{"id":50467,"date":"2014-10-05T21:00:07","date_gmt":"2014-10-06T01:00:07","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=50467"},"modified":"2014-10-05T21:15:45","modified_gmt":"2014-10-06T01:15:45","slug":"two-weeks","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2014\/10\/05\/two-weeks\/","title":{"rendered":"two weeks!&#8230;"},"content":{"rendered":"\n<ul>\n<div align=\"justify\">A response to:<\/div>\n<\/ul>\n<blockquote>\n<div align=\"justify\" class=\"big\"><a target=\"_blank\" href=\"http:\/\/ajp.psychiatryonline.org\/Article.aspx?ArticleID=1906049\">Uncovering  the Hidden Risk Architecture of the Schizophrenias: Confirmation in  Three Independent Genome-Wide Association Studies<\/a><\/div>\n<p>      <\/p>\n<div align=\"justify\">by<\/div>\n<ol>\n<li>\n<div align=\"justify\">Javier  Arnedo, M.S.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Dragan M. Svrakic, M.D., Ph.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Coral del Val, Ph.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Roc\u00edo Romero-Zaliz, Ph.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Helena Hern\u00e1ndez-Cuervo, M.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Molecular  Genetics of Schizophrenia Consortium<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Ayman H. Fanous, M.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Michele T.  Pato, M.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Carlos N. Pato, M.D., Ph.D. <\/div>\n<\/li>\n<li>\n<div align=\"justify\">Gabriel A. de Erausquin, M.D.,  Ph.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">C. Robert Cloninger, M.D., Ph.D.<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Igor Zwir, Ph.D.<\/div>\n<\/li>\n<\/ol>\n<div align=\"justify\" class=\"middle\"><strong><font color=\"#004400\">American Journal of Psychiatry<\/font><\/strong>. <em>Published in advance on September 15, 2014.<\/em><\/div>\n<\/blockquote>\n<ul>\n<div align=\"justify\">[see <a target=\"_blank\" href=\"http:\/\/1boringoldman.com\/index.php\/2014\/09\/16\/short-list\/\">short-list?&hellip;<\/a>] in <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25219520#comments\" target=\"_blank\">PubMed Commons<\/a> on behalf of:<\/div>\n<\/ul>\n<blockquote>\n<ol>\n<li>\n<div align=\"justify\">Gerome Breen, PhD [Institute of Psychiatry, King&rsquo;s College London, London, UK]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Brendan Bulik-Sullivan [Broad Institute, Cambridge, MA, USA]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Mark Daly, PhD [Broad Institute, Cambridge, MA, USA]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Sarah Medland, PhD [QIMR Berghofer, Brisbane, Australia]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Benjamin Neale, PhD [Broad Institute, Cambridge, MA, USA]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Michael O&rsquo;Donovan, MD PhD [Cardiff University, Cardiff, UK]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Stephan Ripke, PhD [Broad Institute, Cambridge, MA, USA]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Patrick Sullivan, MD [Karolinska Institutet, Stockholm, Sweden]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Peter Visscher, PhD [University of Queensland, Brisbane, Australia]<\/div>\n<\/li>\n<li>\n<div align=\"justify\">Naomi Wray, PhD [University of Queensland, Brisbane, Australia]<\/div>\n<\/li>\n<\/ol>\n<p align=\"justify\">In this study published on September 15, Arnedo et al. asserted that schizophrenia is a heterogeneous group of disorders underpinned by different genetic networks mapping to differing sets of clinical symptoms. As a result of their analyses, Arnedo et al. have made remarkable and perhaps unprecedented claims regarding their capacity to subtype schizophrenia. This paper has received considerable media attention. One claim features in many media reports, that schizophrenia can be delineated into &ldquo;8 types&rdquo;. If these claims are replicable and consistent, then the work reported in this paper would constitute an important advance into our knowledge of the etiology of schizophrenia.<\/p>\n<p align=\"justify\"> Unfortunately, these extraordinary claims are not justified by the data and analyses presented. Their claims are based upon complex [and we believe flawed] analyses that are said to reveal links between clusters of clinical data points and patterns of data generated by looking at millions of genetic data points. Instead of the complexities favored by Arnedo et al., there are far simpler alternative explanations for the patterns they observed. We believe that the authors have not excluded important alternative explanations &ndash; if we are correct, then the major conclusions of this paper are invalidated.<\/p>\n<div align=\"justify\">Analyses such as these rely on independence in many ways: among variables used in prediction, absence of artifactual relationships between genotypes and clinical variables, and between the methods of assessing significance and replication. Below we identify five specific areas of concern that are not adequately addressed in the manuscript, each of which calls into question the conclusions of this study.<\/div>\n<ul>\n<div>A. Ancestry\/population stratification&#8230;<\/div>\n<div>B. X chromosome [chrX]&#8230;<\/div>\n<div>C. Linkage disequilibrium [LD]&#8230;<\/div>\n<div>D. SNP selection&#8230;<\/div>\n<div>E. Replication&#8230;<\/div>\n<\/ul>\n<div align=\"justify\"><strong><font color=\"#200020\">Conclusions:<\/font><\/strong><font color=\"#200020\"><strong> <\/strong><\/font>Given the remarkable claims made by Arnedo et al., it is essential  that alternative explanations be excluded. Unfortunately, the authors do  not provide the necessary evidence. As presented, their methodology is  opaque [even to experts], meaning that their results cannot be  independently validated. Arnedo et al. do not consider alternative  explanations for the phenomena that they observe, such as confounding  from ancestry and LD, even though these are well-known issues for the  statistical methods that they employ and have been studied extensively  in the statistical and population genetics literature. In addition,  their multistep analysis approach is subject to multiple issues as noted  above. We believe that it is highly likely that the results of Arnedo et al.  are not relevant for schizophrenia. We urge great caution in the  interpretation of the results of study.<\/div>\n<\/blockquote>\n<div align=\"justify\">Well, that didn&#8217;t last very long &#8211; just two week. We mortals aren&#8217;t really capable of vetting these genetic studies on such large populations, working with so many genes and complicating factors. We&#8217;re just spectators in a Colosseum<img loading=\"lazy\" decoding=\"async\" width=\"180\" hspace=\"4\" height=\"111\" border=\"0\" align=\"right\" src=\"http:\/\/1boringoldman.com\/images\/colosseum.gif\" \/> watching a Battle of the Titans. At least that&#8217;s where I am when it comes to this kind of research. The criticisms in A-F above that I left out of my summary are far reaching &#8211; untested confounding factors like ancestry and gender, faulty analytic and statistical methodology, replication errors. And their conclusion&#8230;<\/div>\n<ul>\n<div align=\"justify\" class=\"small\"><em><font color=\"#200020\">We believe that it is highly likely that the results of Arnedo et al.  are not relevant for schizophrenia.<\/font><\/em><\/div>\n<\/ul>\n<div align=\"justify\">&#8230; is almost as definite as that in the original paper, in the opposite direction:<\/div>\n<ul>\n<div align=\"justify\" class=\"small\"><em><font color=\"#200020\">Schizophrenia is a group of heritable disorders caused by a moderate  number of separate genotypic networks associated with several distinct  clinical syndromes.<\/font><\/em><\/div>\n<\/ul>\n<div align=\"justify\">I&#8217;m not reporting this with an opinion about who is right here, or if either is right. I just wanted to make a couple of observations. First, this is how the moving edge of science feels &#8211; back and forth, confusing, various investigators and groups working on something we don&#8217;t know, almost in a competition for who is going to get there first, or if there is even a &quot;there&quot; to get to. In the case of these genetic studies, it&#8217;s more like an athletic contest with teams than between individuals &#8211; football as opposed to wrestling. The thing that&#8217;s a bit different here is that they are so definite. This is not a tentative hypothesis versus a light critique. It&#8217;s dogma [a truth] versus dogmatic skepticism [it isn&#8217;t true]. When I wrote about the original paper [<a href=\"http:\/\/1boringoldman.com\/index.php\/2014\/09\/16\/short-list\/\" target=\"_blank\">short-list?&hellip;<\/a>], I was tempted to say that the authors would either end up on a podium in Stockholm [<strong><font color=\"#200020\">Nobel Prize<\/font><\/strong>] or in the annals of <strong><font color=\"#200020\">Retraction Watch<\/font><\/strong> [but decided that was a <em>too-tacky<\/em> comment]. It did seem like an attempt to knock the ball out of the park instead of simply to get a base hit. The modern &quot;Translational Science&quot; motif pushes for that kind of speed to discovery [as if it&#8217;s possible to push a rope].<\/div>\n<p align=\"justify\">But the main thing I wanted to write about was <a target=\"_blank\" href=\"http:\/\/pubmedcommonsblog.ncbi.nlm.nih.gov\/2014\/08\/27\/refining-revising-research-on-the-public-record\/\">PubMed Commons<\/a> &#8211; <font color=\"#200020\">something whose power I hadn&#8217;t quite realized<\/font> Heretofore, once an article was posted in PubMed, it may have had a few things appended over time. Retracted articles were usually annotated. If there were published letters, they might be referenced with links. But it required journal access to see the letters and they were slow in coming. So a questionable article often languished for many months before any sign of the dissent showed up, if it showed up at all. Many of the disreputable industry funded clinical trials have nothing in PubMed to let a reader know of the problems. In the case above, an international consortium was on the case within two weeks. Take a <a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25219520#comments\">look<\/a>. Then look at the infamous <a target=\"_blank\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11437014\">Paxil Study 329<\/a> with the old links above, and the new below, a comment added when PubMed Commons went live a year ago. Here&#8217;s Dr. Karen Dineen Wagner&#8217;s <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12941675\" target=\"_blank\">write-up<\/a> about an equally questionable pair of Zoloft trials with many links, but no comment [just waiting for the comments it deserves]. Any author indexed in PubMed can open a Commons Account and leave a comment. Among the major contributors to the problem with clinical trials of the psychiatric drugs, first was that no one much was looking, but even if they were, there was no easy <strong><font color=\"#200020\">public <\/font><\/strong>way to post comments to flag the literature.<\/p>\n<p align=\"justify\">It&#8217;s easy to get discouraged when reforms that seem so obviously right move so slowly or come in only an incomplete form [<a href=\"http:\/\/1boringoldman.com\/index.php\/2014\/10\/03\/beyond-the-blind\/\" target=\"_blank\">beyond the blind&hellip;<\/a>, <a href=\"http:\/\/1boringoldman.com\/index.php\/2014\/10\/03\/what-we-claim-to-be\/\" target=\"_blank\">what we claim to be&hellip;<\/a>], but probably the most important thing isn&#8217;t necessarily the enduring safeguards, but rather the ongoing awareness and the mechanisms to alert people to instances that need attention. Right now, there&#8217;s a heightened awareness of the problems in our literature. But what matters is that the vigilance lasts beyond the news cycle and we don&#8217;t have to look at empty spaces like this anymore:<\/p>\n<div align=\"center\"><a target=\"_blank\" href=\"http:\/\/www.aacap.org\/iMIS\/ContentManagement\/Search.aspx?SearchTerms=329\"><img decoding=\"async\" width=\"400\" border=\"0\" src=\"http:\/\/1boringoldman.com\/images\/jaacap-329.gif\" \/><\/a><\/div>\n","protected":false},"excerpt":{"rendered":"<p>A response to: Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies by Javier Arnedo, M.S. Dragan M. Svrakic, M.D., Ph.D. Coral del Val, Ph.D. Roc\u00edo Romero-Zaliz, Ph.D. Helena Hern\u00e1ndez-Cuervo, M.D. Molecular Genetics of Schizophrenia Consortium Ayman H. Fanous, M.D. Michele T. Pato, M.D. Carlos N. Pato, M.D., Ph.D. [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_topic_count_hidden":0,"_bbp_reply_count_hidden":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-50467","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/50467","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=50467"}],"version-history":[{"count":30,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/50467\/revisions"}],"predecessor-version":[{"id":50504,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/50467\/revisions\/50504"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=50467"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=50467"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=50467"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}