- Email: [email protected]
Publishing economically
approached 90% for all groups.
of elimination of trophoblastic activity rather than in health status for the women concerned, and the gain evaluation did not include costs beyond the hospital care received. Both of these last two omissions are justifiable when, as was done here, they specified the perspective and the limits of the study. Nevertheless, the results must be judged as partial information in assessing the desirability of laparoscopy over laparotomy. Finding the best treatment for ectopic pregnancy is important for women who suffer its consequences and for the clinicians looking after them. Even so, ectopic pregnancy per se is rare and one doubts whether changes in treatment methods would have an important medical or economic impact. Policy makers and managers have been encouraged by economic arguments, seldom based on sound evaluation, to accelerate the introduction of laparoscopic surgery in the hope of achieving greater benefits from limited healthcare budgets. This study suggests that laparoscopic surgery saves less than has previously been predicted-the 95% CI for the cost differences is so wide there may have been no change in cost between the policies. The study also raises another important issue. How should medical journals tackle economic evaluations? More fundamentally, should they even be entering this arena? Many Lancet readers are no doubt involved in healthcare management, with an interest in well designed and conducted research that addresses pressing economic
terms
do imply colonoscopy indefinitely-ie, every 3-5 years-even after one examination shows no adenomatous polyps? Not necessarily. In the New York study, for example, there was no indication of size, either for recurrent polyps or for incident ones. Another report from the National Polyp Study group suggested that recurrent polyps are usually diminutive (s=5 mm),6 and presumably this would also hold true for polyps found on a subsequent colonoscopy where none was seen on the index examination, provided the examination was complete. Of diminutive polyps, as many as 50% will get smaller with time, while those that continue to grow do so very slowly (about 0-065 mm/year) .7 Thus it might take 10 years or more before an incident or recurrent diminutive polyp becomes mm, when the cancer risk "significant"-ie, >8-10 becomes appreciable. Moreover, the growth rate for diminutive polyps may be age related, only becoming troublesome in individuals between the ages of 50 and 65 and not in older patients. An even more important factor is the lack of clinical information for patients who were not followed up after the index colonoscopy; we do not know how their incidence of colon cancer compared with that in individuals who had single or multiple follow-up examinations. The effect of continued colonoscopic surveillance on lifetime colon cancer risk remains uncertain. Do these latest observations
that
one must
Michael O Blackstone Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, Illinois, USA 1 Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992; 326: 658-62. 2 Winawer SJ, Zauber AG, Nah Ho M, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993; 329: 1977-81. 3 O’Brien MJ, Winawer SJ, Zauber AG, et al. The National Polyp Study: patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology 1990; 98: 371-79. 4 Stryker SJ, Wolff BG, Culp CE, et al. Natural history of untreated colonic polyps. Gastroenterology 1987; 93: 1009-13. 5 Neugut AI, Jacobson JS, Ahsan H, et al. Incidence and recurrence rates of colorectal adenomas: a prospective study. Gastroenterology 1995; 108: 402-08. 6 Winawer SJ, Zauber AG, O’Brien MJ, et al. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993; 328: 901-06. 7 Hoff G, Foerster A, Vatn MH, et al. Epidemiology of polyps in the rectum and colon. Scand J Gastroenterol 1986; 21: 853-62.
Publishing economically See page 1139 The report by Gray and colleagues in this issue compares laparoscopy with laparotomy for ectopic pregnancy in terms of health service resources required as well as relative effectiveness. These researchers describe one type of economic evaluation,’ in this case a cost-effectiveness study. They followed agreed methods and based their conclusions on evidence drawn from a randomised controlled trial. There are some limitations to the study. The trial upon which it is based2 was a small one, and the fact that no significant differences were observed does not assure us that the treatments are equally effective. Furthermore, the researchers measured effectiveness in
questions. They may not have easy access to specialist health economics journals. In its instructions for authors, The Lancet welcomes "any contribution that advances or illuminates medical science and practice", yet it publishes few studies at the applied healthcare end of the range of clinical science research. However, issues of economics cannot be excluded from the journal. Even if authors do not mention costs, they are making an implicit economic statement whenever they make a recommendation about practice. Such statements presume that the resources taken up by the new practice could not be better used in other ways. A decision to publish any health economic study or paper with an economic component should be based on the importance of the subject and the quality of the research, as with any other paper. An economic study might be considered "important" if likely to influence the debate on resources or health or both.3 From my perspective as a health economist I have come across a wide range of published reports, from policy discussions and descriptive cost analyses to economic evaluations. All, when well done, can help decision makers, but most of the discussion about standards for economic studies has concentrated on economic evaluation. Recent reviews of medical publications suggest that a large proportion of so-called economic evaluations are not what they claim to be. 1,5 To reduce the risk of publishing studies based on poor economic methods, editors could seek advice from health economists on the quality of the economics in a paper, and authors of papers who cite costs could be asked either to delete the claim or conform to minimum criteria for economic methods. Those involved in economic evaluation research are currently discussing these criteria,6,7 and have reached a consensus on some basic points. A journal that adopted the policy I have outlined above 1127
i
would lessen its chance of publishing misleading or manipulative economic studies. A further safeguard is to seek, and publish, details of funding sources and other interests of authors, as was discussed recently in response to a policy statement in the New England 7ournal of Medicine.Ido not believe that refusing papers because they are commercially sponsored would reduce bias. Such studies can be good despite their funding source, while many studies not ostensibly funded by such sponsors are biased for other reasons. Miranda
Mugford
National Perinatal 1
2
3 4 5
6
7
8
Epidemiology Unit, Radcliffe Infirmary, Oxford, UK
Drummond MF, Stoddart GL, Torrance GW. Methods for the economic evaluation of health care programmes. Oxford: Oxford University Press, 1987. Lundorff P, Thorburn J, Hahlin M, Källfelt B, Lindblom B. Laparoscopic surgery in ectopic pregnancy: a randomised trial versus laparotomy. Acta Obstet Gynecol Scand 1991; 70: 343-48. Williams A. The cost-benefit approach. Br Med Bull 1974; 30: 252-56. Gerard K. Cost-utility in practice: a policy maker’s guide to the state of the art. Health Policy 1992; 21: 249-79. Jefferson TO, Demicheli V. Is vaccination against hepatitis B efficient? A review of world literature. Health Econ 1994; 3: 25-38. Canadian Coordinating Office for Health Technology Assessment. Guidelines for economic evaluation of pharmaceuticals. Draft 1.2, Feb 1, 1994. Ottawa: CCHOTA, 1994. Department of Health. Virginia Bottomley welcomes pioneering guidelines for the economic evaluation of medicines. DH press release 94/251 May 19, 1994. Kassirer J, Angell M. The journal’s policy on cost-effectiveness analyses. N Engl J Med 1994; 331: 669-70.
Cryptosporidium and The
apple
has
figured
the food
in the affairs of apple cider
ways. A recent report of
supply men
as
a
epidemic cryptosporidiosis implicates apples,
in ruinous cause of and other
fresh fruit and vegetables, as potential vectors of diarrhoeal disease. Millard and co-workers’ report an outbreak of 160 primary cases of cryptosporidiosis among persons who attended a school agricultural fair in Maine and ingested freshly pressed apple cider. Epidemiological investigation determined that apples collected from the ground of an orchard were the source of the infecting inoculum. A calf from the farm surrounding the orchard was excreting Cryptosporidium oocysts and was the presumed source of the outbreak. Although the possibility of Cryptosporidium contamination of foodstuffs has been discussed before,2 this report marks the first welldocumented point-source outbreak. is self-limited in disease Cryptosporidial immunocompetent hosts, but often results in
dehydration. those
with
In
immunosuppressed patients, especially the disease frequently causes
AIDS,
overwhelming watery diarrhoea and death.3 Since 1982, transmission of epidemic cryptosporidiosis via the faecaloral route has been reported in various settings by use of standard epidemiological techniques. Filtered and unfiltered municipal water were the sources of large outbreaks of gastrointestinal disease, including the Milwaukee, Wisconsin, outbreak of 1993 which involved 403000 people.4Smaller outbreaks have been associated with recreational water use.5 Exposure to infected farm animals and children in day-care centres has led to clinical cryptosporidiosis. The importance of sexual 1128
transmission, especially in the AIDS population, has been suggested but not fully assessed. Cryptosporidium is highly infectious and seems to be one of the main causes of infectious diarrhoea in many parts of the world/ Cryptosporidium is shed into the environment as a resistant oocyst that is impervious to chlorine and can survive for up to 3 months at low temperatures. Oocysts are killed by freezing and by brief high temperatures. Existing water quality control standards are insufficient to prevent disease in most areas of the developed world, either because filtration is not undertaken, or because high upstream oocyst loads from agricultural areas escape filtration at the time of backwashing of the filters. The inoculum causing infection in immunocompetent volunteers is low. Experiments recently concluded in Houston by DuPont and colleagues indicate that the ID 50 for healthy persons without serological evidence of previous cryptosporidiosis is 132 oocysts.’ Very high rates of transmission of Cryptosporidium, similar to those established for other highly transmissible enteric pathogens transmitted by the faecal-oral route such as Shigella species and rotavirus, have been documented within families in Brazil. The South American study among others suggests that symptomatic infection results in the development of immunity to disease, presumably mediated by the mucosal immune system. However, immunity does not necessarily mean absence of infection-prolonged symptomless oocyst excretion after symptomatic infection has been noted. These infections can be dangerous: studies in Guinea Bissau, West Africa, indicate that cryptosporidiosis is an important cause of death in otherwise healthy children in developing countries.9 Lastly, cryptosporidiosis may be an opportunistic infection in early AIDS, and the natural history of cryptosporidial diarrhoea in HIV-infected persons is highly variable. Although many patients become profoundly dehydrated with electrolyte abnormalities and rapid progression to death, the prognosis is not uniformly poor. Extended periods of oocyst excretion without symptoms or with mild symptoms, as well as spontaneous remission, may occur in this patient population Much has been learned in the past decade but several urgent issues remain. First, there is no specific therapy for cryptosporidiosis. The mainstay of treatment for symptomatic cases consists of intravenous fluids, electrolyte management, non-specific anti-diarrhoeal agents, and nutritional supplements. Very little is known about the biology which would allow us to exploit chemotherapeutic targets. We do not know, for example, why agents that are useful against other protozoan infections (eg, quinine, pyrimethamine, and sulpha analogues) are not useful for the treatment of cryptosporidiosis. Second, the epidemiology of the disease is poorly understood. What are the usual reservoirs from which human beings become infected-water, other persons, domestic animals, food? We need to determine whether symptomatic infection is usually due to an undetected common source outbreak or to ongoing lowlevel endemic transmission. Perhaps there is a reservoir of infected but not diseased persons who excrete and transmit the organism. What accounts for the variable course of infection in HIV-infected persons-ie, virulence factors in the organism or the level of pre-existing mucosal B-cell immunity to Cryptosporidium?
of elimination of trophoblastic activity rather than in health status for the women concerned, and the gain evaluation did not include costs beyond the hospital care received. Both of these last two omissions are justifiable when, as was done here, they specified the perspective and the limits of the study. Nevertheless, the results must be judged as partial information in assessing the desirability of laparoscopy over laparotomy. Finding the best treatment for ectopic pregnancy is important for women who suffer its consequences and for the clinicians looking after them. Even so, ectopic pregnancy per se is rare and one doubts whether changes in treatment methods would have an important medical or economic impact. Policy makers and managers have been encouraged by economic arguments, seldom based on sound evaluation, to accelerate the introduction of laparoscopic surgery in the hope of achieving greater benefits from limited healthcare budgets. This study suggests that laparoscopic surgery saves less than has previously been predicted-the 95% CI for the cost differences is so wide there may have been no change in cost between the policies. The study also raises another important issue. How should medical journals tackle economic evaluations? More fundamentally, should they even be entering this arena? Many Lancet readers are no doubt involved in healthcare management, with an interest in well designed and conducted research that addresses pressing economic
terms
do imply colonoscopy indefinitely-ie, every 3-5 years-even after one examination shows no adenomatous polyps? Not necessarily. In the New York study, for example, there was no indication of size, either for recurrent polyps or for incident ones. Another report from the National Polyp Study group suggested that recurrent polyps are usually diminutive (s=5 mm),6 and presumably this would also hold true for polyps found on a subsequent colonoscopy where none was seen on the index examination, provided the examination was complete. Of diminutive polyps, as many as 50% will get smaller with time, while those that continue to grow do so very slowly (about 0-065 mm/year) .7 Thus it might take 10 years or more before an incident or recurrent diminutive polyp becomes mm, when the cancer risk "significant"-ie, >8-10 becomes appreciable. Moreover, the growth rate for diminutive polyps may be age related, only becoming troublesome in individuals between the ages of 50 and 65 and not in older patients. An even more important factor is the lack of clinical information for patients who were not followed up after the index colonoscopy; we do not know how their incidence of colon cancer compared with that in individuals who had single or multiple follow-up examinations. The effect of continued colonoscopic surveillance on lifetime colon cancer risk remains uncertain. Do these latest observations
that
one must
Michael O Blackstone Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, Illinois, USA 1 Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992; 326: 658-62. 2 Winawer SJ, Zauber AG, Nah Ho M, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993; 329: 1977-81. 3 O’Brien MJ, Winawer SJ, Zauber AG, et al. The National Polyp Study: patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology 1990; 98: 371-79. 4 Stryker SJ, Wolff BG, Culp CE, et al. Natural history of untreated colonic polyps. Gastroenterology 1987; 93: 1009-13. 5 Neugut AI, Jacobson JS, Ahsan H, et al. Incidence and recurrence rates of colorectal adenomas: a prospective study. Gastroenterology 1995; 108: 402-08. 6 Winawer SJ, Zauber AG, O’Brien MJ, et al. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993; 328: 901-06. 7 Hoff G, Foerster A, Vatn MH, et al. Epidemiology of polyps in the rectum and colon. Scand J Gastroenterol 1986; 21: 853-62.
Publishing economically See page 1139 The report by Gray and colleagues in this issue compares laparoscopy with laparotomy for ectopic pregnancy in terms of health service resources required as well as relative effectiveness. These researchers describe one type of economic evaluation,’ in this case a cost-effectiveness study. They followed agreed methods and based their conclusions on evidence drawn from a randomised controlled trial. There are some limitations to the study. The trial upon which it is based2 was a small one, and the fact that no significant differences were observed does not assure us that the treatments are equally effective. Furthermore, the researchers measured effectiveness in
questions. They may not have easy access to specialist health economics journals. In its instructions for authors, The Lancet welcomes "any contribution that advances or illuminates medical science and practice", yet it publishes few studies at the applied healthcare end of the range of clinical science research. However, issues of economics cannot be excluded from the journal. Even if authors do not mention costs, they are making an implicit economic statement whenever they make a recommendation about practice. Such statements presume that the resources taken up by the new practice could not be better used in other ways. A decision to publish any health economic study or paper with an economic component should be based on the importance of the subject and the quality of the research, as with any other paper. An economic study might be considered "important" if likely to influence the debate on resources or health or both.3 From my perspective as a health economist I have come across a wide range of published reports, from policy discussions and descriptive cost analyses to economic evaluations. All, when well done, can help decision makers, but most of the discussion about standards for economic studies has concentrated on economic evaluation. Recent reviews of medical publications suggest that a large proportion of so-called economic evaluations are not what they claim to be. 1,5 To reduce the risk of publishing studies based on poor economic methods, editors could seek advice from health economists on the quality of the economics in a paper, and authors of papers who cite costs could be asked either to delete the claim or conform to minimum criteria for economic methods. Those involved in economic evaluation research are currently discussing these criteria,6,7 and have reached a consensus on some basic points. A journal that adopted the policy I have outlined above 1127
i
would lessen its chance of publishing misleading or manipulative economic studies. A further safeguard is to seek, and publish, details of funding sources and other interests of authors, as was discussed recently in response to a policy statement in the New England 7ournal of Medicine.Ido not believe that refusing papers because they are commercially sponsored would reduce bias. Such studies can be good despite their funding source, while many studies not ostensibly funded by such sponsors are biased for other reasons. Miranda
Mugford
National Perinatal 1
2
3 4 5
6
7
8
Epidemiology Unit, Radcliffe Infirmary, Oxford, UK
Drummond MF, Stoddart GL, Torrance GW. Methods for the economic evaluation of health care programmes. Oxford: Oxford University Press, 1987. Lundorff P, Thorburn J, Hahlin M, Källfelt B, Lindblom B. Laparoscopic surgery in ectopic pregnancy: a randomised trial versus laparotomy. Acta Obstet Gynecol Scand 1991; 70: 343-48. Williams A. The cost-benefit approach. Br Med Bull 1974; 30: 252-56. Gerard K. Cost-utility in practice: a policy maker’s guide to the state of the art. Health Policy 1992; 21: 249-79. Jefferson TO, Demicheli V. Is vaccination against hepatitis B efficient? A review of world literature. Health Econ 1994; 3: 25-38. Canadian Coordinating Office for Health Technology Assessment. Guidelines for economic evaluation of pharmaceuticals. Draft 1.2, Feb 1, 1994. Ottawa: CCHOTA, 1994. Department of Health. Virginia Bottomley welcomes pioneering guidelines for the economic evaluation of medicines. DH press release 94/251 May 19, 1994. Kassirer J, Angell M. The journal’s policy on cost-effectiveness analyses. N Engl J Med 1994; 331: 669-70.
Cryptosporidium and The
apple
has
figured
the food
in the affairs of apple cider
ways. A recent report of
supply men
as
a
epidemic cryptosporidiosis implicates apples,
in ruinous cause of and other
fresh fruit and vegetables, as potential vectors of diarrhoeal disease. Millard and co-workers’ report an outbreak of 160 primary cases of cryptosporidiosis among persons who attended a school agricultural fair in Maine and ingested freshly pressed apple cider. Epidemiological investigation determined that apples collected from the ground of an orchard were the source of the infecting inoculum. A calf from the farm surrounding the orchard was excreting Cryptosporidium oocysts and was the presumed source of the outbreak. Although the possibility of Cryptosporidium contamination of foodstuffs has been discussed before,2 this report marks the first welldocumented point-source outbreak. is self-limited in disease Cryptosporidial immunocompetent hosts, but often results in
dehydration. those
with
In
immunosuppressed patients, especially the disease frequently causes
AIDS,
overwhelming watery diarrhoea and death.3 Since 1982, transmission of epidemic cryptosporidiosis via the faecaloral route has been reported in various settings by use of standard epidemiological techniques. Filtered and unfiltered municipal water were the sources of large outbreaks of gastrointestinal disease, including the Milwaukee, Wisconsin, outbreak of 1993 which involved 403000 people.4Smaller outbreaks have been associated with recreational water use.5 Exposure to infected farm animals and children in day-care centres has led to clinical cryptosporidiosis. The importance of sexual 1128
transmission, especially in the AIDS population, has been suggested but not fully assessed. Cryptosporidium is highly infectious and seems to be one of the main causes of infectious diarrhoea in many parts of the world/ Cryptosporidium is shed into the environment as a resistant oocyst that is impervious to chlorine and can survive for up to 3 months at low temperatures. Oocysts are killed by freezing and by brief high temperatures. Existing water quality control standards are insufficient to prevent disease in most areas of the developed world, either because filtration is not undertaken, or because high upstream oocyst loads from agricultural areas escape filtration at the time of backwashing of the filters. The inoculum causing infection in immunocompetent volunteers is low. Experiments recently concluded in Houston by DuPont and colleagues indicate that the ID 50 for healthy persons without serological evidence of previous cryptosporidiosis is 132 oocysts.’ Very high rates of transmission of Cryptosporidium, similar to those established for other highly transmissible enteric pathogens transmitted by the faecal-oral route such as Shigella species and rotavirus, have been documented within families in Brazil. The South American study among others suggests that symptomatic infection results in the development of immunity to disease, presumably mediated by the mucosal immune system. However, immunity does not necessarily mean absence of infection-prolonged symptomless oocyst excretion after symptomatic infection has been noted. These infections can be dangerous: studies in Guinea Bissau, West Africa, indicate that cryptosporidiosis is an important cause of death in otherwise healthy children in developing countries.9 Lastly, cryptosporidiosis may be an opportunistic infection in early AIDS, and the natural history of cryptosporidial diarrhoea in HIV-infected persons is highly variable. Although many patients become profoundly dehydrated with electrolyte abnormalities and rapid progression to death, the prognosis is not uniformly poor. Extended periods of oocyst excretion without symptoms or with mild symptoms, as well as spontaneous remission, may occur in this patient population Much has been learned in the past decade but several urgent issues remain. First, there is no specific therapy for cryptosporidiosis. The mainstay of treatment for symptomatic cases consists of intravenous fluids, electrolyte management, non-specific anti-diarrhoeal agents, and nutritional supplements. Very little is known about the biology which would allow us to exploit chemotherapeutic targets. We do not know, for example, why agents that are useful against other protozoan infections (eg, quinine, pyrimethamine, and sulpha analogues) are not useful for the treatment of cryptosporidiosis. Second, the epidemiology of the disease is poorly understood. What are the usual reservoirs from which human beings become infected-water, other persons, domestic animals, food? We need to determine whether symptomatic infection is usually due to an undetected common source outbreak or to ongoing lowlevel endemic transmission. Perhaps there is a reservoir of infected but not diseased persons who excrete and transmit the organism. What accounts for the variable course of infection in HIV-infected persons-ie, virulence factors in the organism or the level of pre-existing mucosal B-cell immunity to Cryptosporidium?