- Email: [email protected]
Clinical assessment incorporating a personal genome
Correspondence
The report by Feng-Cai Zhu and colleagues (Sept 11, p 895)1 of a highly effective recombinant hepatitis E vaccine is very encouraging. However, it is to be hoped that this vaccine is developed and made available to people who need it more promptly than the previous highly effective hepatits E vaccine. Years have passed since the development of this vaccine, with no real gain for the people in the country where it was tested nor across the wider global community. In Patan Hospital alone in Kathmandu, Nepal, the mortality rate in pregnant women who present with hepatitis E is 20–30%. A potentially very useful vaccine (96% effective) against this disease was developed and subsequently assessed in 2001 in Kathmandu, Nepal, and published in 2007.2 GlaxoSmithKline (GSK), the US Army (Walter Reed Armed Forces Institute of Medical Sciences), and the Nepal Army collaborated in this study. I was a member of the Data Safety Monitoring Board. A recent enquiry of mine revealed that apparently GSK retains the intellectual property rights to the vaccine, but there are no current plans to develop it further. Similarly, a conjugate typhoid vaccine was assessed in Dong Thap Province in southern Vietnam in 1998; the study was completed in 2000 and the report published in 2001. The vaccine was 90% effective.3 This study was undertaken by the National Institute of Child Health and Human Development, USA, and Aventis Pasteur, Lyon, France. Annually, about 27 million people are affected by typhoid and approximately 200 000–300 000 die, many more than are affected by meningococcal meningitis, Japanese encephalitis, or human papillomavirus.4 These vaccines against hepatitis E and typhoid are not available, despite their proven efficacy and safety. If GSK, Walter Reed Armed Forces Institute of Medical www.thelancet.com Vol 376 September 11, 2010
Sciences, the National Institute of Child Health and Human Development USA, or Aventis Pasteur were not going to develop these vaccines or make them available after their successful testing in Nepal and Vietnam, why were they tested? And if these organisations will not develop them further, is there a responsibility to make them available to others who might? I declare that I have no conflicts of interest.
Buddha Basnyat [email protected] Oxford University Clinical Research Unit—Nepal, Patan Hospital, PO Box 3596, Kathmandu, Nepal 1
2
3
4
Zhu F-C, Zhang J, Zhang X-F, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet 2010; 376: 895–902. Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007; 356: 895–903. Lin FY, Ho VA, Khiem HB, et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med 2001; 344: 1263–69. De Roeck D, Jodar L, Clemens J. Putting typhoid vaccine in the global health agenda. N Engl J Med 2007; 357: 1069–71.
wide association studies that could be used for this purpose.2 Although Ashley and colleagues include some, but not all, of these established loci (eg, HNF1B was omitted), they include several other loci that have not shown consistent association with risk of type 2 diabetes (eg, KLF11 SNP rs3592711253). We have similar concerns about several SNPs used to estimate risk for prostate cancer, myocardial infarction, and Alzheimer’s disease. Ashley and colleagues acknowledge that they are most confident about associations consistently reported in large studies, although this uncertainty was not accounted for in the risk estimation. To avoid confusion over which variants show “established” associations, future studies of this nature should focus on variants that have well characterised and replicable associations with disease risk. Before we begin to assess the clinical use of genetic variants for risk estimation, we need to understand their clinical validity on the basis of established criteria.
See Editorial page 845 See Comment page 849 See Articles page 895
We declare that we have no conflicts of interest.
Clinical assessment incorporating a personal genome
*Brandon L Pierce, Habibul Ahsan
Euan Ashley and colleagues (May 1, p 1525)1 make an impressive and ambitious effort to use full-genome sequence data in the clinical setting. They estimated a patient’s risk of several common diseases using several pieces of information, including single nucleotide polymorphisms (SNPs) that have been associated with the risk of these diseases. Unfortunately, Ashley and colleagues estimated these risks using many SNPs that show inconclusive evidence of association. For example, their risk estimate for type 2 diabetes was generated using 42 SNPs with “associations established from genome-wide association studies”. In our view, at the time of publication, there were only about 20 loci for type 2 diabetes “established” from genome-
1
[email protected] Department of Health Studies (BLP, HA) and Departments of Medicine and Human Genetics and Cancer Research Center (HA), University of Chicago, Chicago, IL 60637, USA
2
3
Ashley EA, Butte AJ, Wheeler MT, et al. Clinical assessment incorporating a personal genome. Lancet; 375: 1525–35. McCarthy MI, Zeggini E. Genome-wide association studies in type 2 diabetes. Curr Diab Rep 2009; 9: 164–71. Florez JC, Saxena R, Winckler W, et al. The Kruppellike factor 11 (KLF11) Q62R polymorphism is not associated with type 2 diabetes in 8,676 people. Diabetes 2006; 55: 3620–24.
Science Photo Library
Neglected hepatitis E and typhoid vaccines
Authors’ reply Brandon Pierce and Habibul Ahsan raise an important point—that, in the clinical application of genetic data, individual practitioners will have differing opinions on which genetic variants to include and how to synthesise their interaction. Our figure 4 is one possible solution for common variants. We display
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
869
The report by Feng-Cai Zhu and colleagues (Sept 11, p 895)1 of a highly effective recombinant hepatitis E vaccine is very encouraging. However, it is to be hoped that this vaccine is developed and made available to people who need it more promptly than the previous highly effective hepatits E vaccine. Years have passed since the development of this vaccine, with no real gain for the people in the country where it was tested nor across the wider global community. In Patan Hospital alone in Kathmandu, Nepal, the mortality rate in pregnant women who present with hepatitis E is 20–30%. A potentially very useful vaccine (96% effective) against this disease was developed and subsequently assessed in 2001 in Kathmandu, Nepal, and published in 2007.2 GlaxoSmithKline (GSK), the US Army (Walter Reed Armed Forces Institute of Medical Sciences), and the Nepal Army collaborated in this study. I was a member of the Data Safety Monitoring Board. A recent enquiry of mine revealed that apparently GSK retains the intellectual property rights to the vaccine, but there are no current plans to develop it further. Similarly, a conjugate typhoid vaccine was assessed in Dong Thap Province in southern Vietnam in 1998; the study was completed in 2000 and the report published in 2001. The vaccine was 90% effective.3 This study was undertaken by the National Institute of Child Health and Human Development, USA, and Aventis Pasteur, Lyon, France. Annually, about 27 million people are affected by typhoid and approximately 200 000–300 000 die, many more than are affected by meningococcal meningitis, Japanese encephalitis, or human papillomavirus.4 These vaccines against hepatitis E and typhoid are not available, despite their proven efficacy and safety. If GSK, Walter Reed Armed Forces Institute of Medical www.thelancet.com Vol 376 September 11, 2010
Sciences, the National Institute of Child Health and Human Development USA, or Aventis Pasteur were not going to develop these vaccines or make them available after their successful testing in Nepal and Vietnam, why were they tested? And if these organisations will not develop them further, is there a responsibility to make them available to others who might? I declare that I have no conflicts of interest.
Buddha Basnyat [email protected] Oxford University Clinical Research Unit—Nepal, Patan Hospital, PO Box 3596, Kathmandu, Nepal 1
2
3
4
Zhu F-C, Zhang J, Zhang X-F, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet 2010; 376: 895–902. Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007; 356: 895–903. Lin FY, Ho VA, Khiem HB, et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med 2001; 344: 1263–69. De Roeck D, Jodar L, Clemens J. Putting typhoid vaccine in the global health agenda. N Engl J Med 2007; 357: 1069–71.
wide association studies that could be used for this purpose.2 Although Ashley and colleagues include some, but not all, of these established loci (eg, HNF1B was omitted), they include several other loci that have not shown consistent association with risk of type 2 diabetes (eg, KLF11 SNP rs3592711253). We have similar concerns about several SNPs used to estimate risk for prostate cancer, myocardial infarction, and Alzheimer’s disease. Ashley and colleagues acknowledge that they are most confident about associations consistently reported in large studies, although this uncertainty was not accounted for in the risk estimation. To avoid confusion over which variants show “established” associations, future studies of this nature should focus on variants that have well characterised and replicable associations with disease risk. Before we begin to assess the clinical use of genetic variants for risk estimation, we need to understand their clinical validity on the basis of established criteria.
See Editorial page 845 See Comment page 849 See Articles page 895
We declare that we have no conflicts of interest.
Clinical assessment incorporating a personal genome
*Brandon L Pierce, Habibul Ahsan
Euan Ashley and colleagues (May 1, p 1525)1 make an impressive and ambitious effort to use full-genome sequence data in the clinical setting. They estimated a patient’s risk of several common diseases using several pieces of information, including single nucleotide polymorphisms (SNPs) that have been associated with the risk of these diseases. Unfortunately, Ashley and colleagues estimated these risks using many SNPs that show inconclusive evidence of association. For example, their risk estimate for type 2 diabetes was generated using 42 SNPs with “associations established from genome-wide association studies”. In our view, at the time of publication, there were only about 20 loci for type 2 diabetes “established” from genome-
1
[email protected] Department of Health Studies (BLP, HA) and Departments of Medicine and Human Genetics and Cancer Research Center (HA), University of Chicago, Chicago, IL 60637, USA
2
3
Ashley EA, Butte AJ, Wheeler MT, et al. Clinical assessment incorporating a personal genome. Lancet; 375: 1525–35. McCarthy MI, Zeggini E. Genome-wide association studies in type 2 diabetes. Curr Diab Rep 2009; 9: 164–71. Florez JC, Saxena R, Winckler W, et al. The Kruppellike factor 11 (KLF11) Q62R polymorphism is not associated with type 2 diabetes in 8,676 people. Diabetes 2006; 55: 3620–24.
Science Photo Library
Neglected hepatitis E and typhoid vaccines
Authors’ reply Brandon Pierce and Habibul Ahsan raise an important point—that, in the clinical application of genetic data, individual practitioners will have differing opinions on which genetic variants to include and how to synthesise their interaction. Our figure 4 is one possible solution for common variants. We display
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
869