{"id":41749,"date":"2018-03-29T14:28:09","date_gmt":"2018-03-29T13:28:09","guid":{"rendered":"https:\/\/blogs.bmj.com\/bmj\/?p=41749"},"modified":"2018-04-06T12:41:46","modified_gmt":"2018-04-06T11:41:46","slug":"jeff-aronson-when-i-use-a-word-austin-bradford-hills-viewpoints","status":"publish","type":"post","link":"https:\/\/blogs.bmj.com\/bmj\/2018\/03\/29\/jeff-aronson-when-i-use-a-word-austin-bradford-hills-viewpoints\/","title":{"rendered":"Jeffrey Aronson: When I use a word . . . Austin Bradford Hill\u2019s viewpoints"},"content":{"rendered":"<p><a href=\"https:\/\/blogs.bmj.com\/bmj\/files\/2014\/12\/jeffrey_aronson.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-32935\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2014\/12\/jeffrey_aronson-223x300.jpg\" alt=\"jeffrey_aronson\" width=\"117\" height=\"144\" \/><\/a><\/p>\n<p class=\"c4\">In my last two blogs I have used Austin Bradford Hill\u2019s <span class=\"c14\"><a class=\"c6\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1898525\/\">lecture<\/a><\/span>, \u201cThe Environment and Disease: Association or Causation?\u201d, which he gave in 1965 to the Royal Society of Medicine\u2019s then newly formed Section of Occupational Medicine, as a reason for discussing the words \u201c<span class=\"c14\"><a class=\"c6\" href=\"https:\/\/blogs.bmj.com\/bmj\/2018\/03\/16\/jeffrey-aronson-when-i-use-a-word-criteria\">criteria<\/a><\/span>\u201d and \u201c<span class=\"c14\"><a class=\"c6\" href=\"https:\/\/blogs.bmj.com\/bmj\/2018\/03\/23\/jeff-aronson-when-i-use-a-word-guidelines\">guidelines<\/a><\/span><span class=\"c9\">\u201d. Although Hill outlined what he called \u201cnine viewpoints\u201d that he suggested could help in analysing causation in associations between two variables, they have commonly been called criteria. However, only one of his viewpoints is actually a criterion, and I suggested that we might better refer to them as guidelines.<\/span><\/p>\n<p class=\"c4\">The two words \u201cguide\u201d and \u201cview\u201d come from the same IndoEuropean root, WEID, to see. \u201cGuide\u201d comes via the Gothic <em><span class=\"c2\">witan<\/span><\/em>\u00a0followed by consonantal shift of <em><span class=\"c2\">w<\/span><\/em>\u00a0to <em><span class=\"c2\">g<\/span><\/em>\u00a0and <em><span class=\"c2\">t<\/span><\/em>\u00a0to <em><span class=\"c2\">d<\/span><\/em>. \u201cView\u201d comes via the Latin <em><span class=\"c2\">videre<\/span><\/em><span class=\"c9\">, to see. So \u201cguideline\u201d is a good modern substitute for \u201cviewpoint\u201d.<\/span><\/p>\n<p class=\"c4\">Just as a guideline was originally a line used to guide something, before the word started to be used figuratively, so a viewpoint originally had a literal meaning: \u201cA place or position from which something is viewed, esp. one which offers a particularly extensive or attractive view of the surrounding area, a natural feature within it, etc\u201d (<em><span class=\"c2\">Oxford English Dictionary<\/span><\/em>). The word was a surprisingly late addition to English\u2014the first example given in the <em><span class=\"c2\">OED<\/span><\/em>\u00a0dates from 1839\u2014although it was not long before it began to be used figuratively (\u201cA mental position or attitude from which a subject or question is considered\u201d); the earliest example dates from 1856. The surprise is that the phrase \u201cpoint of view\u201d dates from the start of the 18<span class=\"c19\">th<\/span><span class=\"c9\">\u00a0century in the literal sense of \u201cthe position from which something is seen or viewed\u201d, although it was not until the end of the century that it started to be used in the figurative sense of \u201ca mental position or attitude\u201d.<\/span><\/p>\n<p class=\"c4\"><span class=\"c9\">Hill\u2019s nine viewpoints were:<\/span><\/p>\n<ul class=\"c24 lst-kix_list_29-0 start\">\n<li class=\"c4 c13\"><span class=\"c9\">the strength of the association;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">consistency of the observed association;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">the specificity of the association;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">the temporal relationship of the association;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">biological gradient, or dose-response curve;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">biological plausibility;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">coherence with other generally known facts;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">experimental, or semi-experimental, evidence;<\/span><\/li>\n<li class=\"c4 c13\"><span class=\"c9\">analogy.<\/span><\/li>\n<\/ul>\n<p class=\"c4\"><span class=\"c9\">Of these, only temporality can be regarded as a criterion\u2014if the outcome precedes the putative cause there can be no cause and effect relation, although other time courses may afford poor evidence. The other items are guidelines. This is not a mere verbal quibble. It emphasises, as Bradford Hill did, that none of the items in his list specifies a cause and effect association.<\/span><\/p>\n<p class=\"c4\">This also underlines the fact that some of Bradford&#8217;s Hill&#8217;s items are asymmetrical, and that not only their presence but also their absence should be taken into account. The extreme case of this is temporality, whose absence is strong evidence against an association, while its presence is of little confirmatory value. Conversely, the presence of similar effects produced by analogous interventions provides strong evidence in favour of an association; its absence is unhelpful. However, some of the other guidelines are more equally balanced. For example, the presence of what Hill called \u201cgradient\u201d (i.e. <span class=\"c14\"><a class=\"c6\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26119837\">dose responsiveness<\/a><\/span><span class=\"c9\">) supports an association, while its absence is strong evidence against. Similarly, consistency (i.e. the ability to replicate findings in different settings and at different times) provides strong evidence in favour of an association, while its absence is strong evidence against, although one must consider the possibility that different susceptibility factors may be operating in different circumstances. Women, for example, are more susceptible to QT interval prolongation in response to a medication than men are.<\/span><\/p>\n<p class=\"c4\">Hill\u2019s <span class=\"c14\"><a class=\"c6\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19417051\">guidelines<\/a><\/span><span class=\"c9\">\u00a0are listed in Table 1, showing how their presence and absence can be interpreted in the special case of adverse drug reactions.<\/span><\/p>\n<p class=\"c4\"><span class=\"c29\">Table 1.<\/span><span class=\"c9\">\u00a0Guidelines for assessing the strength of evidence in favour of or against a hypothesised association between a cause or an intervention and an effect, with examples from adverse drug reactions<\/span><\/p>\n<table style=\"border: 1px solid black\">\n<tbody style=\"border: 1px solid black\">\n<tr style=\"border: 1px solid black\">\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"2\">Hill\u2019s guidelines<\/td>\n<td colspan=\"2\" rowspan=\"1\">Interpretation<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"2\">Examples<\/td>\n<\/tr>\n<tr style=\"border: 1px solid black\">\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">If present<\/td>\n<td colspan=\"1\" rowspan=\"1\">If absent<\/td>\n<\/tr>\n<tr style=\"border: 1px solid black\">\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Strength<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The stronger the association, the more likely it is to be a causative one; typically (e.g. in English courts) an odds ratio of 2 represents the watershed<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Absence of association is weaker evidence against cause and effect than its presence, since it may be due to lack of power<\/td>\n<td colspan=\"1\" rowspan=\"1\">The association of third-generation contraceptive progestogens with thrombophlebitis was not considered proven by an <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1123767\/\">English court<\/a>\u00a0because the odds ratio was less than 2<\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Consistency<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Replicability in different settings and at different times provides strong evidence in favour of an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Failure to replicate is strong evidence against an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">People with the HLA B*5701 genotype are consistently likely to have a <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29564734\">rash<\/a>\u00a0in response to abacavir<\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Specificity<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Demonstration of a specific group of individuals with a particular susceptibility is strong evidence in favour of an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Absence of specificity is unhelpful<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Adverse reactions with identifiable susceptibilities, e.g. thalidomide-associated teratogenicity<\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Temporality<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The cause\/intervention should precede the effect and the effect should occur after a plausible interval; in addition the effect should occur at the same site as the intervention if relevant<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">If the effect precedes the intervention \u00a0there cannot be an association; if it occurs too soon or too long after it the association is not supported<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24186821\">Thrombophlebitis<\/a>\u00a0due to amiodarone follows soon after intravenous administration into a peripheral vein<\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Biological gradient<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The presence of dose-responsiveness and reversibility provides strong evidence in favour of an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Absence of evidence is unhelpful; evidence of no dose-responsiveness is against an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The dose-related effect of paracetamol on the \u00a0INR in people taking warfarin suggests an <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/9496982\">interaction<\/a><\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Biological plausibility<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The presence of biological, chemical, or mechanical plausibility supports an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The absence of biological, chemical, or mechanical plausibility provides evidence against an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The paracetamol-warfarin interaction cited immediately above as being dose-related is also <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5524527\/\">biologically plausible<\/a><\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Coherence<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Consistency with the current scientific paradigm supports an association [note the relation to biological plausibility]<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Absence of consistency with the current scientific paradigm provides strong evidence against an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">COX-2 inhibitors are less likely to cause <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28410794\">gastrointestinal bleeding<\/a><\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Experiment: size of effect is not attributable to plausible confounding<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">The larger the effect and the fewer the identifiable confounding factors, the stronger the evidence in favour of an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Clinical trials evidence of no association may be evidence against but is not necessarily conclusive<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">There is poor <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16437448\">trials evidence<\/a>\u00a0of an association of metformin with lactic acidosis, but a strong <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24842984\">signal<\/a>\u00a0from observational studies and case reports<\/td>\n<\/tr>\n<tr>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Analogy: similarity<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">If similar effects are produced by analogous interventions, this provides strong evidence in favour of an association<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">Lack of analogous effects is unhelpful<\/td>\n<td style=\"border: 1px solid black\" colspan=\"1\" rowspan=\"1\">\n<p id=\"h.gjdgxs\">That no other drugs have been reproducibly reported to cause phocomelia does not vitiate the case against thalidomide<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p><em><strong>Jeffrey Aronson<\/strong>\u00a0is a clinical pharmacologist, working in the Centre for Evidence Based Medicine in Oxford&#8217;s Nuffield Department of Primary Care Health Sciences. He is also president emeritus of the British Pharmacological Society.<\/em><\/p>\n<p><strong>Competing interests:<\/strong>\u00a0None declared.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>In my last two blogs I have used Austin Bradford Hill\u2019s lecture, \u201cThe Environment and Disease: Association or Causation?\u201d, which he gave in 1965 to the Royal Society of Medicine\u2019s [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/blogs.bmj.com\/bmj\/2018\/03\/29\/jeff-aronson-when-i-use-a-word-austin-bradford-hills-viewpoints\/\">More&#8230;<\/a><\/p>\n","protected":false},"author":1,"featured_media":38359,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[5762],"tags":[],"class_list":["post-41749","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-jeff-aronsons-words"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.5 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Jeffrey Aronson: When I use a word . . . 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