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Insignificant seasonal and geographical variation in incidence of biliary atresia in Japan: a regional survey of over 20 years
Journal of Pediatric Surgery (2007) 42, 2090–2092
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Insignificant seasonal and geographical variation in incidence of biliary atresia in Japan: a regional survey of over 20 years Hidemi Wada⁎, Toshihiro Muraji 1 , Akiko Yokoi, Tatsuya Okamoto, Shiiki Sato, Shigeru Takamizawa, Jiro Tsugawa, Eiji Nishijima Division of Pediatric Surgery, Kobe Children's Hospital, Kobe, Hyogo 654-0081, Japan Received 8 August 2007
Index words: Biliary atresia; Seasonality; Clustering; Time-space clustering
Abstract Purpose: Biliary atresia (BA) is the leading cause of obstructive jaundice in the newborn and the major indication for liver transplantation in Japan. Viral infection has been implicated in its etiology because of seasonality and space clustering. However, this has been controversial among whites. The present study investigates space-time clustering of the incidence of BA in Japan. Methods: Birth prevalence rates of BA were analyzed in infants born in Hyogo prefecture between 1985 and 2004 to assess time clustering among 3 seasons. The birth prevalence rates were also analyzed for space clustering between the northern (Hokkaido) and the southern islands (Kyushu) (difference of latitude, 10°) based on the Japanese Biliary Atresia Society Survey 1996-2004. We compared the prevalence rates between these groups using relative risks (RRs) calculated from 2 × 2 contingency tables. Results: One hundred nineteen infants were born with BA in Hyogo (1.1/10 000 live births). Seasonal clustering in April to July did not significantly differ from that of the reference period (RR, 1.45; 95% confidence interval, 0.93-2.27). Based on Japanese registry data, space clustering between the northern and southern islands did not significantly differ (RR, 1.24; 95% confidence interval, 0.83-1.86). Conclusions: Neither seasonal nor spatial clustering was statistically proven in Japan. © 2007 Published by Elsevier Inc.
Presented at the 40th annual meeting of the Pacific Association of Pediatric Surgeons, Queenstown, New Zealand, April 15-19, 2007. ⁎ Corresponding author. Division of Pediatric Surgery, Kobe Children's Hospital, 1-1-1 Takakuradai, Suma-ku, Kobe, Hyogo 654-0081, Japan. Tel.: +81 78 732 6961; fax: +81 78 735 0910. E-mail addresses: [email protected] (H. Wada), [email protected] (T. Muraji). 1 Sponsor: Division of Pediatric Surgery, Kobe Children's Hospital, 11-1 Takakuradai, Suma-ku, Kobe, Hyogo, Japan 654-0081. Tel.: +81 78 732 6961; fax: +81 78 735 0910. 0022-3468/$ – see front matter © 2007 Published by Elsevier Inc. doi:10.1016/j.jpedsurg.2007.08.035
Biliary atresia (BA) is the leading cause of obstructive jaundice among newborns and the major indication for liver transplantation in Japan. The annual number of patients with BA is approximately 100, of which 20 to 40 undergo livingrelated liver transplant because the concept of brain death is not accepted in Japan [1]. The etiology of BA remains unknown, and therefore, therapeutic strategies based on pathogenesis have not yet been established. Although environmental factors such as viral infection have been proposed as the etiology [2-4], exhaustive international investigations have not yet identified a universally accepted
Insignificant seasonal and geographical variation in incidence of BA in Japan responsible virus [5]. The prevalence rate of BA has been epidemiologically analyzed from seasonal and geographical aspects because seasonality and space clustering can provide useful environmental evidence for advocates of the viral infection theory [6,7]. However, this has been controversial according to reports describing whites, and only one brief report from Asia has been published. We conducted a statistical analysis of BA time and space clustering in Japan.
1. Methods Hyogo prefecture is located in the midwest of Japan, and the population is 5.6 million. Approximately 65% of the population is concentrated on the southeast coast facing the Inland Sea. The number of annual live births is about 50 000. Between 1985 and 2004, 94 infants with BA were transferred to our hospital, which specializes in infants and children. Because 25 more patients born with BA in Hyogo were found by personal communications with local pediatric surgeons, we analyzed a total of 119 BA patients. The diagnosis of BA was based on operative findings and liver biopsies according to the medical records of the infants. The population at risk in this study included 1 086 234 live births in Hyogo prefecture between 1985 and 2004 according to the monthly birth rates published in the annual reports of the Hyogo Prefectural Government. Analysis based on Hyogo series: We established the periods, April-July, August-November, and DecemberMarch, according to a report describing seasonal variations in birth prevalence rates [8]. Hyogo prefecture was divided into regions comprising the north, west, east-north, east-south, and Awaji island. The north region has the most land and the smallest population. Big cities are concentrated in the east-south region with the largest number of live births. Awaji island, with a population of 150 000, is isolated from the other areas. We analyzed geographic variations among all the regions as well as between the urban (east-south area) and rural (the others) areas in Hyogo. Analysis based on the Japanese Biliary Atresia Society survey: To analyze the relationship between temperature and
2091
the prevalence of BA, we compared the northernmost (Hokkaido) and southernmost (Kyushu) islands of Japan. The 2 islands differ by 10° latitude and by 10°C in annual average temperature. Birth rates were analyzed in terms of space clustering between Hokkaido and Kyushu between 1996 and 2004 [1]. The prevalence of BA among newborns according to season, region, and sex were calculated using population data. We compared the prevalence rates between groups using relative risks (RRs) calculated from 2 × 2 contingency tables. Our institutional review board approved the study protocol (IRB approval number: 16).
2. Results Between 1985 and 2004, the rate of infants with BA (75 females and 44 males) born in Hyogo prefecture was 1.1 per 10 000 live births (females, 1.43; males, 0.81). All of the infants were Asian. The annual number of infants with BA varied between 3 and 10, and the prevalence rate ranged from 0.49 to 1.88 per 10 000 live births. Fig. 1 shows the monthly incidence of BA during the investigated period. Rates of BA per 10 000 live births were 1.31 during April to July, 1.10 during August to November, and 0.90 during December to March. Seasonal clustering in April to July did not significantly differ from the reference period (RR, 1.45; 95% confidence interval [CI], 0.93-2.27) (Table 1). The rate of BA per 10 000 live births varied by region from 0.51 in the northern to 1.50 in the western region. The differences in the RR estimates among regions were not statistically significant. The rates were 1.13 in the urban (east-south) and 1.07 in the rural (the others) areas (not significantly different; RR, 1.06; 95% CI, 0.73-1.52). The prevalence rate of BA was higher for female than for male infants, and the difference was statistically significant (RR, 1.80; 95% CI, 1.24-2.62). The rates of BA per 10 000 live births were 0.71 and 0.88 in the northern and southern islands, respectively, indicating no significant difference in space clustering (RR, 1.24; 95% CI, 0.83-1.86).
3. Discussion
Fig. 1
Monthly variation in rates of BA per 10 000 live births.
The incidence of BA ranges from 0.5 per 10 000 live births in the Netherlands to 3.2 in French Polynesia [9,10], and in Japan, the incidence is 1.0 to 1.2 per 10 000 live births according to the registry data of Japanese Biliary Atresia Society [1]. The present population-based study of BA found an incidence of 1.1/10 000 live births in the Hyogo area. Thus, the prevalence rates of BA among 119 patients did not significantly correlate with either time or space over a period of 20 years. The only significant difference was female predominance. However, a much larger sample size, such as
2092
H. Wada et al.
Table 1 Frequency, prevalence rates, and RRs of BA among newborns by season, region, and sex in Hyogo prefecture, Japan, 1985-2004 Variable
Season April-July August-November December-March Region North West East-north East-south Awaji island Sex Male Female
No. of BA
Rate of BA per 10 000 live births
RR (95% CI)
48 39 32
1.31 1.10 0.90
1.45 (0.93-2.27) 1.18 (0.74-1.89) Reference
2 27 16 70 4
0.51 1.50 0.76 1.13 1.34
Reference 2.94 (0.70-12.36) 1.49 (0.34-6.49) 2.21 (0.54-8.99) 2.63 (0.48-14.37)
44 75
0.81 1.43
Reference 1.80 (1.24-2.62)
a nation-wide survey or even a worldwide survey, is likely needed to address this question. A preponderance of affected infants during the fall (August-October) was reported by Strickland and Shannon [11] and Danks et al [12], and seasonal patterns varied geographically with spring births at highest risk in New York City and September-November births at highest risk in other areas of New York state [13]. In contrast, the results of studies in Hawaii, the Netherlands, Michigan, and England did not support seasonal variation [9,14-17], and more recent and larger population-based study in France has not identified either seasonal variation or time clustering [10]. However, all of these data are from western communities, and therefore, a similar investigation is required from Asia. One Japanese study of 87 infants over 29 years briefly described in the English literature indicated that lower air temperature is likely to have a deterministic influence on the incidence of BA [18]. Yoon et al [8] also found that the prevalence rate in Atlanta between December and March was tripled. However, we could not duplicate the finding that a cooler temperature is associated with a higher incidence of BA from a comparison of 2 representative parts of Japan that differed in average temperature by 10°C. With regard to space clustering, Strickland and Shannon [11] reported that the incidence is higher in rural than in urban areas, whereas Caton et al [13] reported that the ratio of BA was 2.19-fold higher in New York City than in other areas in New York state. In contrast, population-based studies in metropolitan France, Atlanta, the Netherlands, and West Germany have not identified any geographic variations [8,9]. Chardot et al [10] compared the prevalence rates between French Polynesia and other regions in France and found that urbanization does not affect the prevalence of BA. These discordant conclusions on seasonal distribution or space clustering might be because of discrepancies in
statistical methodology or the number of samples [10]. We could not identify significant time and space clustering, but our sample size was insufficient to achieve more than 80% power to statistically confirm the absence of such clustering. Although our report is the largest series from Asia in the English literature addressing this controversial issue, a much larger sample size is required to satisfy the minimum of 3 million live births for such analysis.
Acknowledgments We very much appreciate the cooperation of the local pediatric surgeons in Hyogo Prefecture, Dr Kosaku Maeda, Dr Katsuya Hisano, Dr Masao Yasufuku, Dr Yasuji Seki, Dr Yasuhiro Matsukawa, Dr Tetsuo Katayama, and Dr Hisashi Sawada.
References [1] Japanese Biliary Atresia Society. The data of nation-wide survey of biliary atresia in 2004. J Jap Soc Pediatr Surg 2006;42:287-94. [2] Morecki R, Glaser JH, Cho S, et al. Biliary atresia and reovirus type 3 infection. N Engl J Med 1982;307:481-4. [3] Riepenhoff-Talty M, Gouvea V, Evans MJ, et al. Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 1996;174:8-15. [4] Fischler B, Ehrnst A, Forsgren M, et al. The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998;27:57-64. [5] Brown WR, Sokol RJ, Levin MJ, et al. Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. J Pediatr 1988;113:670-6. [6] Perlmutter DH, Shepherd RW. Extrahepatic biliary atresia: a disease or a phenotype? Hepatology 2002;35:1297-304. [7] Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 2005;57:87R-94R. [8] Yoon PW, Bresee JS, Olney RS, et al. Epidemiology of biliary atresia: a population-based study. Pediatrics 1997;99:376-82. [9] Houwen RHJ, Kerremans IIA, van Steensel-Moll HA, et al. Timespace distribution of extrahepatic biliary atresia in the Netherlands and West Germany. Z Kinderchir 1988;43:68-71. [10] Chardot C, Caton M, Spire-Bendelac N, et al. Epidemiology of biliary atresia in France: a national study 1986-96. J Hepatol 1999;31:1006-13. [11] Strickland AD, Shannon K. Studies in the etiology of extrahepatic biliary atresia: time-space clustering. J Pediatr 1982;100:749-75. [12] Danks DM, Campbell PE, Jack I, et al. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child 1977;52:360-7. [13] Caton AR, Druschel CM, McNutt LA. The epidemiology of extrahepatic biliary atresia in New York State, 1983-98. Paediatr Perinat Epidemiol 2004;18:97-105. [14] Shim WKT, Kasai M, Spence MA. Racial influence on the incidence of biliary atresia. Prog Pediatr Surg 1974;6:53-62. [15] Ayas MF, Hillemeier AC, Olson AD. Lack of evidence for seasonal variation in extrahepatic biliary atresia during infancy. J Clin Gastroenterol 1996;22:292-4. [16] Davenport M, Kerker N, Mieli-Vergani G, et al. Biliary atresia—the King's College Hospital experience. J Pediatr Surg 1997;32:479-85. [17] Davenport M, Dhawan A. Epidemiologic study of infants with biliary atresia. Pediatrics 1998;101:729-30. [18] Nakamizo M, Toyobe S, Kubota M, et al. Seasonality in the incidence of biliary atresia in Japan. Acta Paediatr 2006;95:511-2.
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Insignificant seasonal and geographical variation in incidence of biliary atresia in Japan: a regional survey of over 20 years Hidemi Wada⁎, Toshihiro Muraji 1 , Akiko Yokoi, Tatsuya Okamoto, Shiiki Sato, Shigeru Takamizawa, Jiro Tsugawa, Eiji Nishijima Division of Pediatric Surgery, Kobe Children's Hospital, Kobe, Hyogo 654-0081, Japan Received 8 August 2007
Index words: Biliary atresia; Seasonality; Clustering; Time-space clustering
Abstract Purpose: Biliary atresia (BA) is the leading cause of obstructive jaundice in the newborn and the major indication for liver transplantation in Japan. Viral infection has been implicated in its etiology because of seasonality and space clustering. However, this has been controversial among whites. The present study investigates space-time clustering of the incidence of BA in Japan. Methods: Birth prevalence rates of BA were analyzed in infants born in Hyogo prefecture between 1985 and 2004 to assess time clustering among 3 seasons. The birth prevalence rates were also analyzed for space clustering between the northern (Hokkaido) and the southern islands (Kyushu) (difference of latitude, 10°) based on the Japanese Biliary Atresia Society Survey 1996-2004. We compared the prevalence rates between these groups using relative risks (RRs) calculated from 2 × 2 contingency tables. Results: One hundred nineteen infants were born with BA in Hyogo (1.1/10 000 live births). Seasonal clustering in April to July did not significantly differ from that of the reference period (RR, 1.45; 95% confidence interval, 0.93-2.27). Based on Japanese registry data, space clustering between the northern and southern islands did not significantly differ (RR, 1.24; 95% confidence interval, 0.83-1.86). Conclusions: Neither seasonal nor spatial clustering was statistically proven in Japan. © 2007 Published by Elsevier Inc.
Presented at the 40th annual meeting of the Pacific Association of Pediatric Surgeons, Queenstown, New Zealand, April 15-19, 2007. ⁎ Corresponding author. Division of Pediatric Surgery, Kobe Children's Hospital, 1-1-1 Takakuradai, Suma-ku, Kobe, Hyogo 654-0081, Japan. Tel.: +81 78 732 6961; fax: +81 78 735 0910. E-mail addresses: [email protected] (H. Wada), [email protected] (T. Muraji). 1 Sponsor: Division of Pediatric Surgery, Kobe Children's Hospital, 11-1 Takakuradai, Suma-ku, Kobe, Hyogo, Japan 654-0081. Tel.: +81 78 732 6961; fax: +81 78 735 0910. 0022-3468/$ – see front matter © 2007 Published by Elsevier Inc. doi:10.1016/j.jpedsurg.2007.08.035
Biliary atresia (BA) is the leading cause of obstructive jaundice among newborns and the major indication for liver transplantation in Japan. The annual number of patients with BA is approximately 100, of which 20 to 40 undergo livingrelated liver transplant because the concept of brain death is not accepted in Japan [1]. The etiology of BA remains unknown, and therefore, therapeutic strategies based on pathogenesis have not yet been established. Although environmental factors such as viral infection have been proposed as the etiology [2-4], exhaustive international investigations have not yet identified a universally accepted
Insignificant seasonal and geographical variation in incidence of BA in Japan responsible virus [5]. The prevalence rate of BA has been epidemiologically analyzed from seasonal and geographical aspects because seasonality and space clustering can provide useful environmental evidence for advocates of the viral infection theory [6,7]. However, this has been controversial according to reports describing whites, and only one brief report from Asia has been published. We conducted a statistical analysis of BA time and space clustering in Japan.
1. Methods Hyogo prefecture is located in the midwest of Japan, and the population is 5.6 million. Approximately 65% of the population is concentrated on the southeast coast facing the Inland Sea. The number of annual live births is about 50 000. Between 1985 and 2004, 94 infants with BA were transferred to our hospital, which specializes in infants and children. Because 25 more patients born with BA in Hyogo were found by personal communications with local pediatric surgeons, we analyzed a total of 119 BA patients. The diagnosis of BA was based on operative findings and liver biopsies according to the medical records of the infants. The population at risk in this study included 1 086 234 live births in Hyogo prefecture between 1985 and 2004 according to the monthly birth rates published in the annual reports of the Hyogo Prefectural Government. Analysis based on Hyogo series: We established the periods, April-July, August-November, and DecemberMarch, according to a report describing seasonal variations in birth prevalence rates [8]. Hyogo prefecture was divided into regions comprising the north, west, east-north, east-south, and Awaji island. The north region has the most land and the smallest population. Big cities are concentrated in the east-south region with the largest number of live births. Awaji island, with a population of 150 000, is isolated from the other areas. We analyzed geographic variations among all the regions as well as between the urban (east-south area) and rural (the others) areas in Hyogo. Analysis based on the Japanese Biliary Atresia Society survey: To analyze the relationship between temperature and
2091
the prevalence of BA, we compared the northernmost (Hokkaido) and southernmost (Kyushu) islands of Japan. The 2 islands differ by 10° latitude and by 10°C in annual average temperature. Birth rates were analyzed in terms of space clustering between Hokkaido and Kyushu between 1996 and 2004 [1]. The prevalence of BA among newborns according to season, region, and sex were calculated using population data. We compared the prevalence rates between groups using relative risks (RRs) calculated from 2 × 2 contingency tables. Our institutional review board approved the study protocol (IRB approval number: 16).
2. Results Between 1985 and 2004, the rate of infants with BA (75 females and 44 males) born in Hyogo prefecture was 1.1 per 10 000 live births (females, 1.43; males, 0.81). All of the infants were Asian. The annual number of infants with BA varied between 3 and 10, and the prevalence rate ranged from 0.49 to 1.88 per 10 000 live births. Fig. 1 shows the monthly incidence of BA during the investigated period. Rates of BA per 10 000 live births were 1.31 during April to July, 1.10 during August to November, and 0.90 during December to March. Seasonal clustering in April to July did not significantly differ from the reference period (RR, 1.45; 95% confidence interval [CI], 0.93-2.27) (Table 1). The rate of BA per 10 000 live births varied by region from 0.51 in the northern to 1.50 in the western region. The differences in the RR estimates among regions were not statistically significant. The rates were 1.13 in the urban (east-south) and 1.07 in the rural (the others) areas (not significantly different; RR, 1.06; 95% CI, 0.73-1.52). The prevalence rate of BA was higher for female than for male infants, and the difference was statistically significant (RR, 1.80; 95% CI, 1.24-2.62). The rates of BA per 10 000 live births were 0.71 and 0.88 in the northern and southern islands, respectively, indicating no significant difference in space clustering (RR, 1.24; 95% CI, 0.83-1.86).
3. Discussion
Fig. 1
Monthly variation in rates of BA per 10 000 live births.
The incidence of BA ranges from 0.5 per 10 000 live births in the Netherlands to 3.2 in French Polynesia [9,10], and in Japan, the incidence is 1.0 to 1.2 per 10 000 live births according to the registry data of Japanese Biliary Atresia Society [1]. The present population-based study of BA found an incidence of 1.1/10 000 live births in the Hyogo area. Thus, the prevalence rates of BA among 119 patients did not significantly correlate with either time or space over a period of 20 years. The only significant difference was female predominance. However, a much larger sample size, such as
2092
H. Wada et al.
Table 1 Frequency, prevalence rates, and RRs of BA among newborns by season, region, and sex in Hyogo prefecture, Japan, 1985-2004 Variable
Season April-July August-November December-March Region North West East-north East-south Awaji island Sex Male Female
No. of BA
Rate of BA per 10 000 live births
RR (95% CI)
48 39 32
1.31 1.10 0.90
1.45 (0.93-2.27) 1.18 (0.74-1.89) Reference
2 27 16 70 4
0.51 1.50 0.76 1.13 1.34
Reference 2.94 (0.70-12.36) 1.49 (0.34-6.49) 2.21 (0.54-8.99) 2.63 (0.48-14.37)
44 75
0.81 1.43
Reference 1.80 (1.24-2.62)
a nation-wide survey or even a worldwide survey, is likely needed to address this question. A preponderance of affected infants during the fall (August-October) was reported by Strickland and Shannon [11] and Danks et al [12], and seasonal patterns varied geographically with spring births at highest risk in New York City and September-November births at highest risk in other areas of New York state [13]. In contrast, the results of studies in Hawaii, the Netherlands, Michigan, and England did not support seasonal variation [9,14-17], and more recent and larger population-based study in France has not identified either seasonal variation or time clustering [10]. However, all of these data are from western communities, and therefore, a similar investigation is required from Asia. One Japanese study of 87 infants over 29 years briefly described in the English literature indicated that lower air temperature is likely to have a deterministic influence on the incidence of BA [18]. Yoon et al [8] also found that the prevalence rate in Atlanta between December and March was tripled. However, we could not duplicate the finding that a cooler temperature is associated with a higher incidence of BA from a comparison of 2 representative parts of Japan that differed in average temperature by 10°C. With regard to space clustering, Strickland and Shannon [11] reported that the incidence is higher in rural than in urban areas, whereas Caton et al [13] reported that the ratio of BA was 2.19-fold higher in New York City than in other areas in New York state. In contrast, population-based studies in metropolitan France, Atlanta, the Netherlands, and West Germany have not identified any geographic variations [8,9]. Chardot et al [10] compared the prevalence rates between French Polynesia and other regions in France and found that urbanization does not affect the prevalence of BA. These discordant conclusions on seasonal distribution or space clustering might be because of discrepancies in
statistical methodology or the number of samples [10]. We could not identify significant time and space clustering, but our sample size was insufficient to achieve more than 80% power to statistically confirm the absence of such clustering. Although our report is the largest series from Asia in the English literature addressing this controversial issue, a much larger sample size is required to satisfy the minimum of 3 million live births for such analysis.
Acknowledgments We very much appreciate the cooperation of the local pediatric surgeons in Hyogo Prefecture, Dr Kosaku Maeda, Dr Katsuya Hisano, Dr Masao Yasufuku, Dr Yasuji Seki, Dr Yasuhiro Matsukawa, Dr Tetsuo Katayama, and Dr Hisashi Sawada.
References [1] Japanese Biliary Atresia Society. The data of nation-wide survey of biliary atresia in 2004. J Jap Soc Pediatr Surg 2006;42:287-94. [2] Morecki R, Glaser JH, Cho S, et al. Biliary atresia and reovirus type 3 infection. N Engl J Med 1982;307:481-4. [3] Riepenhoff-Talty M, Gouvea V, Evans MJ, et al. Detection of group C rotavirus in infants with extrahepatic biliary atresia. J Infect Dis 1996;174:8-15. [4] Fischler B, Ehrnst A, Forsgren M, et al. The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998;27:57-64. [5] Brown WR, Sokol RJ, Levin MJ, et al. Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis. J Pediatr 1988;113:670-6. [6] Perlmutter DH, Shepherd RW. Extrahepatic biliary atresia: a disease or a phenotype? Hepatology 2002;35:1297-304. [7] Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 2005;57:87R-94R. [8] Yoon PW, Bresee JS, Olney RS, et al. Epidemiology of biliary atresia: a population-based study. Pediatrics 1997;99:376-82. [9] Houwen RHJ, Kerremans IIA, van Steensel-Moll HA, et al. Timespace distribution of extrahepatic biliary atresia in the Netherlands and West Germany. Z Kinderchir 1988;43:68-71. [10] Chardot C, Caton M, Spire-Bendelac N, et al. Epidemiology of biliary atresia in France: a national study 1986-96. J Hepatol 1999;31:1006-13. [11] Strickland AD, Shannon K. Studies in the etiology of extrahepatic biliary atresia: time-space clustering. J Pediatr 1982;100:749-75. [12] Danks DM, Campbell PE, Jack I, et al. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child 1977;52:360-7. [13] Caton AR, Druschel CM, McNutt LA. The epidemiology of extrahepatic biliary atresia in New York State, 1983-98. Paediatr Perinat Epidemiol 2004;18:97-105. [14] Shim WKT, Kasai M, Spence MA. Racial influence on the incidence of biliary atresia. Prog Pediatr Surg 1974;6:53-62. [15] Ayas MF, Hillemeier AC, Olson AD. Lack of evidence for seasonal variation in extrahepatic biliary atresia during infancy. J Clin Gastroenterol 1996;22:292-4. [16] Davenport M, Kerker N, Mieli-Vergani G, et al. Biliary atresia—the King's College Hospital experience. J Pediatr Surg 1997;32:479-85. [17] Davenport M, Dhawan A. Epidemiologic study of infants with biliary atresia. Pediatrics 1998;101:729-30. [18] Nakamizo M, Toyobe S, Kubota M, et al. Seasonality in the incidence of biliary atresia in Japan. Acta Paediatr 2006;95:511-2.