makeup before full application. Doctors can also check costumes for vision obstructions and confirm that costumes are flame resistant. And then just your overall COVID recommendations, as again that we've been recommending for about 18 months now is just good hand hygiene, practice good social distancing, cover coughs and sneezes, but particularly for the unvaccinated in congested indoor settings, it's highly recommended that they continue to wear a mask. And even for those that are vaccinated in communities with high levels of transmission, which were still in that in that area, unfortunately, even for those at high risk indoors should likely should wear their mask. Here at Pikeville Medical Center's Heart and Vascular Institute, we have assembled a comprehensive team of cardiac specialists bringing expertise from all regions of the nation and the world. We have coupled that with cutting edge technology, providing them the best equipment and operating rooms available. The result is comprehensive cardiac care for the people of our region that is second to none. The Heart and Vascular Institute at Pikeville Medical Center. The Pike County Health Department also recommends individuals at high risk in congested areas to wear masks and avoid poorly ventilated areas. Probably the most important public health recommendation of all is to protect those around you, especially these younger children who to date cannot vaccinate.  It is still our number one defense against COVID-19. Trick-or-treat times in Pike County and Pikeville are from 6 to 8 p.m. October 28th. If you have questions regarding Halloween safety, you can visit fda.gov keyword Halloween safety tips. For Mountain Top News, I'm Joel Korgel.


The next item of business is a member's business debate on motion 15226, in the mead of Alexander Stewart, on world hearing day and hearing awareness week 2019. This debate will be concluded without any questions being put. Can I ask those members who wish to speak in the debate to please press their request to speak buttons now? Just before I call Mr Stewart, can I say that we have signers here so that we can speak clearly and more slowly in your contribution, that would be very helpful, and no Mr Stewart will set the bar high. I call Alexander Stewart to open the debate, Mr Stewart, please. Thank you, Deputy Presiding Officer. I am delighted and grateful of the privilege of being able to open this member's debate on world hearing day and hearing loss awareness week. I would like to extend a welcome to guests who are joining us this afternoon in the gallery. For me, this member's business motion and subsequent debate are something of a double-edged sword, as they create awareness of two separate events, but with one single thread, hearing awareness. Firstly, world hearing day takes place on 3 March each year in order to raise awareness of how to prevent deafness and hearing loss, as well as the promotion of ear and hearing across the world. Indeed, this year, the World Health Organization plans to draw attention to the importance of early identification and intervention for hearing loss. Many people live with unidentified hearing loss, often failing to realise that they are missing out on certain sounds and certain words. Mili-checking once hearing regularly will be the first step to addressing some of those issues. Secondly, hearing awareness week, which runs from 3 March to 9 March, has been fully adopted here in Scotland. It provides an opportunity to reflect on our collective actions, practices and environments that support good hearing experiences. Poor acoustics can often be a significant cause of discomfort, distress and exclusion. Individuals with conditions such as tinnitus and sensitive hearing are at a real disadvantage when it comes to employment and enjoying a normal lifestyle. Therefore, it is only right that we work to create much more awareness of how well and at what degree that someone can actually hear. With some 11 million people in the United Kingdom with hearing loss, for them attending meetings, events and trips to the cinema and concerts can be a terribly stressful and frustrating experience. Common issues of poor acoustics, for example, or maybe a presenter who script is hard to understand, plus even background noise can all act as barriers to participation. Also, other people's reaction to someone with hearing loss can be a source of stress, as many people react inappropriately to those who are unable to hear, and they are impatient with them. I recently received an invitation from a highly innovative company called Ideas for Ears, which is based in my region in Dumblane. Headed up by director Sally Shaw, who is in the gallery today, the company launched the UK's first hearing access protocol last year at GoLive at the Green in Glasgow. As an MSP, I was delighted to attend that event, and I found it extremely motivating and interesting. The initiatives that they have identified have a number of protocols. Meetings and events should be accessible for everybody, no matter what their hearing is. With some basic principles, hearing access is influenced by the venue, the facilities or the equipment that is made available and the way that a meeting is run and structured. Poor hearing access can be difficult or impossible for the individual to overcome through their own actions and deeds alone. Therefore, the hearing access protocol is designed to enable organisers of work-related meetings and events to arrange their own organisational policies and procedures around access and inclusion in a way that recognises our language and communication as a fundamental human right. It sets out objectives in a clear, practical way, covering everything from speaking clearly and facing the audience to interpreting loops and having support from BSL sign language interpreters. That is especially important at public consultation and community engagement events. Those have been welcomed by Health and Social Care Alliance Scotland, Disability Equality Scotland as well as Deaf Scotland. They recognise the importance of the protocol not only as an essential framework but also as a way in which we may contribute, collaborate and ensure that we can communicate to our full potential. Deputy Presiding Officer, I echo ideas for Ian's hopes that the protocol will be adopted right across Scotland and the United Kingdom as a good and proper practice for all meetings and events that will bring about substantial change for those millions of individuals who have hearing loss. There is a massive variation in the way in which people are able to hear and that very much needs to be recognised and responded to. I commend and congratulate all who are playing their part to assist and support individuals and groups as they move forward with hearing loss. I would also like to pay tribute to the cross-party group in this Parliament for the work that they have undertaken and wish them continued success with their endeavours to assist people who suffer from deafness and hearing loss. If you are hard of hearing or deaf then we all have a duty to ensure that we can do all that we can to ensure that the opportunities are there to participate. I look forward to hearing and hearing those protocols being developed and I would be delighted and I am delighted that I have had the opportunity this afternoon to throw my weight behind many of those fantastic initiatives. People in Scotland only have to attend a GP or private hearing advisor to find out what their hearing situation is like and have it checked. We already know that hearing loss in the working age individuals can contribute to the feelings of isolation, alongside communication difficulties, which in turn mean that employees do not fulfil their full potential. Employers are urged to introduce employees to practices and procedures that will ensure that individuals with hearing loss are supported. All staff, especially if they work with colleagues who have already suffered a loss of hearing or deafness, are encouraged to attend the awareness training courses that are put on. In conclusion, I look forward to hearing from the minister what the Scottish Government will do to play its part in the process and what initiatives it will bring forward, because the Government has a duty to provide support, funding and drive the need for change in co-operation with many of the leading charities and groups who play such a vital role in assisting individuals who have hearing loss or deafness. Mark Griffin, we have followed by Annabelle Ewing. At the outset, I apologise to the chamber that I may not be able to stay for the duration of the debate, as the Scottish Government will be giving early sight of statements that it plans to discuss later on this afternoon, which I will be involved in. I apologise for that. I thank Alexander Stewart for bringing his debate today and ensuring that World Hearing Day and Hearing Awareness Week 2019 are celebrated in this Parliament. He is a convener of the cross-party group on deafness. I am hugely grateful to ideas for years and deaf Scotland for working with Mr Stewart today so that we can debate the issue of hearing access to public and community spaces. Indeed, the cross-party group on deafness is always looking for new members, and I encourage anyone here today to come along to our next meeting. Hearing access is a particularly acute need to support the 1 million-plus community who are either deaf or hard of hearing, but it can and does affect all people in Scotland. As the motion details, noise and poor acoustics can cause significant discomfort and exclusion from group activities for older age groups, as well as people with conditions such as dementia and autism. Some members in the chamber may be aware that I now use a hearing aid, and prior to having that hearing aid fitted. I experienced the frustration of being unable to hear discussions clearly, sometimes in the chamber, when there were interventions from certain positions, sometimes that meant missing out on key debating points. However, I might be able to manage those situations and be more able to speak up when I experience such situations. For other groups, deaf people, older people or dementia and autism, they might be less able to feel less comfortable to speak up and manage that situation. We are all undoubtedly diminished for losing out in their participation. It is therefore vitally important that we consider how hearing access is prioritised to ensure greater public involvement and participation in the many varied events that we have. As Dave Scotland pointed out, communication is a two-way process, so if your ability to communicate has affected the contribution that you are then able to make to society and your culture is entirely impeded, as a result, being unable to communicate really puts a person's mental and physical health at risk because of that isolation. On the cross-party group and at the heart of the debate during the passage of the BSL bill, we talked about how being unable to communicate puts barriers in the ways of accessing services, educational attainment and even accessing health services. As I said, BSL users and deaf people can quite often be marginalised and misunderstood. In recent weeks, we have debated how social isolation is increasingly a social and public health epidemic, and one area that all parties are agreed to action is needed. In my contribution to that debate, I spoke about how yet more cuts to local services and local government will only dismantle and undermine some of the services that keep communities together. When you take into account those cuts and think about hearing access, you can really begin to get a picture of how that isolation is created. I know firsthand how much we need to improve the infrastructure and make it more inclusive, although we are today talking about managing noise to aid hearing. During the BSL bill, I spoke about how few BSL interpreters are in Scotland at that time, only 80. Last summer, I organised a series of meetings and it was highlighted again just how difficult it was to source interpreters and secure the funding along with the other associated costs. That is why the proposal in that motion is to look at the employability opportunities to roll out noise absorption panels and enhancement devices to help. Tackle noise and acoustic issues should be particularly thought-provoking for Government. Once again, I would like to thank ideas for Ears, Deaf Scotland and Mr Stewart for bringing this debate to the chamber. I hope that we can go away ahead of the world here in day and here in access week 2019. I think about how we can make public spaces more inclusive, free of noise and to encourage healthy communication. I thank you very much. I call Annabelle Ewing to be followed by Jeremy Balfour. Mr Balfour will be the last speaker in the open debate, Ms Ewing. I, too, am pleased to have been called to speak today to mark world hearing day and hearing awareness week. I would also congratulate Alexander Stewart on securing this important member's debate. I recall when I spoke in a debate some years ago on a similar occasion, my colleague, Dennis Robertson, who used to sit just there, within one sentence of my starting to speak had already intervened to tell me to speak more slowly. I hope that I am achieving that today of Dennis's listening. I do listen to what other people say. As we have heard, the focus of hearing awareness week this year is very much on the importance of early identification and intervention for hearing loss, with the strap line being check your hearing. Out of my remarks, I wish to formally recognise the excellent work that is done on behalf of deaf people by a range of national and local organisations and individuals right across Scotland. They all work unstintingly to improve the lives of those who are deaf or otherwise suffer hearing loss and to challenge the removal of barriers that remain to this day for the more than one million individuals who are deaf or suffer hearing loss. In Scotland, it is recognised, I believe, that we have made significant improvements in a number of areas, such as the development of quality standards for NHS audiology services with regular meetings of NHS audiology heads of service to co-ordinate and share best practice, such a meeting, I understand, taking place today at PRI in Perth. We have also seen an increase in the provision of lit reading classes and the launch of a national joint sensory strategy. We have also seen, as Mark Griffiths referred to, his historic British Sign Language Bill in 2015, with the Scottish Government launching its first groundbreaking national plan for BSL in October 2017. Just to remind those who may not know, the plan is to run until 2023 and set forth 70 discrete action points that the Government is to take in the first three years to 2020 of the plan, with a progress report to be published at that time. It was shaped by the input of more than 1,000 individuals and dozens of organisations and covers many aspects, including, of course, the important early years and education. Therefore, the Parliament will wish to ensure, no doubt, that the progress report that is expected next year is subject to full scrutiny to ensure that the action points that are promised are being delivered on the ground, for it is indeed necessary to ensure, as far as the BSL national plan and other service issues are concerned, that improved services are available to people in their local communities. That is what will make the key difference in ensuring that those who are deaf or who have suffered hearing loss can access their rights as full and equal citizens. In that regard, action on hearing loss Scotland did a part of work with its comprehensive report of a few years ago entitled, Hearing Matters. A number of important issues were raised at that time, and I know and suspect that some of those issues will still be present to this day, in terms of the challenges that are still to be overcome. It would be helpful, therefore, when closing. If the minister and I do recognise that a number of those issues are issues that are dealt with across Government portfolio, but if the minister could clarify and if she cannot clarify, she will undertake to refer the comments to the relevant minister in charge, but clarify the position as to how matters stand with respect to, for example, hearing loss research. The ask was that that was to be a strategic priority. How the number, as Mark Griffin said, of BSL interpreters meets demand at the present time. How the participation of deaf young people has ffaird in programmes like the hugely successful modern apprenticeship programme run by Skills Development Scotland. What progress has been made to ensure that all transport is fully accessible, including, of course, the important provision of information. At the same time, perhaps the minister can clarify what the Scottish Government's response has been to the call from action on hearing loss Scotland, aged Scotland and Scottish War Blinded for timely screening of veterans further to the excellent joint initiative that it has been working on to compile the combating site and hearing loss guide booklet, which, in fact, was launched last month. In conclusion, I would like to stress that it is these practical issues that will, if resolved, make a key difference to the lives of deaf people and people who suffer hearing loss. We, as parliamentarians, have a duty not to take our eye off the ball but rather to persist with our questions and our ambitions to change lives for the better. I add my thanks to Alexander Stewart for securing this important debate on world hearing day and hearing awareness week 2019. In Scotland, there are over 1 million people with some degree of loss, of whom approximately 546,000 are over the age of 60. In the 2011 census, over 350,000 of the Scottish population aged three or over listed deafness or partial hearing loss has a long-term health condition. Those numbers are challenging and I welcome any progress groups, companies and charities can make to raise awareness on how to prevent deafness and hearing loss. I am sure that we all know someone who is affected by hearing loss and how it impacts on his or her quality of life. My mother has a hearing loss and I am aware sometimes at family gatherings that she is missing out on conversation and information because she finds it difficult to hear and, as a result, it can affect or enjoyment at an event and stop her paying the bill. Activities that a hearing person takes for granted can present challenges for a person with hearing loss. Take, for example, a conversation with a driver when you are a passenger in a taxi. I recently contacted local authorities across Scotland and discovered that out of the 30 who have responded to my request for information, only one local authority requires taxes to have a hearing loop in their vehicles, while no local authority requires private hires to include hearing loops—hardly an example of inclusive communication. Deafblind Scotland wants communication to be acknowledged as a human right. I believe that systematic failure such as the one that I have just cited remains a significant problem in Scotland and leads to everyday breaches of human rights for the deaf community. Ideas for years is a community-led social enterprise that provides consultancy support to help business and organisations to most successfully meet the needs of customers, staff and other stakeholders who are having hearing loss. The advocate for hearing loss is about the application of practices that make hearing and following conversation and audible information more possible for more people. Hearing access needs to be a priority, and I support the ideas of years view that among people in Scotland who have hearing loss, the majority have the capability to hear and follow what has been said well or adequately as long as the environment is right. Sadly, by and large, the environment in many workplaces, including this one, is still not right for people with hearing loss. Research by ideas for years amongst employees identified that 74 per cent of respondents with hearing loss sometimes regularly are always experiencing difficulties hearing at work meetings. For many who acquire disability during their work in life, the development of an impairment will bring about a crisis point in the workplace, bringing their future into doubt. According to deaf action, one in four people have left their job due to discrimination. The number of people with hearing loss is at an all-time high and is increasing as the population continues to age. With 40 per cent of working age population predicted to have a long-term health condition by 2030, it is a crucial moment to address what good work means for a large section of the population. In a recent report published by Leonard Cheslaw about inclusion of employment, he identified that we need to adapt workplaces to build a more resilient workforce. To enable disabled people to participate in the labour market, they place emphasis on the need to ensure that disabled people have access to reasonable adjustments and assistive technology that supports them to carry out their job. For a person with hearing loss, that could be an electronic note-taker service or a hearing enhancement device that can potentially be funded through the UK Government's access to work scheme that provides financial support to ensure that somebody's disability or health condition does not hold them back at work. We need to challenge entranced attitudes in the workplace. Leonard Cheslaw's report identifies that 24 per cent of employers saving would be less likely to employ someone with a disability who employ sightings at the cost of workplace adjustments and concerns that a disabled person would struggle to do the job as reasons not to employ them. We need to create the right environment for deaf people who can make a positive contribution. I therefore welcome initiatives such as Hearing Awareness Week that raises awareness of hearing loss, encourages us all to think about good hearing health and to work collectively to ensure that we create more inclusive society for people living with hearing loss. I thank Alexander Stewart for bringing this important motion to the chamber today. As we have heard across the chamber, there is support to improve the care and opportunities for people with hearing loss. This year, World Hearing Day focuses on the importance of early identification and intervention for hearing loss, as many people live with an unidentified or hidden hearing loss. I also want to ensure that adults and children with a sensory impairment have the same access to services and opportunities as everyone else. That is why our See Here strategy focuses on children and adults and covers deafness, sight loss and dual sensory loss. Partnerships and communication are crucial to the effectiveness of See Here. The strategic framework recommends that local partnerships between statutory and third sector bodies should consider options for introducing basic sensory checks at agreed times in care pathways. I am delighted that those have been introduced in care homes in some local areas, and I hope that it continues to expand. We have also been working with partners to explore the delivery of enhanced community audiology services in a GP practice setting. Initial pilots in NHS Ayrshire Narn and NHS Tayside link with third sector providers in those commenced this month, and they will run over the next 12 months. See Here also enables training and development. For example, more than 200 people have accessed the Sensory Champions training programme, a bespoke training course that was created in partnership with RNIB and Action on Hearing Loss, providing core training and skills across key aspects of sensory loss and rehabilitation. Additionally, three e-learning modules focusing on the awareness of communication strategies will be available on the NHS training website TURAS, and that will be available for all. I am grateful that the See Here national co-ordinator worked closely with partners to support and promote the ideas for ears hearing access protocol for ensuring accessible meeting spaces throughout the country. I know the difficulties faced by people living with sensory impairment. I recently met staff from Deaf Scotland to discuss the issues facing people with hearing loss, and I fully appreciate that each person will have their own individual unique communication preference. That links directly to individual communication strategies and language acquisition. If hearing loss is congenital, then the person will almost certainly have learned British Sign Language as a first language, and English being a very separate and second language. I am proud that this Government funds Contact Scotland BSL, the UK's first publicly funded online BSL video relay service that enables deaf and deafblind BSL users to contact and interact with Scottish public sector bodies and third sector services. That allows users to self-manage their own calls, live as independently as possible and to retain a level of privacy, no longer having to rely on family and friends to make calls for them. The World Health Organization confirms that as people live longer, the prevalence of disability will increase, so it follows that in Scotland the risk of people with or who develop a hearing loss will increase. They may also have other primary conditions such as dementia, autism or learning disabilities, and their hearing loss may be a hidden condition that exasperates their primary condition. I know that people with sensory impairment who develop dementia face additional challenges, including an increased sense of disorientation and risk of social isolation. The onset of dementia may be more difficult to detect by family and carers, and equally it may be difficult for the person with sensory impairment to communicate what is actually going on. In 2017, we published our third three-year national dementia strategy, and that includes continuing our national focus on dementia health, social services in housing and the workforce development by implementing the national dementia skills and competencies framework, promoting excellence and the national allied health professionals dementia framework. NHS Health Scotland's report into dementia and equalities issues identified dementia and sensory impairment as a key area where improvements are required. We are undertaking national work through the two dementia workforce programmes to improve service in those areas. Integrated dementia support packages will include attention to recognising or identifying sensory issues. For example, everyone in Scotland newly diagnosed with dementia is entitled to be offered a minimum of a year's worth of dedicated post-diagnostic support. A named and trained key worker will co-ordinate the individual's dementia care with other elements of their care and support, including those elements addressing sensory impairment. People whose primary condition is autism can have a range of sensory issues over and above and under sensitivity to noise, light and smell. That was highlighted to me during my recent visit to reach Laneture Autism in my constituency of Rutherglen. Our priorities for the next three years are to ensure that we provide high-quality training to all health and social care and education staff in order to better understand the impact of being autistic. That should cover what measures need to be taken in various environments to reduce the impact of sensory sensitivity and to ensure that people with autism and learning disabilities have choice and control over the services that they receive and are supported to be independent and active citizens. In December, we launched a fairer Scotland for disabled people and employment action plan, which sets out our commitment to at least half Scotland's disability employment gap by 2038 and the initial range of actions to support it. Implementation of the plan is now under way across Government, and our partnership with the sector will continue as we drive the plan forward. It contains five longer-term actions and 93 actions to make meaningful progress towards those ambitions, support services that meet disabled people's needs, decent incomes and fairer working lives, places that are accessible to everyone, protected rights and active participation. Just before I close, I thank all the valuable contributions that we have had from across the chamber, from Jeremy Balfour, from Mark Griffin and from Annabelle Ewing. I undertake to come back to her with answers to some of the questions that she asked and some of the challenges to the Scottish Government. With regard to veterans, I can reassure her that veterans, including those who have served as reservists, receive priority access to NHS primary, secondary and tertiary care for any condition relating to their service, and that is based on clinical need. That includes audiology and hearing aids. I hope that that gives her a level of reassurance. Presiding Officer, everyone should feel valued and included and accepted by society, and it is only then that we can all live in a fairer Scotland, a more equal Scotland and a Scotland for everyone. Thank you very much. That concludes the debate, and I suspend this meeting of Parliament until 2 o'clock.


Thanks very much. Can people hear me at the back? Is this working okay? Just a little bit up. That's right. Okay. That's much better. All right. Thank you. All right. So it's a great pleasure to be here today. I wanted to spend my presentation today talking about the analysis we've been doing in individuals who, as far as we know, do not actually suffer from severe diseases. So this is not a rare disease sequencing effort. This is really about trying to collate information from as many people as possible who don't actually have severe diseases and see what we can learn from that effort. And this is an effort that falls under the general umbrella of the exome aggregation consortium or EXAC. So the fundamental idea behind everything that we do is that in order to make sense of the variants that we discover in any one patient's genome, we need to be able to interpret those variants within a population context. So ideally, what we'd like to be able to do is, for instance, in my lab, we study patients with rare neuromuscular diseases. We'd like to be able to take every variant in one of those patients, look that up in everyone who's ever been sequenced anywhere in the world, and to say, has that variant ever been seen before? If so, how common is it in a variety of different populations? And do the carriers of that variant have any specific phenotype that resembles what we see in our patients? And in many ways we live in a golden age for these types of studies. We know worldwide somewhere north of a million genomes and exomes have been sequenced, or at least that's our best estimate of the current numbers out there. So this is a phenomenal amount of data about the patterns of human genetic variation that at least in theory we could access. Now in practice, of course, everyone here knows that most of these data are largely inaccessible for a whole variety of different reasons. There's ethical constraints, there are political reasons why people don't want to give up their data for the academic advantage or commercial advantage, and of course there's also very mundane technical reasons. It's hard to move large amounts of data around, and also critically, each of the project that's generating these data tends to use their own slightly idiosyncratic pipeline for processing and calling the variants. So it's difficult to merge these data together. So since about 2013 I've been leading a consortium, the exome aggregation consortium, or EXAC, with the goal of trying to overcome some of these barriers and pull together a large and harmonised collection of exome sequencing data for the benefit of the broader rare disease community. So our first release, which was made public back in October 2014, started with a collection of raw sequencing data from 92,000 human exomes. As you can see in this table here, these come from a whole range of different projects, with the lion's share of the data coming from large case control studies of common complex diseases like type 2 diabetes, heart disease, and neuropsychiatric conditions. There's also data from TCGA here, I should emphasise these are germ line exomes only, not tumor exomes. We took the roughly a petabyte of raw sequencing data, that's about 1,000 terabytes of raw sequencing data, from these 92,000 samples. We pushed all of that data using computing resources at the Broad Institute, through the same processing pipeline, and then did joint variant calling across all of those samples, and that resulted in a single unified call set. We then proceeded to remove about a third of those samples and release a publicly accessible call set of just over 60,000 samples that is clean, in the sense that we have restricted only to high quality samples, to individuals who are unrelated to one another, to those who have consent for public data sharing, and also to individuals who, as far as we can tell, do not have severe pediatric disease, and are not the first degree relatives of those with severe pediatric disease, although we don't know that for everyone, as I'll mention later. So this reference data set, although we can't for consent reasons share the individual level genotypes for these 60,000 people, is a data set where we can share frequency data for all of the variants that we discover. This is a massive data set, it's by far the largest collection of sequenced individuals that's been made available to date. Here, in this slightly grandiose slide, I'm comparing the size of EXAC compared to the two previously publicly available data sets of genetic variation in terms of the number of individuals. This is the 1000 Genomes project, this is the NHLBI's exome sequencing project. In EXAC, we were able to assemble nearly 10 times the number of samples compared to the ASP, and although we do have a very European centric component to EXAC, that's this big blue chunk here, we do have representation from thousands of individuals from many other continental groups as well. So there's a substantial amount of genetic diversity here. And overall, the project has generated by far the largest catalogue of human protein coding genetic variation. Over 10 million variants in total, so that corresponds to approximately one variant every six base pairs throughout the coding region and their flanking sequences. So it's an incredibly high resolution of genetic variation. The vast majority of these variants are novel, they've never been seen before. We believe that almost all of them are real, based on a whole series of QC analyses that I'm not going to go into here. And most of them are extremely rare. So in fact, if you look at this plot here, you can see that half of the variants, more than 50% of the variants that we discover in EXAC, are seen only once in our dataset. So that's an allele frequency of less than 1 in 100,000 and more than 75% are seen with an allele frequency of less than 1 in 10,000. So that's great, this gives us an unprecedented insight into this really low end of the frequency spectrum, which is where we expect most severe disease causing mutations are found. The goal of producing this dataset was to create something for the broader community. So in October, 2014, we launched a website, which hopefully many of you have already looked at, exac.brotinstitute.org, where you can access coverage information and variant information for your favorite gene. You can look up any variant that you've seen in your patient and see whether we've seen it or not and how common it is across different populations. You can also visualize, for many sites, the raw read data that gives you a sense to how confident we are that we've actually called it. This has been very successful. So as sometime this week, we will just tick over 4 million page views for the exac browser, and it's now become one of the default go-to reference datasets for clinical genomics. Now, of course, there's a number of major caveats to the exac sample collection. The first one is that we've been entirely opportunistic here. We simply took samples from the largest exome sequencing projects that we could get our hands on, where the PIs were amenable to sharing their data. That means that most of the samples have extremely limited phenotype data, and almost none of them are actually consented for recontact. We think maybe a quarter to a third of the samples are consented for possible recontact. Many of those, we haven't tried that yet. Also, although we've tried to remove severe pediatric disease cases, or severe Mendelian disease cases in general from this dataset, some will remain. We have some projects where we really have almost no phenotype data, so it's possible that some of these people do actually have severe disease. Nonetheless, those caveats aside, and I'll return to them later, exac improves the analysis of variants of uncertain significance in a number of important ways, and I'm just gonna step through three of them in this talk. The first, I think, and really obvious one, is that it allows us to improve our ability to filter our variants seen in a patient, which is simply too common in the general population to be causal for a particular disease. I'll show some data on that. The second thing we can do is in that, if we're fortunate enough to have large collections of disease cases for a particular disease, we can do a case control comparison that allows us to assess the pathogenicity and the penetrance of a whole range of variants that are discovered within that particular disease, and I'll use the example of prion disease to illustrate that. And then finally, and this is work that we're still very actively working on, it's possible to use this data, as we discussed this morning, to identify genes or regions of genes that are extremely depleted for variation in the general population, and therefore represent regions where we believe disease-causing variation is much more likely to be found. So first, just to illustrate the power of EXAC for rare disease filtering, here in this very simple analysis, what we've done is to take 100 independent individuals from each of five different continental populations, and then simply ask, if we were to apply a 0.1%, that is a one in a thousand frequency filter, using either the exome sequencing project or EXAC, how many variants are we left with within that particular exome? So this is a reasonable filter we might apply if we were looking, for instance, at a dominant disease. And the short answer is, if we were to apply the, if we were to use ESP as our reference dataset, we're left with somewhere between 600 and 1,000 variants based on frequency filtering alone. EXAC, because it's much bigger, and importantly, because it's much more diverse, reduces that number much further. So we have somewhere between 100 and 200 variants that we can then filter through using segregation, functional information, and other approaches. So both size and ancestral power are extremely important in improving this filtering capabilities. Now we of course can apply this to our own patients or to anyone else's patients, but we can also go back to the literature and to databases of reported pathogenic variants and see how many of those are actually present at frequencies that are too common to be consistent with disease causation. And the answer, as I suspect many of you have guessed, is that there is a depressingly large number of variants in basically all databases of alleged disease-causing mutations that are clearly not pathogenic, that have resulted from an incorrect assertion of pathogenicity. Just to give you perhaps the most obvious examples, here we took a set of variants that had been reported as being pathogenic in either ClinVar or HGMD, but that had a frequency of greater than 1% in at least one of the EXAC populations. And then Anne O'Donnell, a medical student in my lab, went through and manually curated the evidence supporting pathogenicity for each of those variants. And exactly as you would expect, basically none of these turned out to actually be pathogenic, with a handful of exceptions, CFTR, Delta 50, F508, and a handful of other mild Mendelian diseases. Most of them are clear frank errors in the literature and some of them are database errors. But even once we remove these really obvious errors, we're left with many hundreds to thousands of variants in the EXAC dataset that are clearly present, that we believe that are confidently asserted in the literature has been causal, that are very rare in the general population and that are nonetheless present in EXAC individuals who we believe probably don't have severe disease. So the question is, what is going on with these particular variants? And there's multiple possible explanations. Firstly, I think the default explanation is that many of these are, in fact, false assertions of pathogenicity. It's also possible that some of them are present in undiagnosed cases of disease within EXAC. We have identified some examples of somatic mosaicism where there is clearly a variant present in that person's blood, but it is present at a low allele balance, suggestive that it is actually just increased in frequency within their blood cells, but is not present in other tissues within their body. And finally, and I think importantly, there's the possibility that this variant is indeed a disease-causing variant, is indeed carried by that individual, but there is incomplete penetrance. So for whatever reason, that person is not actually suffering from that disease. So to pick apart that last case, we actually, this is work that was just published a couple of months ago in Science Translational Medicine. We chose to use prion disease as a model for studying, for picking these particular mutations apart. We chose to pursue this for a number of different reasons. Prion diseases are severe fatal, invariably fatal, adult onset, neurodegenerative diseases. They're rare, they have a lifetime frequency of about one in 10,000. We know that approximately 15% of these are genetic. The rest appear to be caused by sporadic misfolding of prion protein within the brain. These 15% of genetic cases, as far as we know, are all due to dominant gain of function mutations in the PRNP gene, which encodes the prion protein. One of the benefits of studying prion disease is that virtually every case of prion disease that occurs in the industrialized world is reported to a surveillance center and the PRNP gene is sequenced. And the reason there's such close surveillance of these cases is of course, because of the notorious 1% of prion disease cases that are infectious in origin. So we have PRNP frequency for almost every individual who's reported to have prion disease in pretty much every industrialized country. So if we are to take the 60 or so reported dominant gain of function mutations in PRNP and look them up in EXAC, what we find is an overall frequency of people carrying these mutations that is 30 times higher than what we would expect given the frequency of the disease in the general population. So clearly something is going on here. It cannot be the case that we have 30 times more people who will die of prion disease than we expect. Something is happening that is resulting in these variants being much more common than we would expect. And the answer comes when we compare the frequency of these variants in cases versus controls. So here what Eric Minnickel in my lab managed to do through various feats of political heroism is to assemble 10,500 sequenced cases of prion disease from surveillance centers in US, UK, Australia and Japan and to then compare the frequency of those variants in the cases that's here on this X-axis against the frequency of the same variants in the EXAC dataset, our 60,000 population controls shown here on the Y-axis. And what we find is that our prion disease variants, our ledgered prion disease variants cluster into three broad categories. Sitting along the X-axis, we have variants that are present in cases but basically absent in controls. And these are basically all variants with very strong evidence for pathogenicity and these all appear to be completely penetrant as far as we can tell. On the X-axis, we have variants that are seen rarely if at all in cases but are present at some reasonable frequency and controls. And we believe almost all of these are actually false assertions of pathogenicity. There's no evidence here that these are actually pathogenic. They almost certainly just happened to turn up in an individual who had a sporadic case of prion disease and therefore there was a false assertion of pathogenicity. And then there's three very interesting variants clustering in the middle here who were too common in cases to be completely benign but also too common in controls to be fully pathogenic. And we can show statistically that all three of these variants have evidence for genuine but incompletely penetrant effects on disease risk with wildly differing effects on lifetime risk ranging from less than one in a thousand lifetime risk up to nearly 10% lifetime risk for suffering from these catastrophic diseases. So this is the first time we've been able to put quantitative estimates using these very large sample sizes on the lifetime risk of this type of disease. And obviously this has major implications for genetic counseling for the families affected by these particular diseases. So that's how we can use large data sets to quantitatively assess penetrant. So I wanted to finish by talking about how we can also study variants that not just the variants that are present in these data sets but also the variants that are missing from these data sets in particular using a mutational model that Cricket mentioned this morning that was developed by Caitlin Simoka and Mark Daly's group. We can actually predict for every gene in the genome how many variants we should expect to see under a random mutational model and then look up those same genes in XR can say how many variants we do actually observe and the difference between those two numbers tells us how strongly that particular gene is depleted for that particular class of variation. So here, for instance, you can see for synonymous variants that Caitlin's model on the X-axis provides an extremely good fit for the exact data on the Y-axis. That's for silent mutations. If we now look at loss of function mutations, you can see every dot here is a gene that most genes in the genome have substantially fewer loss of function mutations than we would expect to see by chance and that's absolutely no surprise. All that it tells us is that most loss of function variants are deleterious and are acted against by natural selection. What's cool about this data is that with 60,000 samples for the first time, we can actually see how far below the line each gene falls and so we can infer how strong the natural selection is that's acting against those loss of function variants in each gene. So let me just give you two very quick examples. This is a gene where we know exactly what happens if you have a heterozygous missense or loss of function mutation. It causes catastrophic neurodevelopmental diseases. This gene, Dink1H1, is a well-known de novo cause of a whole variety of different neurodevelopmental diseases. In this gene, we can see Caitlin's model predicts almost perfectly the number of synonymous variants in the population. There is a two-thirds deficit of missense mutations and an almost complete absence of protein truncating variants in this gene consistent with the fact that most of these variants actually do result in very severe phenotypes and are therefore removed from the population and are not observed in EXAC. So that's for a gene where we know what happens when you inactivate it. This is a gene where we actually have no idea what disease is associated with it. We know that this gene, UBR5, is somehow involved in the ubiquitin pathway. We know that if you knock it out in mice, it kills them during embryogenesis. But to date, as far as I know, there's no known human loss of function phenotype and yet this gene has a profile of missense depletion and most strikingly of loss of function depletion that is completely consistent with a very nasty haploinsufficient disease gene. So you can see here a nearly complete absence of loss of function mutations in our population. So that suggests that although we've never observed an individual who has a disease caused by these mutations that in fact even heterozygous loss of function in this gene does have some quite severe effect on human phenotypes. You may be wondering what's happening with this one individual here. We think in that particular case, this variant is not actually loss of function. It's close to the end of the gene. So overall, using this approach, we can identify over 2,500 genes that have a high probability of loss of function intolerance statistically. So that means they have far fewer loss of function variants in EXAC than we would expect to see by chance. This category of genes contains almost all of the known haploinsufficient disease genes, but more than three quarters of them, we have absolutely no idea what they do when they're inactivated. So this set of course is now a very high priority set for assessing for the potential for causal mutations in severe diseases and has already proved successful in autism and schizophrenia. I'm gonna fly through this last data slide, which basically is some early results from Caitlyn showing that we can also apply the same approach to missense constraint in particular regions. And here in the CDKL5 gene, we show that the constrained, the missense constrained region of the gene is in fact exactly where almost all of the known dominant missense mutations that cause this disease are found. So even if we had no idea where disease mutations were found, we could predict that this N-terminal region was the most constrained region of the gene. So what next for EXAC? Firstly, we're building up our sample sizes. The next release will have 120,000 exomes. We're also very interested in expanding this to include non-coding variants. So we have completed a test run on five and a half thousand genomes. We're hoping to release a data set spanning over 20,000 genomes later on this year. And then finally, we're starting to test genotype-based recall. So taking individuals in EXAC who are very extreme or unusual genotypes, like homozygous loss of function or dominant disease-causing mutations and recalling that very small percentage of them where we actually have the ability to do so to learn whether or not they actually have that disease and if so, what other information we can gain from that. I wanted to finish with a slide that I think summarizes some of the key challenges that we've learned about in performing EXAC and that I think may provoke some discussion later on this afternoon. The first is that it's critical that we build that for almost all of the analysis that I described today, bigger samples will make an enormous difference to our power to actually do these analyses. So having more samples, making sure that the data are harmonized and centralized and the variants can actually be linked ethically to phenotypes is absolutely critical moving forward. That will require regulatory support, both for data aggregation and for reuse. And this often falls into a very difficult ethical gray area at the moment. We need much more clarity in that space. And that will be extremely useful for instance, for the ability to reuse the many tens of thousands or hundreds of thousands of samples, and sequence as part of the common disease centers as reference data sets for rare disease. We need an increased focus on sequencing samples that are consented upfront for recontact, deeper phenotyping and data sharing. That's no surprise to anyone in this room. And of course, it's already a focus for the PMI and other projects. And if we want to be able to assess penetrance uniformly, we also need to be collecting large, well-acetained collections of cases for a whole variety of diseases, not just common diseases, but also rare to really understand the full spectrum of variation in those genes. So with that, I'll finish by thanking everyone involved in putting the EXAC data set together, the analysts in my lab, as well as Caitlin and Mark's lab, all of the principal investigators, and huge thanks to the broad genomics and data sciences platform, which provided all of the resources that were required to make this project possible. Thanks very much. Great, thank you. We have time for a couple of questions. Eric? Daniel? Two questions. I'm just trying to get my head around a couple of numbers if you know them. So one number is, you're talking about at the very beginning something like over a million genome sequence, the great majority of those being exomes. Do you know what that ratio is? Or are you an estimate of what that ratio might be? Exomes versus whole genomes? So there's a number of difficult things about this calculation. I mean, that number includes whole genomes, both low coverage and high coverage. There are obviously many more low coverage genomes out there than high coverage genomes. I think Richard Durbin told me there's probably somewhere around the order of somewhere between 50 and 100,000 whole genomes that have been sequenced to date, and the rest of the numbers we think are mostly in the exome space. Okay, and that's about the number that's consistent with the number I've heard from others. So maybe just barely at the threshold of 100,000 for whole genomes. That's what you said, right? That's right, 100,000, yeah. Second question is, if you look, based on all of the collected variants that you've now put across the exome, what fraction of exome bases have you detected a variant on? So it's about one in six exome bases we have detected a variant. And at some bases there are some classes of base that we've almost completely saturated. So for instance, if we look at CPG sites, we observe an EXAC, 80% of all possible CPG mutations we observe at least once in EXAC. So it depends on how high the mutation rate is, but we're hitting a big chunk of it. But overall, that was about one in six. That's correct, yeah. Thanks. I didn't see any other hands, so what, oh, I'm sorry, Stephen. Just a quick, very technical question. So one thing that we've learned fairly recently is that most variant calling algorithms over correct removing novel ultra-rare variants. Could you just speak to that in terms of your variant calling algorithms? Yeah, we spent a lot of time tweaking the GOTK sensitivity parameters to overcome that, because you're absolutely right. With large-scale joint calling, there is a bias against rare variants. We took a number of metrics, I'm happy to talk to you about it afterwards, we took a number of metrics that correlate to singleton sensitivity and basically tweaked those until we hit the point that we were capturing the vast majority of singletons without, surprisingly, without increasing our false positive rate highly for the common variants. So it actually does seem to work quite well.  And just one follow-on question, if I'm allowed. You've got some very powerful assets there in terms of genes that are likely to be associated with a phenotype and probably also genes that we can eliminate from being candidates for novel phenotypes. Are those available? Sure, yeah, so, I mean, all the data, of course, the raw data is at a per variant level is fully, freely available and anyone can download that. The constraint data is also available through the EXAC FTP site. The second question that you asked, which is genes that we can rule out as being causal. So this is actually a little bit more subtle. So there are many genes that contain at least one homozygous loss of function variant in the general population. The challenge here is that homozygous loss of function variants in EXAC are enriched for false positives, relatively few sequencing errors, but lots of annotation false positives. So you have to be extremely careful about ruling out a gene on the basis of observing, for instance, loss of function variants in EXAC. But I'm happy to talk to you more about that offline. I think we're gonna move on to the next, and so save your question for the open discussion. So next up will be Douglas Fowler.


My father was a policeman, then he had friends, policemen, policemen friends, that hit that date diet with terror, of the terrorists, of the father. His friend, your father's friend, yes. How are things now in Colombia, the situation I understand is very different today. Yeah, now in this moment, yeah, it's different. For example, I was reading that the government is in negotiations with the FARC in Cuba. Then they are talking about peace and probability Colombia will be in peace in this year.


On June 21st in Cambridge, Mass at the Sinclair in Harvard Square, tech tackles cancer is back after COVID hiatus with live band Karaoke and some local tech celebrities raising money for a great cause. The Cube is a media sponsor of the event and Josh Epstein, local marketing exec and one of the events organizers is here to tell us more. Josh, good to see you, welcome. Good to be here, Dave. So tell us about this event. What's going on? What are the logistics? How's that all working? We're super excited. So as you said, June 21st at the Sinclair in Harvard Square, Sinclair if you haven't been there is just a great old school rock club. So we'll be there from six to 10. We will have live band Karaoke. So the main event and kind of the primary fundraising approach here is that we have some celebrity technology rock gods, these featured performers like Chris Lynch who was the founder of Tech Tackles Cancer who are raising money from basically now up until June 21st.  And the winners, the awards will be given out to the most money raised, the best performance, and the best stage presence. So it's going to be a lot of fun. So the fundraising format is I sign up to sing through the karaoke with a live band, which is a little bit different than Karaoke. And then I raise as much dough as possible. So obviously that's competitive. That's it's competitive. I think that we ask for a minimum of $10,000 targeted for each of the fundraisers. But knowing these guys, knowing guys like Chris Lynch, they don't like to lose. So the bet here is that people are going to go out. They're going to hit their network and they are going to look to raise the most money. So we anticipate this to be a really great event with a lot of money raised and a lot of fun. So we have a graphic. Alex, if you could bring that up of the people who have signed up for this already. We got Steve DuPlessie, founder of ESG Scenarios. They sold their company to Tech Target, which is awesome. Congratulations to those guys. And thank you for stepping up. George Hope, who heads partner sales for HPE. Joe LeMay of Rocketbook. Nathan Hall from Pure Storage, system engineering guy. And of course, Stiney, Ken Steinhart from Infinidat. He was at EMC. He's the field CTO now. He's going to be up there singing. So of course, Chris. Absolutely, these are just the early entrants here. So we just started really working our networks, right? And obviously, I'm a Boston Tech guy, kind of working the storage networks and networking networks and kind of the other folks that are around. So as we come out of stealth here in April and start really recruiting, we anticipate having probably 10 to 15 of these featured performers, really fundraising performers that will sing and then we're also obviously soliciting broader donations from anyone who wants to come to the event or just give to the cause and the corporate sponsorships as well. So you've got corporate sponsorships. You can sing. You can donate. You can be there just to support it. That's fantastic. And the awards, how does that work? Yeah, so we're excited. So first off, most money raised wins an award, right? So we'll have a leaderboard on the website. People can kind of track who's raised what. At the events, we're going to have some celebrity judges that will be actually voting for their favorites and then have a crowdsourced component as well. So we'll introduce what that mechanism is. But as people either at the events or are watching and streamed live on LinkedIn Live, we'll actually vote for their favorite performance as well as their pick for best stage presence, which we know in rock and roll is half the battle. Now, this cause has raised a bunch of, I think last time you guys did this, it was probably a quarter million or close to it. And you support multiple causes, right? What causes are you supporting? Sure, yeah, actually, I think since they founded the event several years ago, they raised over $2 million this year for this format, where we're looking we can really up our game here. But this year, we're supporting two really great causes that are both focused on pediatric cancer. The first is St. Baldricks that is really committed to raising funds for research to really help stamp out pediatric cancer really, that the approach to researching cures and treatments to pediatric cancer is very different from regular adult cancer. So St. Baldricks does a great job of picking those research projects that really target in on those pediatric cancer causes. And the second is One Mission. And One Mission really looks to help make pediatric cancer patients that are spending time in the hospital making their time less stressful, less painful, less sad, less boring. And so they do a lot of fundraising and contributions targeting children's hospitals really around the country for those pediatric cancer floors. Josh, amazing cause. Thanks so much for coming on to theCUBE and explaining all that. Okay, thanks Dave. All right, June 21st, go to ttcfund.org. Tech Techles Cancer Fund, ttcfund.org for more information and you can donate. We'll see you there.


What's up, everyone? It's your girl, Kenzie here from Leighton Sports Guards and I am ripping 2223 Panini Don Russelie basketball hobby four box break number 28. Pick your team got Alex C. Hawks, Chang S. Spurs, Chiakai L. Pelicans, Christian F. Thunder, Chun Wei W. With the Mavs Grizzlies, Daniel P. Heats, Edward P. With the Nets Raptors, Frank C. Nick's Glen W. Celtics Nuggets, Bucks, Greg H. Bulls. Thanks, Greg, for closing us out. James F. Hornets, Jason T. T Wolves, John H. Clippers, Kahun K. Blazers, Lee M. Warriors, Minsu K. Rockets, Mo S. Pacers, Patrick G. Cavs, Patrick M. Kings, Paul G. Magic Suns, Jazz and Wizards, Shagnori U. Pistons, Seguru S. Lakers and Sixers. All right, here we go. Up next, we've got Don Russelie football. Again, we did have to shuffle the schedule a little bit as we had to move the McDonald's All-American basketball tops chrome to the end of the day and there's still 11 spots left in that. So definitely need help getting that one filled. It is a 12 box case break. Random box style. So you are guaranteed a whole box, two autos per box out of that as well. 174.99 a spot. So let's, let's get that one going. Jaylen Green, Power Formals. Up next, we've got Don Russelie football. Again, that's a three box break. We've got three of those. Pick your team style. Three teams remain in that one. Zion, Die Cut. Packers being one of them. Packers got a couple of their brickies. Lebron, Full Throttle. So Clifford says, John, come on, let's see something. Uh, Purple Anthony Davis for the Lakers of 49. We have, wow, look at that. John Regas, 20 of 49. RJ Barrett.  I believe this is one of the short print autos too. Wow. That is nasty.  Nick's in the past two breaks have been crazy. Frank C, 20 of 49.  Do you imagine like being that guy in the background, like seeing yourself on a car like that? That's pretty cool. That's disgusting. I have yet to see one of those. Very nice. Right, John? For real. That's Spellbound, Steph Curry. It's been a pretty solid case of elite. I'm not going to lie. Spellbound, Die Cut, Luka Donchik. Purple, Jama Rant, Power Formulas, Grizzlies to 49. Green, Lamello Ball, Star Status. Turn of the Century Auto of Bogdanovich. Fox, Spellbound of Trey Young. Daniel Moore, group breaks tonight, starting at five. Trey Young Craftsman with some hockey. Matt is currently live around the LSE Baseball Channel as well. Zion Spellbound, ripping some baseball product. Got Bryce McGowan's rookie. Got Shaquille O'Neal, Back to the Future with Young Shaq. Orange, Anthony Edwards, Steph Curry, Power Formulas. Orange, McDermott. We've got Ogbaji, Brookie, Jazz. Last pack, box one. I have Devon Booker on the deck, Acetate. All right, box two. Two more autos coming our way. Packers, Texans, Titans left in Donra's football. Again, that breaks next. All on sale. Yearbook, rookie of Jake Laravia, Grizzlies. Orange, Anthony Melton. Got Spellbound, Steph Curry. Orange, Rui Hachimara. Got Wendelmore Jr. Rookie, T-Wolves. Seen a lot of him today, saw him a lot coming out of origin. Steph Curry on the title waves, Warriors. Spellbound of Anthony Edwards. Orange, Spellbound, Dicut, LeBron, Lakers. Hope everyone's having a great Thursday. Kyrie, Power Formulas. Is it just me, or has this week felt like super, super long? Red, Dicut to 77, Aaron Naismith? No. No? It's been feeling pretty normal. Maybe just because I've been doing so much and moving and unboxing, it's been like, like- That was, I'll do it. Rookie, yearbook auto, Trevor Kiehl's Nix again. Man. Who's that? Five Nix autos in the last six boxes. Orange, Kobe White. Jimmy Bucket, Star of Status. Orange, Franz Wagner. We still feel like it's October of 2022. Nice one here, Magic. Palo Bencaro. First time we've seen him all day.  In a minute, I'm going to need a sentimental woman to call me a Power Formulas LeBron. I'm going to need like two shots in my cup. Full throttle, Kyrie. Donny's like, oh my god. I just, I don't know. I don't know. I don't know it. You don't know, Lizzo? Nope. Oh my goodness. Star status of Damian Lillard. Orange, Rookie of Kendall Brown. Pacers. Backbox too. We've got a blue Haliburton in 99. Who's doing that, Serena? Everyone's just eating, eating good food. It's jealous. Box three. So, Pacers, Texans, Titans left in the next break, y'all. Pacers 44, Texans 24, Titans 54. Let's get those taken up. Still great teams there. We've got Spellbound Dicut, Ant-Man. Simmons, Gruso, Wattford. Buy the money and buy the actors. Right? A couple of Rookie's are chasing there. Malik Willis with the Titans. And, uh, Berks. Blue to 99, Nurkitsch. Quite a job in that style last night. I'm not sure, John. I didn't, I didn't get to watch the game. Genre graphs again! Penny Hardaway this time for the magic. Wow. Two Genre graphs in four box break. That's sick. Nice one there, Magic. Nice break for the Magic with a Palo, Rookie. And now the Penny Hardaway. Orange, Anthony Edwards. Hero, Starstatus, Devon Booker, Dicut. There are Purple, Trey Young to 49. Sub-Luca, Spellbound of Anthony Edwards. You've got Turn of the Century of Kenny Skywalker. Nix again. Man, Nix-Case. This has just been crazy. Jaw, Power Formulas. Damian Lillard, Full Throttle. Devon Booker, Starstatus. You've got Iqbaji, Rookie. Jazz. My pretty dirt bike. Nice! That sounds sick. Shaq on the back to the Futures. You've got Spellbound, Luka. You've got Trey Young, Spellbound. Orange, Ludort. Trevor Keele's Rookie for the Nix. I bet. That's cool. I don't think I've ever ridden on dirt bike. You've got Devon Booker, Dicut. Acetate. Lamello, Power Formulas. And Bice. Last box here. Little Packers, Texans, and Titans left y'all. You've got Luka Donchich on the Clarity Acetate Mask. Siak on Power Formulas. Orange, Anthony Edwards, Spellbound. First Titans, Texans. Again, all on sale. That breaks right after this box. Spellbound, LeBron. You've got Blue, Reggie Bullock, Color Match for the Mavs to 99. And Red, Dicut to 77. Dremont Green. Dremont Crop, Baby Green. You've got Rookie Yearbook of Marjan Bochamp. Milwaukee. Orange, Narcich. Donovan Mitchell, Power Formulas. Aten Orange. You've got Jaden Hardy, Rookie Mask. You've got Impact Impressions Auto of Artist Gilmore, Bowls. Last team's taken, Mojo. Grats on that one, Chicago. That's two breaks when that's happened. They've hit big. Ant-Man T-Wolf, Spellbound. Spellbound of Trey Young, Hawks. Orange, Bradley Beale. Rookie Kendall Brown, Pacers. You've got Chauncey Billups on the Tidal Waves, Pistons. Star Status, Jason Tatum. Star Status, Dicut, Devin Booker, Sons. Black Donovanitch, Couple Packs. Last team. We've got Zion, Blue, Spellbound. That one is 64 out of 99. Pelagons. And last factor. Blue, Robert Williams of 3rd to 99, Celtics. Thanks. Quick recap here of our autos. We had Artist Gilmore, Bowls. Bochamp, Bucks. A Kenny Skywalker, Nix. Penny Hardaway on the Genre Graphs, Magic. Trevor Kiehl's, Nix. Jake Lariva, Grizzlies. Bogdan Bogdanovitch, Hawks. And the Genre Graphs to 49, R.J. Barrett, Nix. Alrighty, that will do it for Elite Basketball. We've got Don Russo football coming up.