Boys, Carol

Cunningham, Cliff

McKenna, Down

Robertson, Penny

Weeks, Daniel J.

Wishart, Jennifer

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Prenatal screening for Down's syndrome: editorialresponsibilitiesCitation for published version:Boys, C, Cunningham, C, McKenna, D, Robertson, P, Weeks, DJ & Wishart, J 2008, 'Prenatal screening forDown's syndrome: editorial responsibilities' The Lancet, vol 372, no. 9652, pp. 1789-1791.Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:The LancetPublisher Rights Statement:©Boys, C., Cunningham, C., McKenna, D., Robertson, P., Weeks, D. J., & Wishart, J. (2008). Prenatalscreening for Down's syndrome: editorial responsibilities. The Lancet, 372(9652), 1789-1791General rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Apr. 2017Commentwww.thelancet.com   Vol 372   November 22, 2008 1789Naturally, such research would include replication of Ennis and colleagues’ results in large independent cohorts as well as functional studies. A point to keep in mind is that Ennis chieﬂ y investigated HapMap tag SNPs in SERPING1, with the idea that these SNPs serve as a proxy for the causal variants in the presence of strong linkage disequilibrium across the region. This assumption might not hold true in all populations. In view of potential diﬀ erences in linkage disequilibrium, these tag SNPs might not always adequately represent the disease risk of non-examined variants in the gene, which is a particular concern when causal SNPs are rare or have small eﬀ ects.Therefore a logical next step would be to search for true susceptibility alleles. SERPING1 is located on chromosome 11q12-13.1 and is a moderately sized gene with eight exons that span 17 kb. Mutations in this gene are the primary cause of hereditary angioedema.11 The mutation spectrum is large for this disease; the mutations include missense, nonsense, and splice-site mutations, and they reside in almost all exons.10 More common disease-associated variants in SERPING1 have not been described extensively. One of the few common missense variants in the coding region, rs4926 or V480M, which is associated with nasal carriage of Staphylococcus aureus, has already been excluded.12 The gene harbours a total of 65 SNPs according to public databases, of which 18 could have a functional eﬀ ect on coding or regulation of the protein.13,14Examination of SNPs such as these as well as sequencing of a suitable surrounding interval, including the coding region, in a large group of well-deﬁ ned cases and controls will help identify variants with functional implications, and further establish SERPING1 as a true risk factor for age-related macular degeneration.*Caroline C W Klaver, Arthur A B BergenDepartment of Ophthalmology and Department of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam 3000CA, Netherlands (CCWK); and Department of Ophthalmogenetics, Netherlands Institute for Neurosciences, Amsterdam, Netherlands (AABB)carolineklaver@yahoo.comWe declare that we have no conﬂ ict of interest.1 Resnikoﬀ  S, Pascolini D, Etyaále D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004; 82: 844–51.2  Swaroop A, Branham KEH, Chen W, Abecasis G. Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 2007; 16: R174–182.3 Conley YP, Jakobsdottir J, Mah T, et al. CFH, ELOVL4, PLEKHA1, and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet 2006; 15: 3206–18.4 Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006; 38: 458–62.5 Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007; 357: 553–61.6 Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J. Association between apolipoprotein E polymorphisms and age-related macular degeneration: a HuGe review and meta-analysis. Am J Epidemiol 2006; 67: 813–22.7 Ennis S, Jomary C, Mullins R, et al. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case–control study. Lancet 2008; published online Oct 7. DOI:10.1016/S0140-6736(08)61348-3.8 Hageman GS, Luthert PJ, Chong NV, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001; 20: 705–32.9 Scholl HP, Charbel Issa P, Walier M, et al. Systemic complement activation in age-related macular degeneration. PLoS ONE 2008; 3: e2593.10 van Soest S, de Wit GJM, Essing AHW, et al. Comparison of human RPE gene expression in macula and periphery highlights potential topographic diﬀ erences in Bruch’s membrane. Mol Vis 2007; 13: 1608–17.11 Gosswein T, Kocot A, Emmert G, et al. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res 2008; 121: 181–88.12 Duponchel C, Djenouhat K, Fremeaux-Bacchi V, Monnier N, Drouet C, Tosi M. Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH. Hum Mut 2006; 27: 295–96.13 Emonts M, de Jongh CE, Houwing-Duistermaat JJ, et al. Association between nasal carriage of Staphylococcus aureus and the human complement cascade activator serine protease C1 inhibitor (C1INH) valine vs. Methionine polymorphism at amino acid position 480. FEMS Immunol Med Microbiol 2007; 50: 330–32.14 Washington School of Medicine. SNPseek—retrieval and analysis of functionally relevant SNPs. http://snp.wustl.edu/cgi-bin/SNPseek/index.cgi (accessed Oct 3, 2008).On Sept 16, UK television’s Channel 4 News featured an “exclusive” and “shocking” report that, after positive serum or ultrasound screening for Down’s syndrome, diagnostic testing by amniocentesis or chorionic villus sampling results in two healthy babies being miscarried for every three Down’s syndrome births prevented.1 The ﬁ ndings (published early online to coincide with the broadcast) are from an editorial by Frank Buckley and Sue Buckley, Chief Executive and Chief Scientist of Down Syndrome Education International (DSEI), respectively, in Down Syndrome Research and Practice.2 In this editorial, data from the National Down’s Prenatal screening for Down’s syndrome: editorial responsibilitiesSee Correspondence page 1805Comment1790 www.thelancet.com   Vol 372   November 22, 2008Syndrome Cytogenetic Register (NDSCR)3 on prenatal and postnatal diagnoses of Down’s syndrome and on terminations were analysed; fetal losses in pregnancies unaﬀ ected by Down’s syndrome were estimated by statistical modelling because national data on losses in non-aﬀ ected pregnancies were not available. The editorialists used the ﬁ ndings to query whether prenatal screening for Down’s syndrome was justiﬁ able. The editorial was circulated widely to the mass media and to international Down’s syndrome associations.4We write as researchers and advocates for people with Down’s syndrome and their families, but are also sensitive to the views of prospective parents and welcome wider engagement in the social debate about prenatal screening for this condition. We also acknowledge the widely respected educational and advocacy work of DSEI. However, our concern is that in using an editorial to disseminate new interpretations of existing datasets, the independent assessment for scholarly integrity that is the hallmark of peer review has been bypassed. The recognised pathway is to submit such work to a peer-reviewed academic journal as a research article.Three drafts of the editorial were sent for comment to the 34-member editorial board of the journal between July 24 and Sept 16. Both process and timescale were immediately queried. 14 members had responded to the board’s listserver by the online publication date; eight directly addressed the scientiﬁ c content, expressing concerns about its clarity and editorial status and pressing for external reviews. Three external reviewers of early drafts were named and copies of comments from two provided. On Aug 19, the board was told that “six external experts were to review the latest draft, including ﬁ ve experts in UK prenatal screening practice and statistics”5 but was then informed that these reviews could not be shared on “conﬁ dentiality” grounds or because comments had been by telephone.6In view of the importance and complexity of the topic addressed, the editorial would have beneﬁ ted from an independent review process, especially in respect of the literature selected on screening and on Down’s syndrome, and the model used to calculate fetal loss rates. For example, for fetal loss rates, the editorial states that “the best available evidence suggests that the risk of pregnancy loss due to amniocentesis is 1%...and [for] chorionic villus sampling (CVS) is 2%” and the authors maintain they have been “cautious” in applying a 1% loss rate in their modelling of outcomes for pregnancies aﬀ ected and unaﬀ ected by Down’s syndrome.2 The quoted loss levels are similar to those ﬁ rst established in the 1980s, when both procedures were still relatively new.7,8 Recent research indicates lower risk, conservatively 1 in 200–300, with little diﬀ erence between the two procedures when performed skilfully and when indi-vidual obstetric risk factors are considered.9–12The editorial’s claim for a 25% increase in livebirths aﬀ ected by Down’s syndrome, derived from NDSCR data, is similarly questionable. NDSCR has recorded all Down’s syndrome diagnoses in England and Wales since 1989, with its most recent report covering 1989–2006 (ﬁ gure).3 The editorial selected data from 1992–2006 for analysis, modelled missing data for outcomes, and concluded that the number of livebirths was “up 25% over 15 years”.2 However, had the 10-year period 1997–2006 been selected instead, this headline ﬁ gure would have been 10·5%.On a broader front, the editorial also failed to consider adequately the views of pregnant women, recent advances in screening eﬃ  ciency, and what might be argued to be some of the more positive aspects of screening. Many parents wish to be screened: some to reduce the stress of waiting, some to be prepared for unplanned outcomes, and some in case they might wish to consider a termination. Improved methods have reduced the number of invasive tests required at older Year of diagnosis0100200300Number of Down’s syndrome livebirths400500600700800198919901991199219931994199519961997199819992000200120022003200420052006Figure: Number of livebirths aﬀ ected by Down’s syndrome in England and Wales, 1989–2006NDSCR data; ﬁ gure for 2006 is provisional.3Commentwww.thelancet.com   Vol 372   November 22, 2008 1791maternal ages, the percentage of false positives, and the number of invasive diagnostic tests required for each case identiﬁ ed.13 First-trimester non-invasive diagnostic testing may be available within 5–10 years.14Prenatal screening is of major scientiﬁ c and clinical interest, and potentially aﬀ ects 650 000 women per year in the UK alone. Published as an editorial, and without independent peer review, the analysis lacks the necessary authority to assist people in making personal decisions about screening and diagnosis, including families who already have a child with Down’s syndrome. It also distracts attention from the need for increased funding for Down’s syndrome research and for reassessment of research priorities within this ﬁ eld.15Carol Boys, Cliﬀ  Cunningham, Dawn McKenna, Penny Robertson, Daniel J Weeks, *Jennifer WishartDown’s Syndrome Association, Teddington, Middlesex, UK (CB); School of Natural Science and Psychology, Liverpool John Moores University, Liverpool, UK (CC); Down Syndrome Research Foundation, Vancouver, BC, Canada (DM); Down Syndrome International, Jakarta, Indonesia (PR); Department of Psychology, Simon Fraser University, Vancouver, BC, Canada (DJW); and Moray House School of Education, University of Edinburgh, Edinburgh EH8 8AQ, UK (JW) J.Wishart@ed.ac.ukCC and JW were members of the Editorial Board of Down Syndrome Research and Practice, but have recently resigned. DJW, JW, and CC serve on the editorial boards of other journals, including Down Syndrome Quarterly; PR serves as an international correspondent for Down Syndrome Quarterly. CC and JW are unpaid research advisers to the Down’s Syndrome Association (London). JW is an unpaid adviser to several other Down’s syndrome associations, including Down Syndrome Research Foundation, Canada. DJW is an unpaid member of the Board of the Down Syndrome Research Foundation, Canada. CB and DM declare that they have no conﬂ ict of interest. The charities with which all of us have connections are aﬃ  liated to Down Syndrome International, a worldwide federation of Down’s syndrome organisations.1 Channel 4 News. Exclusive: research suggests Down’s screening risk is ‘unacceptable’. Sept 16, 2008. http://www.channel4.com/news/articles/society/health/exclusive+research+suggests+downs+screening+risk+is+unacceptable/2455752 (accessed Oct 21, 2008).2 Buckley F, Buckley S. Wrongful deaths and rightful lives—screening for Down syndrome. Down Syndrome Res Pract 2008; published online Sept 16. DOI:10.3104/editorials.2087 (accessed Oct 21, 2008).3 National Down Syndrome Cytogenetic Register. The National Down Syndrome Cytogenetic Register 2006 annual report. 2008. http://www.wolfson.qmul.ac.uk/ndscr/reports/NDSCRreport06.pdf (accessed Oct 21, 2008).4 Down Syndrome Education International. More people with Down syndrome are being born, achieving more and living longer than ever. Sept 16, 2008. http://blogs.downsed.org/press/2008/09/index.html (accessed Oct 21, 2008).5 Buckley F. DSRP screening editorial (further revised draft). Aug 19, 2008 (email to editorial board of Down Syndrome Res Pract, available from JW).6 Buckley S. Prenatal screening consequences for babies, with and without Down syndrome. Sept 15, 2008 (email to editorial board of Down Syndrome Res Pract, available from JW).7 Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-Pedersen B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986; 1: 1287–93.8 Canadian Collaborative CVS-Amniocentesis Clinical Trial Group. Multicentre randomised clinical trial of chorion villus sampling and amniocentesis: ﬁ rst report. Lancet 1989; 1: 1–6.9 ACOG Practice Bulletin. Invasive prenatal screening for aneuploidy. Obstet Gynecol 2007; 110: 1459–67.10 Caughey AB, Hopkins LM, Norton ME. Chorionic villus sampling compared with amniocentesis and the diﬀ erence in the rate of pregnancy loss. Obstet Gynecol 2006; 108: 612–16.11 Evans MI, Andriole S. Chorionic villus sampling and amniocentesis in 2008. Curr Opin Obstet Gynecol 2008; 20: 164–68.12 Odibo AO, Gray DL, Dicke JM, et al. Revisiting the fetal loss rate after second-trimester genetic amniocentesis: a single center’s 16-year experience. Obstet Gynecol 2008; 111: 589–95.13 Smith-Bindman R, Chu P, Bacchetti P, et al. Prenatal screening for Down syndrome in England and Wales and population-based birth outcomes. Am J Obstet Gynecol 2003; 189: 980–85.14 Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Nat Acad Sci USA 2008; published online Oct 6. DOI:10.1073/pnas.0808319105 (accessed Oct 21, 2008).15 Morris K. Shift in priorities for Down’s syndrome research needed. Lancet 2008; 372: 791–92.China’s HIV/AIDS epidemic: continuing challengesIn 2007, China estimated that there were about 700 000 residents infected with HIV and that 85 000 people had AIDS.1,2 Although the prevalence of HIV infection as a whole was about 0·05%, each of several provinces (including Yunnan, Guangxi, Guangdong, Xinjiang, and Henan) had high numbers of infected people (>30 000).2 Most cases of HIV infection are in injection drug users, men who have sex with men, sex workers, and in infected blood donors who survived the HIV epidemic in rural China during the mid-1990s. The rural focus of the HIV epidemic and low levels of sexual mixing might have prevented a rapid spread, but sexual behaviours are rapidly changing.Although slow to acknowledge the epidemic since 2003, China has made considerable changes to its policies by implementation of innovative strategies and setting up of a comprehensive anti-HIV programme. The objective is to control spread beyond the major risk groups.3,4 But some of the issues remain to be resolved.The weak infrastructure of health care implies that the goal of providing treatment for all in need will be diﬃ  cult, especially in rural areas where most infections occur. Development of drug resistance and toxic eﬀ ects require Published OnlineOctober 20, 2008DOI:10.1016/S0140-6736(08)61357-4

Prenatal screening for Down's syndrome: editorial responsibilities

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