Good morning. Everyone had a good rest yesterday after a long lab? Was it good? The lab? Up until nine o'clock? The open lab? Everyone enjoyed it? Cool. Okay, so you spent a lot of time yesterday hearing and exercising in the field of the biomarker discovery. SOREP did a great job giving you an overview of what the biomarker is, what it's for, and introduced you into full details of the process of the discovery of biomarkers, therapeutic targets. So let's suppose that we have identified our biomarker, which is excellent, has an excellent profile, and you invest a number of years into the development of that biomarker, and then you spend some 200 million dollars on going through all the clinical trials in the ordeal with the FDA approval and everything. And so you put it into the clinical practice, and then it turns out that it's not effective for all patients with this current disease, and even more patients show the full spectrum of the reactions to this particular drug, side effects, adverse side effects, or lack of the therapeutic effect. And so that's why I think it is really important to take into account all of the aspects of a future personalized medicine, which includes both the discovery of novel biomarkers and development of new drugs and the application of those drugs to actual patients. And so in this module, I'm going to focus in the first part on the pharmacogenetics, pharmacogenomics, what it is, and its evolution, because it's basically transformed our understanding of clinical intervention from silver bullet to a personalized medicine. And then I will touch a little bit on the whole genome association studies and how those studies have proved to be useful for pharmacogenomics and pharmacogenetics. And then I will move on to a cancer genomics as a special case of a human disease, which is most complex disease. And then in the second part of this module, I will be talking about the analytical techniques to analyze clinical data. So you've heard a lot about the whole genome and whole transcriptome data yesterday and the ways of its analysis. And today we're going to talk about the clinical data and specifically about the type of clinical data, survival data, and survival analysis, because it's a special type of data and it requires special types of analytical techniques. And these are widely used techniques I'm going to cover. So the pharmacogenetics and pharmacogenomics is the study of the inheritance in variation in drug response. So these drug response can range from life-threatening adverse effects on one end of the spectrum to the equally serious lack of therapeutic effect on the other end of the spectrum. And so over the last top century, pharmacogenetics has actually evolved from a study focused on the monogenic traits, this is pharmacogenetics, to a pharmacogenomics with a whole genome perspective. So the earliest experiments of pharmacogenetics experimentally validated examples were reported back in 1950s and 1960s. And they grew up from the observations that a large, that there is a large differences in response to a standard drug doses in a population of patients. So one of the examples was short-acting muscle relaxant, which was given in the standard dose to a number of patients. And in some of them, it caused a serious side effect, potentially lethal, a prolonged muscle paralysis. So the investigation of a process of a metabolism of this drug led to the discovery of a genetic variation within the enzyme metabolizing this drug, which produced dysfunctional form of this protein in those patients. Another example at the same time was reported about the same time was the anti-tuberculosis drug that was showing a bimodal distribution of a plasma concentration in patients. And those different concentrations were related to the risk for adverse effects. And thorough investigation of the metabolism of this drug has led to the discovery, again, of a genetic variation in the activity of an enzyme NAT2, which was responsible for catalysis of this drug. So these observations served as a stimulus for additional studies in this area. But again, the focus of the pharmacogenetics was a particular factor, and in most cases in pharmacokinetics, and that is a drug metabolism. And it would be usually a typical phenotype to genotype approach, which is widely used in hemogenetics. But the following examples actually illustrate the evolution of pharmacogenetics from a biochemical to a molecular pharmacogenetics. So these are sort of the icons of that era, the C2D6 story. So this gene is a cytochrome B450 family of microsomal drug metabolizing enzymes. This gene catalyzes bio transformation of a wide spectrum of drugs, anti-depressants, anti-arhythmic drugs, and it also activates analgesic protracodion. So and then the thorough investigation of this gene in a population of patients showed that actually those patients had a great number of, a great frequency of genetic variants within this gene. Some of the patients had non-synonymous coding SNPs associated with the decreased activity of this protein. Some of the patients had gene deletion. Other patients had gene duplications, up to 13 copies. And so this plot, this figure actually shows you a frequency, the frequency distribution of a ratio of a drug to its metabolites within a population of patients. And you see here a few groups here. So the major group is, was called an extensive metabolizers. But there were two extreme groups that were called four metabolizers and ultra-rapid metabolizers. And so now you can imagine that the poor metabolizers can suffer from the excessive drug effect when given something like an anti-depressant, for example. But in case of the codeine, they may lack therapeutic effect because this protein is supposed to metabolize codeine into morphine. And conversely, the ultra-rapid metabolizers may suffer from the excessive effect of, say, anti-depressant. But I'm sorry, lack of the therapeutic effect of the anti-depressant. But at the same time, they can be overdosed with codeine because they metabolize codeine into morphine too rapidly. And so there were cases of a respiratory arrest in those patients, which were given as standard doses of a cough depressant containing codeine. So another example is the TPMT story. These protein catalyzes the asymmethylation of thiopurine drugs. And thiopurine drugs are cytotoxic and immunosuppressive drugs. They are used to treat the acute lymphoblastic leukemia of childhood and some other diseases, including inflammatory bowel disease and organ transplant recipients. So these drugs unfortunately have very narrow therapeutic index, meaning that the difference in concentration of a drug necessary to achieve a therapeutic effect and the concentration of a drug that cause toxicity is very small. So the most serious toxicity, which is induced by the thiopurine drugs, is life-threatening myelosuppression, bone marrow suppression. Then it turned out that there is a genetic polymorphism in that t-vating TPMT through protein misfolding. And that genetic polymorphism was associated with the increased risk for myelosuppression. And so those patients who had that mutation had to be given one-tenth to one-fifteenth of a standard dose. And so this example actually was the first example of including pharmacogenetic data into the drug label. And this is very important because you can imagine that, for instance, you put the new drug into the clinical practice. And as I mentioned before, it turns out that it has very serious adverse effects in a large fraction of a population. And it may be ineffective. And you cannot really predict what dose you are supposed to give to a patient. And then in the end of the day, gone through the ordeal of development and testing this drug and putting it into the clinic, you have to withdraw it. So this is very painful process. And it was really a breakthrough that FDA started hearings on this topic. And this was the first example. So this figure just shows you the distribution, frequency distribution of TPMT activity level in red blood cells. And they designated the inactivated isoform with low activity. And the wild type is high activity. And so these patients were homozygous for the low activity allele. These ones were heterozygous. And these ones were homozygous for a wild type allele. So pharmacogenetics has been focusing on a monogenic Mendelian traits and mostly on the pharmacokinetics aspect of a drug.  And the drug responses to a proper therapy is also governed by many factors. So the brutal fact actually was that even if you know the factor that is playing some role in the diverse reaction to the drug, even if you know it, it does not explain 100% of cases of variability in drug response. And so with the following example, I'm going to show you that not only pharmacokinetic factors, but also pharmacodynamic factors actually influence the efficacy of drug and the side effects of the therapy. So the EGFR story here. So endothelogrofactor receptor is overexpressed in non-small cell lung cancer. And there was a number of antibodies developed against this receptor. One of them was Gefitinib. And it was also noted that there was a wide range of response to this antibody. And best responders were women, never smoked, and of East Asian origin. So then when they started to probe different populations, it turned out that there was a genetic variation in the target of this antibody, EGFR, in the ATP binding site. And this mutation actually was activating. So patients with this mutation responded better. And so within this North American population, there was very low frequency of this mutation and very high frequency in East Asian population. And again, very high frequency in responders versus very low frequency in non-responders. So that's how there was a discovered a direct link between this mutation in the drug target, which is a dynamic factor. So here's another story, the warfarin story, which is probably the ultimate example here. So the warfarin is the most widely prescribed oral anticoagulant. And unfortunately, it has serious adverse effects, hemorrhagin and desired coagulation. So this drug is predominantly metabolized by cytochrome P450-chymaline member CYP-2C9. It's another one compared to the first one, but still. So it was found that there were two common polymorphisms present within this gene and they were associated with a decreased activity of this protein. One of them decreased activity down to 12% of the wild type and another one down to 5% of the wild type. So the frequency of polymorphisms was about this level, about 10%. Unfortunately, the Firmaco-Clinetic genetic variation, this one, did not explain most of the variants in response in patients given warfarin. And for quite a long time, the target of this drug would not know until some 2004 when this gene was identified and cloned. This is V4C1 and also no non-synonymous SNPs were found within this gene. Several haplotypes were discovered within this gene that were associated with the final dose of a warfarin. So warfarin's story actually represents probably in the simplified manner a polygenic model that we must expect to see in the future. So this model includes both the Firmaco-Clinetic factors which alter the metabolism and the final concentration of a drug and Firmaco-Dynamic factors which affect the drug target and the pathways downstream of the target. So yesterday, you've heard a lot about the different approaches for detection of new biomarkers using different platforms and techniques. But in this case, I'm just going to touch a little bit on the genome-wide association studies. There were numerous publications using this approach, but I'm just going to give you an example how these type of studies can be used directly in clinic. So what is the genome-wide association study just to remind you? It is a examination of genetic variation across a given genome designed to identify genetic associations with observable traits. These type of analysis require two groups of participants, subjects with the disease cases and subjects without disease controls. So first, you do the genotyping of each individual and then you test the association of set of markers, SNPs, with the disease or trait. So this is just a this is just a list of some of the recent publications where the GWAS has been used for the detection of some polymorphisms that could contribute to risk of a number of diseases including diabetes to breast cancer and others. But unfortunately, the problem with the GWAS studies is that the odds ratio is pretty low. But there is one example and this is a statin's story. So the statins are a class of drugs that are used for controlling a cholesterol level.  So the serious side effect of these drugs is myopathy. And so there was a clinical trial search called search commenced to investigate the effect of the drug dose onto the patient's response. And as a part of it trial, the researchers investigated patients who had a serious myopathy. So they had a number of 85 patients with this condition versus 90 controls. And the genotyping gave the GWAS study gave one single polymorphism in this transporter gene, which had an incredibly high odds ratio. And this is a p-value. So for the genome wide association studies, this is relatively small sample size of patients. But anyway, they proceeded with this funding and they validated this finding in a much larger cohort of 10,000 patients. And they got a lower odds ratio, but still it was 2.6. So the authors stated that they could explain more than 60% of variability in the drug response using this polymorphism. So now I would like to change topic a little bit and to talk about the cancer, which is the most devastating and most complex human disease.  And it is a search within cancer families and patients for the full collection of genes and mutations, both inherited and sporadic somatic that contribute to the development of cancer cells. And it's progression from localized cancer to one that grows uncontrolled and metastasizes. So what is the cancer? Now I think everyone is convinced that cancer is not driven by a single oncogene or tumor suppressor gene. Although there are a depth of this theory, but still it is widely appreciated that cancer is a polygenic disease with many factors involved. And so this is a typical karyotype of a cancer cell. This is a breast cancer cell line, MCF-7, and different colors here mean different portions of different chromosomes. This is a sky image. And so you see a great deal of aberrations happening here within the genome. So the aberrations in cancer happen on practically all levels of cellular function, starting from the aberrations on the genome level. And these are genomic aberrations such as inversions, copy number changes, deletions, translocations. Then there are point mutations with an important genes. The next level is the changes on the transcription level. Those are differentially expressed genes that we were talking about yesterday, the great detail. Then we have changes in splicing regulation. It can be an average splicing due to mutations. It can be altered regulation of splicing. It's a changes on the epigenetic level. And of course it is a change on the protein levels. So in addition to a wide diversity of events that take place on different levels in cancer, there is also another complexity of a reshuffling of the genome within cancer cell. And so this example shows you how complex the amplicon can be within a particular cancer. This is a breast cancer cell line. And this is an amplicon on chromosome 20Q. And the sequencing of this amplicon gave this structure. So you see a lot of different segments coming from different places. Well in this case mostly from the same chromosome but also from another chromosome are concatenated with each other. And this finding was validated using using PCR on junctions and breakpoints. So cancer also is a very heterogeneous disease. So this is a typical copy number frequency plot. And you see copy number increases and deletions. So these aberrations take place not in the 100% of cases with the same disease. And this is also seen here on the expression profiles where you often see heterogeneity in some times you see subtypes of a particular tumor. And so the HER2 story and Trastizimab story actually tells you this is the first story of application of cancer genomics into the discovery of a drug and putting it all the way through the clinic. So the HER2 receptor is a cell surface receptor ties in kinase. And it's a member of the ERB family. There are four members within this family. This is one of them. So the overexpression of this receptor results in the activation of intracellular signaling through the RAS rough ERC and PI3 AKT pathways to promote cell division, cell growth and inhibit aboptosis. So back in 1987 Dr. Islaman an oncologist made a striking observation that a HER2 overexpression was highly correlated with the patient survival and with the tumor sites. And so he started to investigate it and he found an overexpression of this HER2 in 25 to 30 percent of breast cancer patients. And the association with the shortest survival and relapse times was significant. So a little later Genentech in 1990 develops antibodies against this receptor and it was a breakthrough work when they humanized a murine antibody within some 10 months and produced a humanized monoclonal antibody against HER2 receptor. But they were testing this antibody on different spectrum of breast cancer samples. And so they got a only effectiveness only in a few percent of patients. And then there were approach with people who knew about the methods developed to detect HER2 amplification with fish and immunohistochemistry. And once they have coupled these methods of detection of the amplification within breast cancer with the treatment with the antibody they initially they instantly got a excellent response in those patients who had an amplification of HER2. And so the trust to zoom up together with the screening test for the HER2 amplification went into clinical trials already in 1992 and now it is a standard of care the use of tests for HER2 expression status and Herceptin in combination with other drugs. So this slide actually shows you a clinical trials with Herceptin in patients who had a HER2 amplification. So these were a highly selective patients. And so here you see a monotherapy with Herceptin and you can see the response rate was from about 10 to 30 percent. And then there were a number of trials where they used a combination therapy of Herceptin with these different drugs. And within these two clinical trials they had a control cohort where they used just this drug without Herceptin and this is again the response rate. And so you see that the combination therapy with Herceptin and HER2 positive patients gave a response rate of up to 70 percent and that was an exceptional breakthrough. But it also actually points out the necessity of approaching a disease from multiple points from multiple aspects and using different drugs targeting different targets to achieve a desirable response rate. So this was the first example which set the road into this direction. And right now there is a great number of studies being published devoted to predicting outcomes of patients based on some set of blind markers. And yesterday you've heard about this paper. I'm just going to remind you a little bit about it within a few minutes where they used a integrative analysis of copy number and expression to predict outcome of breast cancer patients. So the expression signature of breast tumors showed a distinct subtypes including basal, luminal, and erby 2. Well as Zorab mentioned yesterday it's a little bit of the overstatement here because there is no striking clustering of this expression data. This is slightly the other question I just have to mention that these subclasses of breast cancer had been reported before. But in this case there was and also the same pattern, the same subgroups are observed within the model system such as breast cancer cell lines. And so but these patients have been treated with aggressive therapy and that might contribute to a clustering like this. But anyway you could see some clusters here including basals and erby 2. So what is the survival experience of these groups? It's shown here. This is a Kaplan-Meier curve and I'm going to cover this method later and we will be practicing on this particular data set we will be producing the same Kaplan-Meier curves. So but what it tells you is that erby 2 has the porous prognosis and the basal subtype 2. And this is based on the expression profiles. This figure shows you a clustering of a copy number changes within the same tumors and what you can see is that there is a number of high-level amplifiers within a luminal subgroup. And when they stratified patients into those who have these high-level amplifications and into those who didn't have, they got these survival experiences. So even within a particular expression pattern-based subtype, they could further stratify patients into poorer and better outcome patients based on the copy number changes. So this is just one of the examples to show what sort of research is taking place right now. So the question here now is are we really managing cancer and where are we in this fight? So if you look at the statistics and this comes from the Canadian Cancer Society of the incidence rate and mortality rate for a few selected cancer types, there is actually a very interesting trend. So let's look at the males. These are different cancers. On the left you have incidence. On the right you have mortality. So this is lung cancer. It goes down the incidence rate because of the increasing awareness of a smoke risk factor. Here's the prostate cancer which has a peak about 1992 and that was because of the PSA screening test when into clinic. And so all of those patients that were under diagnosed before were all suddenly diagnosed here. And then you see a decline here again because over time it became evident that the test that they were using was not that adequate. And so a lot of patients were actually over diagnosed at that point. And so that's why it came down. And then it went up again meaning that they came up with the improved screen that gave this incidence rate. And so the mortality from lung cancer goes down. This is good. And the mortality from prostate cancer, where is it? It's not here. But anyway, the mortality from prostate cancer in males is also going down. So this is great. So what do we see in females? It's again very interesting data. So here we have breast cancer and the incidence rate and mortality. So the mortality goes down a little bit because of the improving diagnostic procedures. And sometime around 1985, the mammography, the modern mammography went into the clinic, increasing the rate of the detection of early stage breast cancers. But interesting thing is that for instance, the incidence rate of a lung cancer actually goes up and mortality goes up. So if you look at all of the cancers together, these are males. These are females. This is the overall curve. This is a starting point, the baseline, the rate that it used to be at 1980. And so you see that there is an increase here in the incidence rate and incidence in the mortality. But if you correct for the aging population and for the population growth, you see that the incidence goes just a little bit up in males and the mortality rate goes a little bit down. And this is primarily due to the prostate cancer and lung cancer. In females though, you see that the incidence rate is pretty much flat over time and the mortality also stays about the same. So this actually illustrates that there is still a keen need in novel prognostic and therapeutic biomarkers. And we need to understand in a greater detail what's happening when a patient is given a particular therapy. And then what particular therapy is best for this patient and for that patient. So what have we learned from this part? So the major message is that modern technology and biological knowledge has transformed our perception of clinical intervention. Now it's become clear that there is no one for all decision for every patient, but it should be a personalized medicine. And so, of course, most of the diseases are polygenic traits and that increasing, there is an increasing appreciation of genetic and genomic data that should be used for drug labels. Modern technologies have enabled scanning of the whole genomes and transcriptomes for additional or better prognostic and therapeutic targets. And then we also could see that the integration of multiple level data including genomic expression, epigenetic, histopathological data increases our power of discovery. But it also clear that still much is to be done for putting principles of personalized medicine into practice. So we need new biomarkers, we need new analytical methodology and moreover we need a new legislation for including genetic data into the healthcare. And as for the cancer, still a long way to manage cancer well enough. So now I will take questions. All right, so now for something completely different. Once again. So this part is really meant to be interactive and more of a group discussion. And so I hope that everyone can offer their perspective and opinions as I go through some of this material. So we are entering a brand new world in terms of data generation, where traditionally in bioinformatics, most of the studies up until just a few years ago have been focused on model organisms, the anonymous one human genome project. And the data, bioinformatics has really gained strength from data being put into public repositories as it's being generated and just freely available for research. But we've entered a brand new era where if we just do that with human subjects, we have the potential of introducing some complicating factors in terms of identifying individuals that should remain anonymous. So what this is meant to do is just to really promote an awareness that since we're all working with clinical data, some of the care and precautions that need to be taken when handling this data. So we're really going to go over what identifying data means in research. And then we'll go over just the policies of three example organizations, the ICGC, the European Genotyping Archive, and the Cancer Genome Atlas Project. We'll talk a little bit about controlled or tiered access to data. So really we've come to a situation where we have our generating starts to generate lots of data for the purpose of studying cancer or studying human diseases. And as I said before, what this does is it introduces a bit of a conundrum or dilemma where we want to make advances in research. And we've seen many examples that sharing data in the research community where international collaborators and actually anyone can download data has tremendous benefits in terms of analyzing data. So the more groups that are looking at the data, the more we're going to be able to extract from that. So we want to be able to promote this but still maintain the protection of the privacy of the people that actually donated the samples. So this is really an issue that in bioinformatics has not come up until just the last few years. And so we as the data handlers really have to be quite careful about this. So of course hospitals have to deal with this and physicians have to deal with this for a long time. But as researchers now we need to really become aware of this. So genetic data is identifiable. So what that means is that even with just a very few number of polymorphisms on the order of tens, you can uniquely identify an individual. So we're generating these data, let's say a million SNPs on a chip. But all it takes is a few tens of carefully selected polymorphisms to then be able to identify that individual. And so why is that a problem? Well we want to preserve the anonymity of the donor in order to avoid certain things like just personal embarrassment, legal or financial consequences, stigmatization or even discrimination, insurance companies, employment loans, etc. So there's a very nice paper that really kind of outlines this problem. And I recommend that you read it, it's published in Science in 2007, that really talks about the sort of coming, the balance point between how research is going to be conducted and to get the most out of the data while protecting the privacy of the patient. So maybe I'll just pause there and just take any questions, comments on this whole issue. And what do people think about this era that we're entering in and what kind of consequences or if you have personal stories or about data that you want to share? So I'll just open it up to the floor here, what people are concerned about or not concerned about or if you had your data, if you had donated your samples to research, to what extent would you want your privacy maintained? So let's open it up. Do you not care that much about that? So I generally think that much about it, that they are not aware, as aware, we are talking about the impact of the analysis and the privacy of the patient. So I came across just a piece of news and I'm not sure what the status of this is, I appreciate if anybody knew, but there is a bill put forward in the US about discrimination based on genetics. Does anybody know about that? Yeah, did it actually pass recently? So there are laws now that are catching up to this issue. So any other comments or questions on this? So that's really the setup that one needs to have. So I recently had my laptop stolen and you can imagine how many samples, genetic samples were actually on my laptop, but because I'm in the research side of things, actually there was no harm that could be possibly done there in terms of revealing personal information about the patients because everything was just through anonymous identifiers and only a few people at the cancer agency actually hold the keys to de-anonymize those identifiers. So I mean, I'm sure we all work in institutions where this is safeguarded, but the issue is about when we actually deposit data in writing papers and want to deposit data in public repositories, whether it would take some great heroic efforts, but it is possible for people to potentially de-identify it. Yeah, so you need a matched sample with the linking personal information. And so it's been said also that this problem might be overstated actually that maybe this isn't such a huge problem. So what this paper discusses is that is the growing body of databases like that, though in the police system and other types of institutions like that where they actually have the samples and the results of genetic profiling and the personal information. So if there's a breach there, it's a big issue. Okay, so identifiable data and privacy law. So generally speaking, identifiable data does fall under the privacy laws of most countries. And what this results in is actually controlled and conditional release of data. And so this data is not available for public release. And the question is, is really does this impact research? So as I said before, that research is really benefited tremendously and science has benefited from freely accessible data. Consider the human genome project. So basically as the data was being generated, people were able to analyze it within literally 24 hours of its data generation. And so the labs around the world and the scientific community was trolling through this data as it was being generated. And then we have other examples like GenBank, which is contains all the sequences that have been generated and put in public repository. This has been an absolutely invaluable resource when trying to functionally characterize your sequence or what have you. And so these rich sources of data, we want to probably, we want to do something like this for clinical genomics. But will this model work? So that's the question. And so I think we're still all navigating this space. But yeah, please. So one of the things that people do is, for example, they make, for example, birth dates less precise. So they just say the year in which someone was born. And maybe just don't put an address certainly in the clinical data, things like that. So absolutely so that it doesn't take, even if you don't have precise information, it doesn't take many variables to be able to specifically narrow down an individual. So that's a very good point. So I just want to go over now how the large scale data providers are actually dealing with this problem. So here's the International Cancer Genome Consortium. They have a white paper here that outlines their policy. And so again, I encourage you to visit this because there's some interesting ideas. So let's just go over the core bioethical elements that are in this document. So it says, for prospective research, ICGC members should convey to potential participants that the ICGC is a coordinated effort among scientific research projects being carried out around the world. Participation in the ICGC and its components projects is voluntary. Samples and data collected will be used for cancer research, which may include whole genome sequencing. The patient's care will not be affected by their decision regarding participation. So basically, the patient has to understand that this is a donation that's not going to come. There's no communication back to the patient at all. So the samples collected will be in limited quantities, access to them will be tightly controlled, and will depend on the policy and practices of the ICGC member project. At least a small percentage of the samples may be shared with international laboratories for the purpose of performing quality control studies. Data derived from the samples collected and data generated by the ICGC members will be made accessible to ICGC members and other international researchers through either an open or a controlled access database under terms and conditions that will maximize participant confidentiality. So I was speaking with Francis last night about this. It's dinner, and so the freely available data, either through the open data, this is going to be pooled data. So you'll have, for example, all patients with particular cancer, the SNPs will be just pooled together and it'll be made as a frequency assessment. So it's a summary of a pooled data, whereas the individual data will be under controlled access. So those accessing data and samples will be required to affirm that they will not attempt to re-identify participants. And then there's a declaration that there is a remote risk of being identified from data available on the databases. So and then just to finish off, so once data is placed in open databases, the data cannot be withdrawn later. So once it's there, it's available and you can't just take it back. In controlled data access databases, the links, local data that can identify an individual will be destroyed upon withdrawal and data previously distributed will continue to be used. ICGC members agree not to make claims possible, to possible intellectual property derived from primary data and no profit from eventual commercial products will be returned to subjects donating samples. So these are the types of guidelines and rules that are governing the ICGC. Are there any comments or questions on this? And this is literally something that I just pulled out from this white paper, but it's actually a really quite interesting relevance, I think, to this workshop. Any questions? Yeah, so I'm not sure what implications that has for the ICGC. Householdman Francis is going to be here this morning, but maybe he'll turn up a little later. But so I can give you a perspective from BC is that so with our ethics review board, we had to keep going back like this over and over again. And eventually, I think their top ethicists said actually, so you don't need to actually do that. So the patients, in terms of that our ethics actually consented for kind of any kind of experimental analysis, but in generally speaking, that I think you're right that most of the review boards really require specific testing. So I'm not sure how they're going to reconcile that. Brother, on using those samples, but if there is, you would have to say, in your project, you would require to go to the clean conservation in the chart or whatever, then you cannot go back to the chart, then you are free to do that if the patient can consent for water and research. I have a lot of understanding from a conversation with someone that understands that this is a priority, you know, that kind of thing. And access, make their chart to get extra clean information in the future, right? So even though you cannot make a consent form, that you would ask the patient to sign? Yes, if in the consent, you state that you accept the clean conservation from the chart and if the patient is consenting for that, you cannot ask them to, or rather, do anything you want. If the patient, if the consent form says that you will not accept the only kind of consent between the term and the patient, then you can, you can ask the patient to sign. Great, well, thanks for that perspective. Okay, so here's the, the Cancer Genome Atlas and what their, their governance says. So the TCGA pilot project anticipates that its data will be of high value in a number of research areas and will be used in many ways. Those include, but are not limited to the development of new analytical methods, identification of the genomic etiology of individual tumor types and subtypes, and development of new experimental diagnostic, therapeutic and preventative approaches and strategies for cancer. Thus, the TCGA project recognizes that the data should be available to all users for any purpose, limited only by the need to avoid identifiability of the research participants, and they cite the same paper that I cited earlier. So now this one seems much more relaxed in terms of, in terms of its governance. And so, so I think that as long, so what they're basically saying is that as long as I, I, de-identification is maintained, then, then data should be, should be made, made, release, releaseable. Yeah, yeah, please. It's a, the problem with this type of data space is that problem of control. Meaning, if you don't have access anymore to the patient, you don't know what's going to be the future of the patient. You, you're assuming to see the healthy control and you find out the plighter of the patient, because not an healthy control, you'll lose that information. Yeah, right. So the, the problem of the anonymization of the samples and so doing whatever you want with it, will, will jeopardize the quality of your control population. Yeah, I think that's an excellent point. Especially with disorders that are not, that are, that can appear later on by texture. And calling, calling it the control population might help you to find out if you don't have access to further, further down, meaningful information, you'll be not having good quality. Great.  They, they were assuming that there would be follow-up on through that. And so you have the, all including on history of the patient. And so we could be using the full history of the patient. That's after the patient's death. Right, right. Yeah, so. Okay, so, to ensure it's going on with the, the TCJ, so this is to ensure protection of genetic privacy for sample donors, data users will have to agree to certain conditions described in TCGA patient protection policy and controlled access policy as to how the data will be used. For example, users will have to agree that they will share these data only with others who also have completed a data access agreement and that they will not patent discoveries in a way that prevents others from using the data. This means that reviewers of a manuscript who needs to see, need to see any controlled access TCGA data underlying a result must also agree to these user access conditions before they can see these data. So this is not a situation where if you have agreed to have access to this data, you can just distribute it again. So the only, the only people you can give it to are the people who have also agreed to the material transfer controlled access policy. So here's the BC Cancer Institutional Policy. So the BC Cancer has supported a collection of de-identified data from more than 1000 individuals. And just the, the, so this is just a description of the resource here. And the data collected by the study have been stripped of all personal identifiers. But the wealth of data available on them might make possible the individual identification of some study participants to protect the confidentiality and privacy of these study participants. The recipient who has granted access to these data must adhere to the requirements of this data access agreement. Failure to comply with the data access agreement could result in denial of further access to study data. Violation of the confidentiality requirements of this agreement is considered a breach of confidentiality and may leave requesting investigators liable to legal action on the part of the study participants, their families, or the Canadian government. So this is a, it's part of an agreement that, as part of our New England Journal of Medicine paper, we wanted to release the data so that other people could, could pull it down. And this is basically part of an agreement that people have to sign when they, when they're downloading the data. So what, where we actually posted the data is this place called the European genome archive, or genome phenome archive. And this is really created to store and disseminate the data from the Welcome Trust Case Control Consortium in the UK, which has genotype data on about 17,000 patients. And Anna talked a little bit about some of those studies that have come out from this population. So, so they have a white paper as well that I encourage you to read. And here's their policy. So the EGA will provide the necessary security required to control access and maintain patient confidentiality while providing access to those researchers and clinicians authorized to view the data. In all cases, data access decisions will be made by the appropriate data access granting organization, not the EGA. The data access organization, such as the BC Cancer Agency, in their case, will normally be the same organization that approved and monitored the initial study protocol or designate of this or approving the organization. So, so what the EGA says is okay, we'll, we'll control, we'll store the data and we'll disseminate the data without, without identifying any, any information. And all of the consent and, and all of the protection is the responsibility of the organization that provided it in the first place. So it's really quite kind of a nice model. And I just wanted to highlight what the process is. So, you know, as we're, we're all involved in some sort of clinical data analysis. And you come to the point where you want to publish your paper, what, what you've done with the EGA. And this is basically the policy here. So, so what we do is we first encrypt, encrypt the data using a key that's known to, so here's what, so let me just give you the example from our own perspective. So, so I create a key and I tell the EGA what my key is and encrypt the data. And then I upload the data to EGA. And then, so it's sitting there in its encrypted form. Actually, so they decrypt it and then, and then encrypt it with a, with another key. And then what happens is it's posted there on the website and you can go to the EGA website and you'll see your little study there. And, and so what happens is a user requests data. And when that happens, then the EGA, so they request data to the EGA. So they informed, they informed a committee, which is made up of myself and a few other people at the institution that of the request and the material transfer agreement is sent to the user. And then material transfer agreement is signed by the user or appropriate institutional rep and representative and then returned back to me to the committee. And, and so then, so this actually goes to our technology transfer office. And then the, the committee notifies the EGA and the user is given their decryption key. The user downloads the data decrypts the data. So it's, it's a bit of a process, but, but it's still anyone who wants to have access to the data can do so. It's just so long as they sign this material transfer agreement. And I think the EGA provided an incredibly valuable service. I would not have, I would not want to be the person that had, had to provide this data myself. And, and so they, they have really set up a beautiful infrastructure for this. And, and I think the ICGC is, is, is poised to, to, to have something similar for the, for the cancer genome projects that are coming out. But if you were at, at a stage where you're writing up your paper and you're publishing SNP chips or, or sequence data, you know, I would highly recommend to get in touch with amazing people to work with. And this is like a really seamless process that I think could have been very, very painful in terms of how to provide data. And they just made it really easy. So this is a, this is certainly the way to go. So just in conclusions and so potentially genetic data is potentially identifiable. Researchers certainly have a legal responsibility to safeguard the privacy of donors. So the way you can do that is simply by working with anonymous identified data. And then several models have now been implemented as to how to safeguard the patient privacy. And one should look at the ICGC, the TCGA and the EGA as, as different types of models to handle and provide potentially identifying data. So are there any comments or questions?


Democratic presidential candidate Senator Elizabeth Borne took the stage in Exeter, New Hampshire on Monday for her 161st Town Hall. To a crowd of around 750 people, the Oklahoma native vowed to strengthen the middle class and support working families. Today, a full-time minimum wage job in America will not keep a mama and a baby out of poverty. That is wrong, and that is why I am in this fight. Borne focused on universal health care and laid out her plan to achieve Medicare for all. And the way we can do that is to ask the top 1% of the big corporations and the tax sheets to pay a little more, and that will give us the money. Borne's supporters hope that her visits to this important battleground state help her to stand out from competitors. She's the real deal. She continues to just be herself. I think the polls will shake out in her favor over time. We knew who Borne was four years ago and he hasn't changed. With the polls showing a close race between Warren, Sanders and Biden, the Democratic candidates continue to ramp up efforts for the 2020 New Hampshire primary. In Exeter, New Hampshire, for BU News Service, I'm Phoebe Mendelson.


Hey, what's with you guys welcome back to my channel if you're new here. Hi. Hello, I'm Lydia and this is vlog 2 Now over the weekend. I'm not gonna be doing daily vlogs because I'm celebrating my birthday and I want to spend time with my family So I'm gonna move this vlog with tomorrow Sunday and Monday and Tuesday So it's four days in one Now unfortunately, I'm not gonna have my advent calendar with me So we'll have to open them when I get back But I can't open number two a little penguin My new best friend I need to go and get my medication to take with me and then we're gonna head off to London, Houston Happy birthday to you Hey guys, I haven't really vlogged much today My uncle and aunt got me this mother of day I have to put on my tippy-toes for this frame Tomorrow I'm gonna be 20 I'm off upstairs because I'm tired My legs They're me out I'm back home My training was delayed by half an hour It's 11 o'clock at night And I'm gonna open my advent calendar for the last three days Start up on number three Santa duck and then today is which is a fifth Christmas decorations on So today I wash my hair I'm skipping evening It was honestly, I feel like shit time to open the doggie. It's a snowman


I'm Palmer Payne, W.N.E.W. News on the Radio Theatre. That's the theme from the Sears Radio Theatre. Tonight, a program of adventure with Richard Widmark as your host. Here's a preview. In any way, they wasted a team of buffalo. You mean this whole mess is over a team of wasted buffalo? They belong to Jop, the chief elder of the village. The Sears Radio Theatre will begin after this message from your local station. Can you complete the title of this Frank Sinatra song? Pocketful of blank. That's all you have to do if we call you to become eligible to see Frank in Atlantic City, April 15th. W.N.E.W. and Resorts International are sending eight lucky couples to see Sinatra. Enjoy a great night at the hotel and $100 in cash. Just send your name, address and your home or work number to a W.N.E.W. touch of class. Almost any time between 8 a.m. and 6 p.m., we may call you and give you a Sinatra song title to complete. Do it correctly and you win $11.30 and eligibility in our concert drawings. And on April 16th, William B. will pick one entry from all cards received for a weekend in Las Vegas with Sinatra at Sears Palace. Send your cards to a W.N.E.W. touch of class. Box 1130 Grand Central Station, New York. Do it right away. By the way, the title I was looking for was Pocketful of Miracles. Of course. This is Howard Dove speaking for Richard Widmark. The sun is setting on Bacau, a small village in Vietnam. The dusty streets glow pink now between the fetched roofs of the mud huts. People in the stalls and timbered doorways watch the progress of Jop, the farmer, the holy man, the chief elder of Bacau as he leads his fine buffalo bulls homeward. Now, leading elements of Charlie Company, fifth mechanized infantry roll under the carved gates of Bacau. The watches become tense now. What will the holy man do? Popples on! Lurek! Leave this! Pull them over, will ya? Off it, old man! Hey, three buddies got dusted off today. I mean it! Make way, you old gulp! Look at this setup. This is our city. They got it fighting your war, old man.  I'm gonna blow that old crank away. You can't do that. Yeah. But I can do this. The holy man's terror lifts from his face, but his features turn to stone. The GIs will pay. The GIs must pay. And that's only the beginning of our story. Here's Radio Theater, a new adventure in radio listening. Live nights of exceptional entertainment every week brought to you in Elliott Lewis' production of The Sears Radio Theater. Our story, a short history of Bacau by Andy Nance. Our stars, Tommy Cook and Keith Andes. The Sears Radio Theater is brought to you by Sears Robuck & Company. Sears, where America shops for value. This year, my mom is dressing me up in pretty things from the Sunny Bunch collection at Sears. That's right. She'll look fresh and feminine in these dresses and separates. I can choose from frilly, colorful dresses, bouncy skirts, pants and just the right coordinating tops. Sizes 7 to 14 in easy care fabric that's machine washable. Whether I'm going to a birthday party or just school, my Sunny Bunch clothes make me feel special. You are special. Thanks, mom. Available at most larger Sears retail stores. How long do your pantyhose last? Do you want the answer in minutes or hours? You should try Sears Endurables. The pantyhose that lasted an average of 18 days of normal wear in a test with 400 women. The women in our test wore Endurables day after day after day and as a group averaged 18 days. A patented process makes them strong so they last and sheer so they look great. No pantyhose lasts forever. How long do your pantyhose last? Endurables at larger Sears retail stores. Tell us the one about Robux jeans, old-timer. You mean genuine Robux jeans from Sears? Checks. The Western Whale Life begins in a pair of authentic Western Robux jeans. Made out of hard-working denim? Roping calves? Rasslet's tears? Why, that's the kind of action heavyweight Robux was made for. Hey, how about looks?  Robux, the men's jeans that won the Golden West and most larger Sears retail stores. Morning comes to Kuchi, the army fire base just south of the village of Bakha. The sun is already high and steaming the triple canopy clouds here. That's normal, but there's something else. Something disturbing here too. There's Captain Dawson for one, charging over the tank trails that ring this fire base. Hey, Private, I want a word with you. Yes, sir. Next time, report, sir. Damn it, Private, don't salute me on the bunker line. You want to get me Sniper? Oh, no, sir. Never mind. No sniper would take that for a salute anyway. What is going on around here? Well, sir, we're rebuilding this bunker. Me and my crew, that is. I know that, Private. These group's been giving you any trouble? My crew? Oh, never. Why, Captain? Well, never, he had a mutiny at Bravo Bunker. You know anything about that? Uh, what, what, sir? This group revolution has hit this base. Half of them didn't show up for work this morning. The rest came to make trouble. You know anything about that? I think so, sir. How? They told me, sir.  Private, what's wrong with these gooks? They don't speak English, sir. Well, if they don't speak English and you don't speak gook, how do you tell them anything? Sign language? No, sir. I, I really don't know, sir. I'll ask Bao. Why can't we talk to each other, Babau? We care for you, Harvey. We have magic words. You care for us? You have magic words. Strong magic. Better than dreams. Very strong magic, Harvey. What did she say? I don't know, sir. Inscrutable, aren't I? I'm over here, Private. Now, every linguist we got couldn't get a hint about this. But you say you know something about it. So lay it on me. Yes, sir. Well, yesterday some soldiers came through the village on big track vehicles, and they must have been on some highly frustrating mission because they... Just stick to the facts. Yes, sir. Anyway, they wasted a team of buffalo. You mean this whole mess is over a team of wasted buffalo? They belong to Jop, the chief elder of the village. So what? Well, sir, he's like the Colonel. He's like our... I get the picture. And they make quite a mess, sir. The Vietnamese have a lot of civic pride, but with the blood and the gore... I get the picture, Private. Now, how long's this old man's tent per can from going to last? Well, he'll have to get some satisfaction, I guess. These gooks know this zop fellow? Yes, sir. Okay, Private, you go talk to them, and I'll tell you what to say. Sir? What now? Well, when you speak of zop, would you please say ang-zop and try not to use the word gook. Okay. Right. Babao, my captain wants me to ask you some questions. Let him ask his own question. Oh, Babao, please. He really wants to help. Oh, very well. Ask her if zop reported this incident to us. Has ang-zop told his trouble to the soldiers at the gate? Of course not. What did she say? Farmers don't speak to soldiers. Don't get smart, Private. Yeah, but they don't, sir. Look, Private, you have got to persuade her that we can't clear this mess up unless we contact ang-zop. Now, ask her if we can go into the village and speak with him. Oh, no way, sir. I'll decide that, Private. Ask the question. All right, sir. Babao, will ang-zop consider holding audience with us? Ang-zop, I entertain the idea of audience with you for a number of days. I have spoken to him about you. Ang-zop would be very pleased to meet you even in this bad season. Come here, Private. What was she saying? Well, sir, she says ang-zop will meet with me but not with you. What, in the same hell? Hey, listen, will ya? She's invited me to meet with the elders. Now, there's no refusing such an invitation. To do so would cut them off from me. I couldn't work with them again. Okay, okay. Now, here's what I want you to do. Tell those goots to take off. When you get back from the gate, get yourself shaped up and, by all means, polish those boots. I'm sure the old man will wanna see you and he'd flip if he sees you like that. Sir, when am I supposed to tell Baao?  No, sir. I don't see what that's got to do with it. Yeah, I thought so. Two grunts slipped across a perimeter for some women, I guess. I found them in the morning hanging in bobbed wire. Three guesses, Private. What's the old man gonna say about this? You have no idea, sir, how important this is. Private, if it was up to me, I'd take you there myself.  A total washout. You could mess up a one-truck convoy. I think it's high time you did something around here in terms of your whole act. Yeah, I'd let you go. You'd come back dead or a silver.  Yeah. But can you tell that old bag you're not going? That's what you can tell her. Why? Because that's the way it works around here. We don't send duds into combat. We let them play in the sand. Did I get through? You are not going. Let's try some word association in. Out. Top. Bottom. Paint. House. What? The whole house needs painting. Hmm, I'm... Off. That's it. Sears $4 off paint sale on each gallon of interior, fashion flat, semi-gloss, and ceiling paint, plus exterior flat house paint. I'll uplift my home and my spirits by painting new life inside and out. Hard. Easy. In April 21st, at most Sears retail stores, dates may vary in Alaska and Hawaii. Today's Man of Action wants slacks that look good, feel comfortable. And at Sears, you'll find great-fitting slacks with dash and durability. What really makes it all happen is four-trell polyester gabardine, woven with two-way stretch that moves with you through a day's worth of action. In popular solid colors, a man can feel comfortable with. Any way you look at it, these stretch woven perma-pressed slacks hold up to the assembly to a hard-driving summer. That's style, sense, and satisfaction at most larger Sears retail stores. Today, more women are celebrating that all-American style and walk of the more American-than-shrt dresses, making a big return to spring. Sears' dress department has them in the great new versions, only $17.99 each. Think of men's wear-shirting going to wrestling, pull close at the waist, for a real American accent. Stripes, plaids, checks and chambrays, an easy-care codenham polyester. This is petite and half-size is available at most larger Sears retail stores. Only $17.99 each while quantities last. Prices may vary in Alaska and Hawaii. I stood there silently, the old Vietnamese woman, the young American soldier. After a few moments, she approached him. Did he insult you? He was afraid I'd get hurt. You might be right. There could be some danger. There were some young men in the village this morning. They walked close like my son, but it is said they are not choose men. But no problem. You can walk to the village with us. You come now. I can't go now, but I'll be there. I'll get there for sure. You come with us right now. I'll be there, Babau. Let me try the best way first. Oh, I don't know. Yeah, I will. Just trust me. I'll come tonight for sure. Have it next time. I've been hearing your name everywhere. All Captain Dawson talks about this evening is Private Eckstein. The same with Lieutenant Ozorowitz. The same with Top. I gotta go see Colonel Marshall. I know. I know. The Colonel wants you front and center at 1900 hours. Even the old man has Private Eckstein on his mind. All this worries me, Eckstein. You know why? I gotta convince him to let me go into the village. It worries me because all these people are talking about Eckstein. And I don't know what's going down with Mr. Eckstein. And when they talk about Eckstein, they're talking about me. Eckstein's my man. I own Mr. Eckstein lock, stock, and barrel. You read me, Eckstein. Now what's the buzz? Well, sir, something awful happened in the village. Two grunts wasted the Chief Elder's buffalo. So Captain Dawson made me find out about it. And one of the old women, her name is Bow, asked me, well, she invited me to the village tonight to talk with the elders. And I gotta do it, Sergeant. I gotta do. They'll really be hurt if I don't. I've got to convince the Colonel. And you gotta help me, Sergeant. We gotta convince the old man. He'll never listen to me, and he's got to listen, Sergeant. Now, we can do it together. He'll listen if you and... Eckstein, Eckstein, at ease. I got the story. Look, Eckstein, I'm gonna give you some fatherly advice because this is Vietnam, and I'm your big daddy over here. If you don't follow it, you can spend the rest of the war cleaning latrines. I've been in the Army 17 years, and I never told a field-grade officer anything. When they ask to see you, they've already made whatever decision is gonna be made. So Eckstein, grow up.   And forget those gooks. I'm sure you'll find something around here for you to do besides hanchoing gooks. Now, there's plenty to do. Now get your weapon and meet me in the orderly room. Yes, Sergeant. Hey, Jackson, I've got guard duty tonight. Watch Eckstein for me, will you? He's crazy enough to try to slip past the bunker line.  Private Eckstein, report, sir. Eckstein, someday I'm gonna teach you how to salute an officer. What's that? Is that a gleam I see in those boots? What happened? Did you spill some polish? No, no, no, Colonel Marshall, sir. Well, anyway, what have you decided? Are you going to town this evening? I didn't know I had a choice, sir. I know you didn't, but now you know. I am the one who has no choice in this matter. There'll never come a day when I order a dud into combat.  So I simply don't have a choice. Only the duds in this man's army that have choices. I'll need a gate pass, sir. Before you make up your mind, you need to know some things. First of all, I've checked out your story with G2 and they tell me you might be right. They also said a VC propaganda team moved into the village last night, so you could be wrong. But I want you to know there's a war going on. Dawson tells me you're pretty chimney with these gooks around here. He thinks you might be deluded. He doesn't think I should send you into a hostile village at night. I'm not sending you in there. I'm giving you a choice. Nevertheless, I feel compelled, yes, Eckstein, compelled to inform you there's a war going on.   And Eckstein, this is the nitty-gritty. You can't expect everybody to love you anymore, you understand? Nobody out here is going to love you, at least of all these gooks. Now think about that. What have you decided? I'm going. Here's Radio Theatre. We'll return after this message from your local station. It's question and answer time. I know the questions, you know the answers, or do you? First question, who is the detective hero created by a famous female British mystery writer? I don't know. Right. Second question, which author was a creator of Sam Spade and a close friend of Lillian Hellman? Martin Mayonnaise. Correct for a thousand bobbling. Third question, what is the name of the greatest killer of all time? Oh, Al Capone. Bugsy Malone. A Bonnie and Clyde of the bullet. Correct for a thousand bobbling. The greatest killer of all time is heart and blood vessel disease. It's no joke. More people die of heart and blood vessel disease each year than of all other causes of death combined. We'd like to change that. We're the American Heart Association. Call us to find out where free blood pressure screenings are being held. Remember, we're fighting for your life. I'm lost and lonely, scared and sad. This song was written by a man now serving time in a state prison. Most of the men and women in prison today abuse children, grow up to abuse their own children. Child abusers can be helped. Find out how. Right prevent child abuse. Box 2866, Chicago, Illinois, 60690. Please stop the hurt. I've suffered since my birth. A message of the head council and the National Committee for Prevention of Child Abuse. Private Eckstein, a young man of sympathy and courage.  Private Eckstein, prepared to risk his life to keep some semblance of peace in the midst of insanity. Well, what have you decided? I'm going. Why, Eckstein? Never mind. I don't want to know. Let's get down to business. What's it going to take to satisfy the job, fella? I don't know, sir. Well, you promise him anything he wants. The old goat's got us over a barrel. Your job is not to bargain. Your job is to report to me exactly where, when and how much. Is that clear? Yes, sir. That's the first step to getting it back here alive. The next is neutralizing that propaganda team. There's around six gooks in one of those outfits. They're a shrewd bunch, but they only carry handguns. I think you and two rangers can handle any firefight, but the key, Eckstein, is not to let them get close in. I don't think they'll try to waste you. They count three rifles. The main thing, Eckstein, is you've got to stay alive. Now, the rangers know their business.  Let me see your weapon. Damn, Eckstein, you can't go into combat with a weapon like this. Here, take mine.   What are you trying to do?  You never asked me what... You want a quartz martial private? Yeah, I apologize for my language, sir. But I want to... You're insubordinate, Private. Are you going to listen to me, sir? I have no intention of listening to you. I've had enough about you. You're dismissed. This is not going to work, sir. The event of me... That's quite enough, Private. You're dismissed. You've got to hear me out. I can have the guards hold you out of here right now, and that's what this is coming to.   I'm not going to call the guards.   You're right, Eckstein. I don't want to hear about it.  I... At ease, Eckstein. I'll hear what you've got to say. I'll hear it.  You'll do about a year for this, Eckstein. It ain't a bit fair, Eckstein, but you understand my position.  But if I was to lay a finger on you, 15 years would be lost. So you're going to pay for it. Not the way I'd have it, but good enough for the likes of you. Fair enough. But you're going to let me see those people first. I think I know a damn side more about the Vietnamese than you do in the first place. The right to talk formally with the elders is a high honor.  The only thing worse than coming armed is coming with an armed guard. Besides, if you have rangers standing outside the elders' hooch, that propaganda team will have the whole village convinced we've wasted the elders.  It's bad showmanship. Now it's got to be done my way. I can do what you've asked me to do, but they aren't Indians and we aren't cowboys. Oh yes, there's a war going on, but it isn't between me and shop. After this, I truly don't care. I'd be sending a certain death. Do you understand the other way won't work?  They don't trust you. They want to talk to me. My way is the only way. We make a combat mission out of it, and it won't work.  Yeah, it's that simple. Eckstein, you're going to have to understand this. You're not old enough to see it yet, but you're going to have to try. I used to think that is, I've always told myself there's a fine line between what's truly courageous and what's foolish. I was wrong. No such line exists. If it succeeds, it's an act of courage. If it fails, it's foolishness. To be a coward or to be a fool, that's the choice. These regulations on my desk, I can't fight a war with them. I've got to try things, that's how wars are fought. What works wins, what fails is part of the cost. I think I understand. I don't think you do. This is the scenario, Eckstein. The gooks get offended sometimes. It's imagined this time it's real. So when comes the VC? Things start happening here on the post. I have to lay off the Vietnamese workers. This makes them unhappier. VC begin to operate from the village. I have to garrison it. Eventually I'll have to reduce it to rubble. You say you know more about them than I do. This is my fourth tour, Eckstein. This thing, exactly this thing has been happening since I first came over. The events over the next four months will cost this battalion over 50 casualties and about a quarter million in material if we don't get overrun. After it's done, we're back where we started. That's the way it's always been. And then you, Eckstein, you come in here and offer me a way out. A way out, Eckstein. That's an incredibly dangerous thing to do. I'm going to give you this pass, Eckstein. I don't expect you to use it. I don't want you to use it. I think if you do use it, you'll be lost. Get up in the morning and go to your duties. No one will ever say anything to you about this. The option is yours. Yes, sir. The rangers and whatever equipment you might need will do well. I won't need this, sir. When can I expect you back? Tomorrow morning. I'll come in with the workers. If you're not at the gate, I'll be coming in after you. Yes, sir. Thank you, sir. It was the coming of how we fought for a very long time. The time we took for the earth to swallow the sun. At first, they were tiny figures from the fire base to the village. They grew larger as they weighted the rice paddies. In the danger in the sun, two raised rifles level omen. I doubted how we'd end. No good could come from this. Oh, I pray for his safety, but I understood his doom. Can they stop at Village Gate? Long moment passed, and then as my heart stopped, the two armed men turned away. How we, alone, unarmed entered the dark streets of Bacca. His body diminished. He slept uneasy. All eyes hidden in darkness. And yet I knew as he walked, he felt them. Then a shadow swallowed him. And when he emerged, he met the young man of whom it was said were not choose men, idling in a market stall. How we stopped. The young men toyed with their weapons. How we stood still. I saw him then about to die. I cried out to him. He not move. I ran to him, though I too might die. And he smiled, but could not speak to lead him to my father's house. Steps were heavier. But as we passed, they grew lighter. And when the danger lay behind us, we were weightless. So came how we to Bacca. Trong the port, we make a song of this. Do you like some rice beer? Oh, thank you, your honor. You must be hungry. I am I am Trong, a farmer. This is a leader. I am much too honored by your presence, sir. You need not worry how we if you become too honored, we will remind you of your humility. You come at the most opportune time in our conversation. We cannot conceive of the cause of a recent incident. Two young men, like yourself, came to the village yesterday and committed a most unreasonable crime. They destroyed my two buffalo. They riddled the animals and then drove their machines over them bloodying these holy streets. We want to know why, how we. I don't think I can give you a reason. No one told me why this thing happened. I was sent by my elders to make amends for it, but I don't know why it had to happen. It's a bad season. How we, you are young and of course you do not know, but all the seasons I remember have been bad. I know how we the question we are asking is difficult. But we must learn the answer before we may proceed. You may Your Honor, I have to confess, I don't know how to meditate. We're just lonely men, Your Honor. We come over here puzzled over the reasons we have come. It doesn't even seem to matter. Our Honor is measured by our loved ones and they're too far away for us even to imagine the distance. Our free minds live with them. Talk to them. We're here as machines. Machines of war, like the machines that trampled your buffalo. And when the season has come for our return to our villages then we will be men again. We are men without families. Men without guidance. Why did the soldiers execute my buffalo? There was no command given to slaughter the animals. It was like an act of passion. Time, I guess. Time passes very slowly for a soldier. Now, I know it's going to be hard for you to understand but time favors the farmer. It's a moral confusion, I guess. I can't find the words for it. Are we? Are we, my son? Yes. How are you, my son? Are you meditating? No, no, Your Honor. I am inexperienced with rice, beer. I thought it was a bad idea. You must leave the rest for us to drink. There was a question in my mind. That is most unusual by our custom. Do they do that in America? We should listen to the young. I need to know what we can do to amend the crime we committed. Ah, yes. What do you think you should do? Well, we should give you something of value. How much? As much as you want. How much is that? Well, it should at least equal the value of two water buffalo. Well, maybe more, I guess. Only two water buffalo equal to water buffalo. That is enough. Would you like some money as well? Well, if you didn't want it, you could give it away. I could not keep it, nor give it to my friends, nor even to my enemies. If money would disorder my life and I am wise, then think how disordered it would make my people. And they would not give it to my enemies but want them more disordered than they already are. Besides, in all my experience there has always been an end to money. But there is no end to the usefulness and productivity of two strong and testicular buffalo. I would take your money because that is what plagues you, but what would I do with it? I have so much to learn from you. That is true. It is not merely, as you said, about the slayers of my buffalo. It is not simply abandonment. That is the cause. The question is why your elders would put so much power in the hands of children? And the answer is you have too much to master. The more one has the harder it is for him. Just as a big man must work harder to curb his appetites. So you either need more mastery or less to master. We have provided for you as is our custom. I don't know the custom. We think you will learn it easily enough. We have provided a woman for you. Now get the full power of the maintenance free Sears 48 battery for a full $7 off its regular low price. The Sears 48 on sale now just $42.99 with trade-in. And get great savings on Sears best-selling belted tire, the Dynaglass belted 25. Now save $14 to $28 on sets of 4 at most Sears tire and auto centers. Prices may vary in Alaska and Hawaii. Tell us the one about Robux jeans, sir. 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We'll pick him up in my jeep. Yes, sir. Where is Colonel? Where? That group up ahead. Yeah, yeah, I see him. You're not accomplished, sir. Congratulations. Don't salute, please. Yes, sir. You weren't really going to salute me in the middle of a race, Patty. Were you, Eckstein? I think he was trying to scratch his nose, sir. I hope so. Eckstein, come over here. Private, for Pete's sakes, where did you leave your rifle? At ease, Dawson, call it stupidity, call it carriage, but this young soldier went into a Vietnamese village at night unarmed. Unarmed? Unarmed! I can't believe it. Let the old goose stick us for, Eckstein. Sir? How much did those two buffalo cost us? You won't believe this, Colonel. Try him, Private. Well, I told Ong Zap to name his price just as you ordered. Good work, son. Forget this, sir. He wouldn't take a thin dime. It's worse than I thought. No, sir! All he wants is two more buffalo! That's all? Yes, sir. Good ones, though. Young and strong. Bulls. He uses them for breeding. That's easy. I don't know. He won't take money, you say? I saw some good ones near T. Singh, sir. That village is V.C. anyway. How are you going to move them, Captain? Deuce and a half, sir. And load them? Crane. We've got to clear the crane through General Wayrime. No way! Couldn't we buy him, sir? That goes through division. Area specialists. We'd be laughed out of the regiment. I don't mind being laughed at. I know Ria Reshalon would stick their nicks out. He wouldn't take money, you say? That's right, sir. Look, Eckstein, turn around and go back to the village. Find Mr. Jop. Tell him like this. See, we're not farmers, so we don't know one buffalo from another. He could end up with a couple of duds if we had to pick them, right? So ask him to shop around when he finds a pair he likes. Tell him to let you know, then you and Captain Dawson go buy them. We'll buy them on condition the owner delivers. You got that? Gee, I don't know if they'll see me uninvited, sir. You don't have to go, son. We can try waiting him out. No. I'll try it, sir. I understand perfectly why you don't want to go back.  I want to go, sir. Well, you don't have to go now. You can put it off for a few days. I'll even give you time off, Eckstein. With all due respect, gentlemen, I really want to finish this up. I understand. Only this time take this rifle. I can't, sir. I order it, pride. I tried that, Captain. It didn't work. I can't allow it this time, sir. I've got a feeling... We don't work that way. You'll get over it, Captain. Wish me luck, gentlemen. If I don't hear from you before lunch, I'm going to be very concerned. Yes, sir. Ong Trong! Ong Trong! Halvee! I hoped you were safely inside the barbed wire. Yes, Your Honor. I would have been, but there was one more problem I wanted to discuss with Ong Xia. You promised you'd safely turn to the barbed wire. You're in great danger here, Halvee. Babao performed her duty as best she could, Ong Trong. My problem seems so very important. I hope to present it to Ong Xia while I still stand in his grace. That's not possible, Halvee. Come inside. Shhh! Sit down. Perhaps if you share this problem and it's not too trifling, I will bear your words to the holy man. Oh, thank you, Ong Trong. My problem is this. We soldiers have no use for the water buffalo. Therefore, we have no experience in procuring them. Very likely, if we saw a pair of water buffalo for Ong Xia, the animals would prove unworthy of his honor's time and care. So, to avoid this misfortune, I wished humbly to ask Ong Xia to choose the animals he most wanted, and then to inform me through your daughter, Babao, of their whereabouts. You see, that way, we could be sure of finding worthy beasts. Do you find this feasible, Ong Trong? Absolutely not. Oh. May I humbly ask a reason, Your Honor? You may, because you're young. I have no right to expect you to understand obvious. Why, Halvee, do you think Ong Xia asks of you the one thing you could not give? I... I don't know, Your Honor. Of course you don't. You're too young. His honor wants nothing from you. Oh, I... I see. Forget the buffalo. Go back to barbed wire. Did you bring alms? No, Your Honor. This once, you sure have. Babao, please, I must ask you... Ong, Ovee, how could you do this to me? Babao, forget that and please help me think. How am I going to explain this to the colonel? Oh, the white-haired one. I thought you were safe with him. Now I have lost face with my father, Halvee. Ovee! Medevac standing by, alert, fourth wolf hounds. What happened, sir? X-times hit, let's go. That clump of villages, a hundred yards off, two o'clock. Shall I open fire, sir? No. You want Medevac ordered forward, sir? No. What are they doing, Corporal? They're coming in, sir. Bring up fourth platoon wolf hounds. I want these bunkers bristling. Yes, sir. Pull out! I want safeties on our weapons unloaded. Yes, sir. They've stopped, sir. Let's go Dawson. Look, sir, that old man has Eckstein slung across his back. I see. You are burdened, old man. We both are, white-haired GI. We have paid dearly for peace. We have peace again, old man?  They have lost face in our village. I'll open my gates to your people. How we have people?  She won't be inserted? I hope not, old man. I sincerely hope not. Soldiers have strange ways. If ever there's trouble again, we'll talk. I would be honored. So long, old man. My first night camping with my family of five, now I'm really glad I packed my Sears family-style tent. It's Sears' best tent, tested by Sir Edmund Hillary, the first man to conquer Mount Everest. This tent stands six feet nine inches in the center and has a sewn-in ten-by-fourteen-foot floor. It sleeps eight, plenty of room for my family and even the dog.  Sears' best family-style tent is built to be lived in and if it's good enough for Hillary, it's good enough for my family. 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Where our policy is satisfaction guaranteed or your money back. Sears where America shops for value. A short history of Baca was written by Andy Nance. Produced and directed by Elliot Lewis. Our stars were Tommy Cook and Keith Andes. Also heard were Dawes Butler, Marvin Miller, Lillian Bayef, Tom Drake, Norman Alden, Sam Edwards and Stanley Director. The music for Sears Radio Theatre was composed and conducted by Nelson Riddle. Art Gilmore speaking. Associate director of Sears Radio Theatre is Ken McManus. Sound effects were created by Bud Tollison. Joanne Thompson is production supervisor. And the recording engineers are Joe Wachter and Hal McDonald. The Elliot Lewis production of Sears Radio Theatre is a presentation of CVI. What in the world happened in April brought to you by your local Navy recruiter? April is admissions day for Maryland admitted in 1788 as our 7th state. And Louisiana admitted in 1812 as our 18th state. George Washington was sworn in as our first president in April of 1789. And the first U.S. Congress began regular sessions at Federal Hall in New York City. In April of 1860, the First Pony Express run was made from Missouri to California in 10 days. The motto in God We Trust was first stamped on all U.S. coins in April of 1864. The Navy's first submarine, the USS Holland, was commissioned in April of 1900. Navy Commander Robert E. Peary and Matthew Henson reached the North Pole in April of 1909. What in the world happened in April is brought to you by your local Navy recruiter who will answer your questions about Navy opportunity or in the continental United States call<PHONE_NUMBER> toll free. In Georgia,<PHONE_NUMBER>. Navy, it's not just a job, it's an adventure. It's run up and down your spine. There's a creeping sensation at the back of your neck. You're listening to CVS Radio Mystery Theatre. I'm E. G. 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A few years ago I made some videos laying out a case against object-oriented programming, and since then I've been meaning to make a positive case for an alternative, a prescription for how code should be written rather than how it shouldn't. It's taken me a while to work out what I think can be said about how to write code with any certainty, and confusingly the prescription in part might sound suspiciously like OO to some ears. I'm not really recanting my prior position though, many people just remain confused about what's unique to OO and what's not, hence I'm calling this object-oriented programming as good, but with an asterisk. A more honest title for this video might be module-oriented programming, where module refers to a unit of reasonably self-contained code, but the even more honest title would be How to Write Good Procedural Code. Incapsulation, polymorphism, and even inheritance will be a part of the story, but as I'll explain, the total picture has profound differences from object-oriented programming. So here's how I think code should be written. Code should be written in units we'll call modules, and these modules come into basic kinds, state modules and logic modules. The distinction is that logic modules contain no internal state, i.e. global variables, and logic modules do not reach out for external state. This means that a logic module consists only of functions, and these functions only touch stateful things which are explicitly passed to them, so a logic function can, for example, read and write to a file if an open file is passed into the function, but a logic function cannot itself open any files. The management of state is not the responsibility of logic code. A logic function may generate new data and also may mutate its inputs, but its only responsibility is to generate and mutate data only as it says it will in its documentation. The side effects of a logic function are actually then the responsibility of its callers. So the relationship between state modules and logic modules is strictly one way. State code can call into logic code, but not the other way around. As for the state modules, each should protect its private state, and state modules should only directly touch each other's public interfaces. In other words, the modules should be encapsulated. And even though logic modules have no state to protect, they too should distinguish between public functions and private functions so as to minimize exposed surface area. Now you might object that modules might sound like objects, but there are two key differences. First, there is no rule about how big modules are allowed to get. They may be tens or even hundreds of thousands of lines long. Very large modules are perhaps not ideal, but I'm not going to give you any hard rules against them. Second, a module is not an instance of a data type. In almost all cases, our state modules are singletons and we're unapologetic about it. Data types in fact don't really belong to any module. The best way to think about data types is that they live outside all modules and when data is transmitted from one module to another, the structure of that data belongs to neither module more than the other. We wouldn't say that a protocol belongs more to a client or more to a server and the same should go for data types. As a practical matter though, a data type must be defined somewhere in code, so we generally define a data type in the module where it's most predominantly used. We may also sometimes want to encapsulate operations on a data type, in which case we'd put the data type and those functions in the same module. Because state management is an ugly problem, the general goal in any code base is to minimize the proportion of state code. As much as possible, we want to punt code from our state modules into logic modules. In some programs, state management may inherently predominate, but in many cases, the state code can be a small fraction of the whole code base. The question that follows is when should we break up modules into smaller modules and along what boundaries? For state modules, a major reason to break them up is to divide and conquer state management. For either kind of module, we might also break them up simply for organization. All code concerning feature A goes into module A, and all code concerning feature B goes into module B, etc. Such structuring can make the code base easier to understand if done well. Just be careful not to overdo it. We also might split up modules for the sake of team collaboration. Group X takes ownership of module X, Group Y takes ownership of module Y, and the modules are coupled only through their public interfaces. Even for logic modules, this can help, because it allows one group to change internal implementation as long as the public interface remains unchanged. For similar reasons, we might split up modules to better formalize an externally exposed API. We don't want to bother our external users with details that don't concern them, and we want freedom to change what we've kept private. Again, many people today accredit these ideas to OO, but the idea is actually predate OO and don't require us to follow the rest of its prescriptions. We should not conflate modules with data types, and we should not obsessively whittle modules down to tiny sizes. So yes, though I spent most of my earlier videos arguing that OO sells an overly aggressive form of encapsulation, I think encapsulation is actually a perfectly useful idea. But then, about polymorphism and inheritance? My take on polymorphism is that interface types, or type classes, or traits, or whatever semi-equivalent in your language, they can be extremely useful. Their utility, however, is primarily across module boundaries, particularly across the boundary between an API and its consumer. With these interface types, we can formalize commonalities between different data types, including data types defined externally to our own code, much like a protocol allows us to treat client, servers, and peers like swappable components, interfaces allow us to interoperate with code that hasn't yet been written. If however, I have no need to allow for such external extensibility, I generally avoid interfaces. An interface requires me to speculatively generalize to imagine needs I don't concretely yet have, and this extra burden does not always pay off. For internal business, for modules well contained within my control, I don't really care about that kind of extensibility. For code I control, flexibility is maintained by favoring the simple solutions to my concrete problems rather than entering the realm of speculation. Now, as for inheritance, inheritance is also a mechanism for expressing the commonality between types, but inheritance additionally shares implementation. A child type automatically shares the implementation of its parent, except for those parts the child overrides. This implementation sharing might be convenient in some cases, but as famously noted, it tends to make code fragile. Changes to ancestor class implementations can affect descendants in unexpected ways, sometimes leading to some pretty nasty bugs. On the other hand, where types have lots of overlap in their data, inheritance makes these overlaps in code clear, and more convenient to write in the first place. This is something I think the go language gets right. A type can inherit the data of another, but this embedding, as they call it, does not create a subtype relationship. So that's actually all I have to say about how to structure code. I think it's a relatively simple picture overall. I'll end though by elaborating on what I think this implies that OO gets wrong. As already discussed, OO conflates modules of encapsulation with data types. Second, OO is overly optimistic about how frequently and easily we can create good abstractions. And third, OO favors design with too many small pieces. So about the second point. The underlying premise of OO is that more abstractions are always better and that we can create good abstractions in the normal course of application development. This is wrong. Good abstractions take a lot of hard thought and time to get right, and typically they emerge only slowly over many iterations. Now, when creating an API, creating good abstractions is part of the job, hence creating a good API can be very difficult. In normal application code, however, we should free ourselves from this burden where it's not truly necessary. These do arise where new abstractions provide better solutions, but our default mode should not be seeking to create new abstractions. As for the size of our code units, the difference between procedural and OO is how and when we subdivide the units. In procedural code, we modularize by accretion, only splitting up modules when they get too unwieldy. In object-oriented code, however, we modularize speculatively, splitting up modules in anticipation of problems later. In theory, OO code is flexible.  But in practice, the burdens of speculative generalization rarely pay off. Good structure is about a thing's relations to other things, but OO wants us to build piecemeal tiny units in isolation. The pieces produced in this process might be easier to build and understand individually, but the whole system is not. Object-oriented design requires context, and these tiny units are isolated from context. Object-oriented design is often sold as the responsible thing to do, the moral equivalent of keeping a closet or drawer meticulously organized. What typical OO designs feel like, though, are tangles of excess packaging. In the worst cases, everything is so fractured, indirected, and abstracted that, like in Wonderland, nothing in code is as it seems. The names of the classes and methods lie about what they actually do, because the real work is always done elsewhere. The procedural alternative comparatively encourages us to introduce subtractions only when they're much more likely to be useful.


Appalachian Wireless is transforming the way you upgrade your smart phone. Trade in, trade up and experience the benefits of Appalachian Wireless's trade-in program. Get your estimate on AppalachianWireless.com now. Better service and bigger savings, that's today's Appalachian Wireless. Since taking office a little more than a month ago, Pike County Judge Executive Ray Jones has vowed to take steps to clean up Pike County, literally. One of those steps was to hire a solid waste enforcement officer. This primary job is to investigate illegal dump sites in the county and enforce county garbage codes. Prior to this administration, there was no county employee tasked with siding people who were dumping illegally, and we have a beautiful county.  It has a direct impact on airability to try to bring jobs to eastern Kentucky. When you have a company that comes in from outside of eastern Kentucky, and you're trying to get them to locate here, and they see the ditches and the creeks full of trash, and they drive by a property that's an illegal dump, that is absolutely not the image that we need for Pike County in eastern Kentucky. And if we catch you dumping illegally, you're going to be prosecuted to the fullest extent of the law. The new solid waste enforcement officer is a sworn law enforcement officer with 15 years experience. Bruce Anderson says this new position with the county is a lot like his former job as a police detective. There's a lot of angles to look at when we do go into these dumps, I'm literally going into garbage and searching, and you would not believe having great progress. As to date, within a three week period, there's been five cases I've already turned into the county attorney, and there's two pending, and this all stems from these people legally dumping garbage. The number one thing that I'm finding in these dumps is you would not believe is these people's mail. They throw their mail away, and I'm talking all sorts of mail, and they simply throw it away. Their names, everything you need, Judge Ray Jones has told me, 100% prosecution until things change. Anderson encourages anyone wishing to report an illegal dump site to do so by calling the Pike County Solid Waste Department.