- Email: [email protected]
Clinical Evidence Epistemology
LETTERS TO THE EDITOR
Uninteresting Conflicts of Interest Journal of Investigative Dermatology (2007) 127, 2668; doi:10.1038/sj.jid.5701108; published online 4 October 2007
TO THE EDITOR As a biomedical researcher, albeit in a long-gone, pre-geriatric existence, I was more saddened than involved by the Stossel/Williams spat (Stossel, 2007; Williams, 2007), because theirs isn’t a conflict: the boys are having a phoney war with wooden swords and paper hats. But it is now past bedtime, the toys can be put away and grandpa will have to tidy up. Of course lots of people get fame and fortune from papers, lectures and opinion-leadering; and of course this influences what they do and say (pace Stossel); and of course public selfexposure will make no difference (pace Williams). But you can forget the wooden swords and paper hats, because, absurd though it may be, the intellectual flashing of ‘COI’ now has to
be tolerated––just as my generation had to tolerate the inquisitorial baring of souls to ethical committees, despite their irrelevance to, and inhibition of, research (Shuster, 1979). Medical history will record the titillating scandal of an ethical committee spawning a bastard offspring, the COI. So my response to the pro- and antiCOI flashers is a curse on both your palaces. The real problem is the almost complete absence of real biomedical research; and, sadly, most people believe the recyclable rubbish now produced (the inane trials and correlative epidemiology done outside the labs, and the pointless technology, such as gene fishing, done within them) is the real thing. This ‘conflict’ is as irrelevant as Aunt Sally’s dead husband: all that matters is
the quality of research, and I don’t give a toss whether Watson and Crick were being secretly supported by God, the Devil or both. CONFLICT OF INTEREST The author declares no conflict of interest other than intellectual.
Sam Shuster1 1 Department of Dermatology, Norfolk and Norwich University Hospital, Norwich, UK E-mail: [email protected]
REFERENCES Shuster S (1979) Why clinical research is failing. New Sci, 270–1 Stossel PT (2007) Full disclosure—nothing less will do. J Invest Dermatol 127:1831–3 Williams HC (2007) Conflicts of interest in dermatology: more than skin deep? J Invest Dermatol 127:1829–30
Clinical Evidence Epistemology Journal of Investigative Dermatology (2007) 127, 2668–2669; doi:10.1038/sj.jid.5700894; published online 17 May 2007
TO THE EDITOR We write to respond to points raised by Dr Rees in the recent editorial ‘‘The Nature of Clinical Evidence: Floating Currencies Rather than Gold Standards’’ (Rees, 2007). We agree with Dr Rees that change is the only constant (Heraclites, c. 475 BC) in clinical evidence, that clinical decisions should be based on the best available evidence (Collier et al., 2006), and that randomized controlled trials (RCTs) are not always necessary (Glasziou et al., 2007). Furthermore, the results of single RCTs, even when published in highly prestigious journals, can be hazardous when read in isola-
tion (Ioannides, 2005), highlighting the need for systematic reviews of all available RCTs. Rees points out that RCTs should not be blindly regarded as a ‘‘fixed’’ gold standard. We agree. While RCTs offer the strongest design to minimize bias in human intervention studies, their quality (in terms of design, conduct, analysis, reporting, and relevance) is highly variable, furthering the argument for systematic reviews to draw attention to such multidimensional components (Bigby, 2003; Williams, 2003). Because systematic reviews are the most cited form of clinical literature (Patsopoulos et al., 2005), if one
Abbreviation: RCT, randomized controlled trial
2668 Journal of Investigative Dermatology (2007), Volume 127
accepts citation impact as a measure of importance, we disagree that the importance of systematic reviews has ‘‘never been subject to experimental study’’ (Rees, 2007). Systematic reviews of all available evidence are also the main source of evidence used by the UK National Institute of Health and Clinical Excellence (http://www.nice.org.uk/) and the US Agency for Healthcare Research and Quality (http://www. ahrq.gov/) to inform health policy. We agree with Rees that there is increasing awareness that ‘‘failure to report studies may lead to error’’ (Rees, 2007). For example, the concealment of serious cardiovascular adverse events for rofecoxib made a significant difference to the positive light thrown on the drug from other trials at that time & 2007 The Society for Investigative Dermatology
K Natsuga et al. ABCA12 Mutations in NBCIE
(Krumholz et al., 2007). When the truth of the real risks emerged, the drug was withdrawn. Systematic reviews serve to foster such enlightenment. We agree with Rees’ description of P-values as indicating false positive error rates when used in the context of elementary frequentist statistical theory. We still maintain, however, that one of the advantages of systematic reviews is that they can improve the precision of estimates derived from smaller similar trials, thus making lots of additional trials unnecessary when an acceptable level of false positive error has been reached. To date, 14 placebo-controlled trials of topical pimecrolimus for atopic eczema have been conducted – do we really need any more to convince the clinical community that pimecrolimus is effective when compared to vehicle? A more serious example is the use of intravenous streptokinase as thrombotic therapy for myocardial infarction. By performing a cumulative meta-analysis of similar RCTs, Lau et al., (1992) showed clear and consistent benefit for streptokinase after just eight RCTs involving 2,432 patients had been performed in 1973. Yet by 1988, a further 25 RCTs involving another 35,542 patients had been performed in isolation addressing the same question without altering the risk estimate, but making the overall
P-value very small indeed (Po0.0001). Such an observation illustrates the human cost of failing to observe the need to bring all evidence together within the body of a systematic reviews, as opposed to wasting valuable patient and doctor resources in continuing to perform one inconclusive trial after another. There comes a point when the likelihood of a false positive results becomes very remote, and even the most skeptical person would say ‘‘enough is enough’’. CONFLICT OF INTEREST
REFERENCES Bigby M (2003) The hierarchy of evidence. In: Evidence-based dermatology. (Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, eds) London: BMJ Publishing Group, 44–8 Collier AP, Johnson KR, Dellavalle RP, Williams HC (2006) The Cochrane Skin Group: promoting the best evidence. J Cut Med and Surg 9:324–31 Glasziou P, Chalmers I, Rawlins M, McCulloch P (2007) When are randomised trials unnecessary? Picking signal from noise. BMJ 334:349–51 Heraclites (c. 475 BC) Wikiquote. Available at: http://en.wikiquote.org/wiki/Heraclitus. Accessed 23 March 2007
Dr Dellavalle and Dr Williams are editor and the co-ordinating editor, respectively, for the Cochrane Collaboration Skin Group.
Ioannides JPA (2005) Contradicted and initially stronger effects in highly cited clinical research. JAMA 294:218–28
ACKNOWLEDGMENTS
Krumholz HM, Ross JS, Presler AH, Egilman DS (2007) What have we learned from Vioxx? BMJ 334:120–3
RPD and SRF were supported by National Institutes of Health (Bethesda, MD) Grant nos. CA92550 and T32 AR07411, respectively, the University of Colorado Cancer Center (RPD), the Dermatoepidemiology Research Unit of the Department of Dermatology (RPD and SRF), and the UK NHS R&D programme (HCW).
Robert P. Dellavalle1,2, Scott R. Freeman2 and Hywel C. Williams3 1
Department of Dermatology, University of Colorado Health Sciences Center, Denver, Colorado, USA; 2Denver VA Medical Center, Denver, Colorado, USA and 3Centre of Evidence-Based Dermatology, Nottingham University Hospital, National Health Service Trust, Nottingham, UK. E-mail: [email protected]
Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mostellar F, Chalmers TC (1992) Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Eng J Med 327:248–54 Patsopoulos NA, Analatos AA, Ioannidis JPA (2005) Relative citation impact of various study designs in the health sciences. JAMA 293:2362–6 Rees J (2007) The nature of clinical evidence: floating currencies rather than gold standards. J Invest Dermatol 127:499–500 Williams HC (2003) How to critically appraise a study reporting effectiveness of an intervention. In: Evidence-based dermatology. (Williams HC, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, eds) London: BMJ Publishing Group, 56–63
Novel ABCA12 Mutations Identified in Two Cases of NonBullous Congenital Ichthyosiform Erythroderma Associated with Multiple Skin Malignant Neoplasia Journal of Investigative Dermatology (2007) 127, 2669–2673; doi:10.1038/sj.jid.5700885; published online 17 May 2007
TO THE EDITOR Non-bullous congenital ichthyosiform erythroderma (NBCIE; OMIM 242100) is a rare, autosomal recessive disorder characterized by prominent erythroderma and fine, white, superficial scales. Mutations in the transglutaminase 1
gene (Laiho et al., 1997; Akiyama et al., 2001; Becker et al., 2003), the 12R-lipoxygenase gene, the lipoxygenase-3 gene (Jobard et al., 2002), ichthyin (Lefe`vre et al., 2004), and FLJ39501 (Lefe`vre et al., 2006) have been identified as causal in human NBCIE.
Abbreviations: LI, lamellar ichthyosis; NBCIE, non-bullous congenital ichthyosiform erythroderma; MM, malignant melanoma
Recently, mutations in the gene encoding the adenosine triphosphate-binding cassette transporter protein ABCA12 (OMIM 607800) have been reported to cause type II lamellar ichthyosis (LI; OMIM 601277) (Lefe`vre et al., 2003) and harlequin ichthyosis (OMIM 242500) (Akiyama et al., 2005; Kelsell et al., 2005). Until now, only a few cases of autosomal recessive congenital www.jidonline.org 2669
Uninteresting Conflicts of Interest Journal of Investigative Dermatology (2007) 127, 2668; doi:10.1038/sj.jid.5701108; published online 4 October 2007
TO THE EDITOR As a biomedical researcher, albeit in a long-gone, pre-geriatric existence, I was more saddened than involved by the Stossel/Williams spat (Stossel, 2007; Williams, 2007), because theirs isn’t a conflict: the boys are having a phoney war with wooden swords and paper hats. But it is now past bedtime, the toys can be put away and grandpa will have to tidy up. Of course lots of people get fame and fortune from papers, lectures and opinion-leadering; and of course this influences what they do and say (pace Stossel); and of course public selfexposure will make no difference (pace Williams). But you can forget the wooden swords and paper hats, because, absurd though it may be, the intellectual flashing of ‘COI’ now has to
be tolerated––just as my generation had to tolerate the inquisitorial baring of souls to ethical committees, despite their irrelevance to, and inhibition of, research (Shuster, 1979). Medical history will record the titillating scandal of an ethical committee spawning a bastard offspring, the COI. So my response to the pro- and antiCOI flashers is a curse on both your palaces. The real problem is the almost complete absence of real biomedical research; and, sadly, most people believe the recyclable rubbish now produced (the inane trials and correlative epidemiology done outside the labs, and the pointless technology, such as gene fishing, done within them) is the real thing. This ‘conflict’ is as irrelevant as Aunt Sally’s dead husband: all that matters is
the quality of research, and I don’t give a toss whether Watson and Crick were being secretly supported by God, the Devil or both. CONFLICT OF INTEREST The author declares no conflict of interest other than intellectual.
Sam Shuster1 1 Department of Dermatology, Norfolk and Norwich University Hospital, Norwich, UK E-mail: [email protected]
REFERENCES Shuster S (1979) Why clinical research is failing. New Sci, 270–1 Stossel PT (2007) Full disclosure—nothing less will do. J Invest Dermatol 127:1831–3 Williams HC (2007) Conflicts of interest in dermatology: more than skin deep? J Invest Dermatol 127:1829–30
Clinical Evidence Epistemology Journal of Investigative Dermatology (2007) 127, 2668–2669; doi:10.1038/sj.jid.5700894; published online 17 May 2007
TO THE EDITOR We write to respond to points raised by Dr Rees in the recent editorial ‘‘The Nature of Clinical Evidence: Floating Currencies Rather than Gold Standards’’ (Rees, 2007). We agree with Dr Rees that change is the only constant (Heraclites, c. 475 BC) in clinical evidence, that clinical decisions should be based on the best available evidence (Collier et al., 2006), and that randomized controlled trials (RCTs) are not always necessary (Glasziou et al., 2007). Furthermore, the results of single RCTs, even when published in highly prestigious journals, can be hazardous when read in isola-
tion (Ioannides, 2005), highlighting the need for systematic reviews of all available RCTs. Rees points out that RCTs should not be blindly regarded as a ‘‘fixed’’ gold standard. We agree. While RCTs offer the strongest design to minimize bias in human intervention studies, their quality (in terms of design, conduct, analysis, reporting, and relevance) is highly variable, furthering the argument for systematic reviews to draw attention to such multidimensional components (Bigby, 2003; Williams, 2003). Because systematic reviews are the most cited form of clinical literature (Patsopoulos et al., 2005), if one
Abbreviation: RCT, randomized controlled trial
2668 Journal of Investigative Dermatology (2007), Volume 127
accepts citation impact as a measure of importance, we disagree that the importance of systematic reviews has ‘‘never been subject to experimental study’’ (Rees, 2007). Systematic reviews of all available evidence are also the main source of evidence used by the UK National Institute of Health and Clinical Excellence (http://www.nice.org.uk/) and the US Agency for Healthcare Research and Quality (http://www. ahrq.gov/) to inform health policy. We agree with Rees that there is increasing awareness that ‘‘failure to report studies may lead to error’’ (Rees, 2007). For example, the concealment of serious cardiovascular adverse events for rofecoxib made a significant difference to the positive light thrown on the drug from other trials at that time & 2007 The Society for Investigative Dermatology
K Natsuga et al. ABCA12 Mutations in NBCIE
(Krumholz et al., 2007). When the truth of the real risks emerged, the drug was withdrawn. Systematic reviews serve to foster such enlightenment. We agree with Rees’ description of P-values as indicating false positive error rates when used in the context of elementary frequentist statistical theory. We still maintain, however, that one of the advantages of systematic reviews is that they can improve the precision of estimates derived from smaller similar trials, thus making lots of additional trials unnecessary when an acceptable level of false positive error has been reached. To date, 14 placebo-controlled trials of topical pimecrolimus for atopic eczema have been conducted – do we really need any more to convince the clinical community that pimecrolimus is effective when compared to vehicle? A more serious example is the use of intravenous streptokinase as thrombotic therapy for myocardial infarction. By performing a cumulative meta-analysis of similar RCTs, Lau et al., (1992) showed clear and consistent benefit for streptokinase after just eight RCTs involving 2,432 patients had been performed in 1973. Yet by 1988, a further 25 RCTs involving another 35,542 patients had been performed in isolation addressing the same question without altering the risk estimate, but making the overall
P-value very small indeed (Po0.0001). Such an observation illustrates the human cost of failing to observe the need to bring all evidence together within the body of a systematic reviews, as opposed to wasting valuable patient and doctor resources in continuing to perform one inconclusive trial after another. There comes a point when the likelihood of a false positive results becomes very remote, and even the most skeptical person would say ‘‘enough is enough’’. CONFLICT OF INTEREST
REFERENCES Bigby M (2003) The hierarchy of evidence. In: Evidence-based dermatology. (Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, eds) London: BMJ Publishing Group, 44–8 Collier AP, Johnson KR, Dellavalle RP, Williams HC (2006) The Cochrane Skin Group: promoting the best evidence. J Cut Med and Surg 9:324–31 Glasziou P, Chalmers I, Rawlins M, McCulloch P (2007) When are randomised trials unnecessary? Picking signal from noise. BMJ 334:349–51 Heraclites (c. 475 BC) Wikiquote. Available at: http://en.wikiquote.org/wiki/Heraclitus. Accessed 23 March 2007
Dr Dellavalle and Dr Williams are editor and the co-ordinating editor, respectively, for the Cochrane Collaboration Skin Group.
Ioannides JPA (2005) Contradicted and initially stronger effects in highly cited clinical research. JAMA 294:218–28
ACKNOWLEDGMENTS
Krumholz HM, Ross JS, Presler AH, Egilman DS (2007) What have we learned from Vioxx? BMJ 334:120–3
RPD and SRF were supported by National Institutes of Health (Bethesda, MD) Grant nos. CA92550 and T32 AR07411, respectively, the University of Colorado Cancer Center (RPD), the Dermatoepidemiology Research Unit of the Department of Dermatology (RPD and SRF), and the UK NHS R&D programme (HCW).
Robert P. Dellavalle1,2, Scott R. Freeman2 and Hywel C. Williams3 1
Department of Dermatology, University of Colorado Health Sciences Center, Denver, Colorado, USA; 2Denver VA Medical Center, Denver, Colorado, USA and 3Centre of Evidence-Based Dermatology, Nottingham University Hospital, National Health Service Trust, Nottingham, UK. E-mail: [email protected]
Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mostellar F, Chalmers TC (1992) Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Eng J Med 327:248–54 Patsopoulos NA, Analatos AA, Ioannidis JPA (2005) Relative citation impact of various study designs in the health sciences. JAMA 293:2362–6 Rees J (2007) The nature of clinical evidence: floating currencies rather than gold standards. J Invest Dermatol 127:499–500 Williams HC (2003) How to critically appraise a study reporting effectiveness of an intervention. In: Evidence-based dermatology. (Williams HC, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, eds) London: BMJ Publishing Group, 56–63
Novel ABCA12 Mutations Identified in Two Cases of NonBullous Congenital Ichthyosiform Erythroderma Associated with Multiple Skin Malignant Neoplasia Journal of Investigative Dermatology (2007) 127, 2669–2673; doi:10.1038/sj.jid.5700885; published online 17 May 2007
TO THE EDITOR Non-bullous congenital ichthyosiform erythroderma (NBCIE; OMIM 242100) is a rare, autosomal recessive disorder characterized by prominent erythroderma and fine, white, superficial scales. Mutations in the transglutaminase 1
gene (Laiho et al., 1997; Akiyama et al., 2001; Becker et al., 2003), the 12R-lipoxygenase gene, the lipoxygenase-3 gene (Jobard et al., 2002), ichthyin (Lefe`vre et al., 2004), and FLJ39501 (Lefe`vre et al., 2006) have been identified as causal in human NBCIE.
Abbreviations: LI, lamellar ichthyosis; NBCIE, non-bullous congenital ichthyosiform erythroderma; MM, malignant melanoma
Recently, mutations in the gene encoding the adenosine triphosphate-binding cassette transporter protein ABCA12 (OMIM 607800) have been reported to cause type II lamellar ichthyosis (LI; OMIM 601277) (Lefe`vre et al., 2003) and harlequin ichthyosis (OMIM 242500) (Akiyama et al., 2005; Kelsell et al., 2005). Until now, only a few cases of autosomal recessive congenital www.jidonline.org 2669