Cystic fibrosis in Ontario

American Journal of Medical Genetics 22:383-393 (1985)

Cystic Fibrosis in Ontario

J.M. Sturgess, E. Czegledy-Nagy, M. Corey, and M.W. Thompson

Departments of Pathology (J. M. S., E. C. - N.), Paediatrics (M. C.), and Genetics (M. W. T), Hospital for Sick Children, Toronto and Warner-LamberiYParke-Davis Research Institute (J. M. S.), Mississauga, Ontario, Canada

The incidence of cystic fibrosis in Ontario, Canada has been determined from clinical data, from the cystic fibrosis database of the Hospital for Sick Children, Toronto, and from population statistics in the Province of Ontario. The survey included 420 confirmed cases of cystic fibrosis born during the period 1966-1980. The mean incidence during this period was one in 2,927. In the last 5-year period, a decline was noted in incidence that may have reflected in part the effectiveness of early diagnosis and genetic counseling in affected families. During the period of the survey, over 60% of cases were diagnosed within the first year of life, 74% by age 2 years, and 90% by age 5 years. Clinical diagnosis in the first year of life was more common in males (65%) than in females (54%), a consistent finding during the period of the survey. The incidence of meconium ileus was 15.7% of ascertained cases of cystic fibrosis, with similar incidences in males (16.4%) and females (14.4%). Although survival has not been the subject of this survey, mortality in the neonatal period was significantly higher in males than in females with cystic fibrosis.

Key words: cystic fibrosis, meconium ileus, genetics, incidence, recessive inheritance

INTRODUCTION

In early reports of cystic fibrosis, suggested incidences were 1 : 500-1 : 1,400 for Caucasian populations based on limited population samples such as autopsy records and hospital questionnaires. Using genetic or epidemiologic methods, estimates of approximately 1 :2,000-4,000 live births have become generally accepted for Cauca- sian populations. The incidence of cystic fibrosis in a Canadian population has not been reported previously.

Received for publication March 4, 1985; revision received May 2, 1985.

Address reprint requests to Dr. J.M. Sturgess, Warner-LambedParke-Davis Research Institute, 2270 Speakman Drive, Mississauga, Ontario, L5K 1B4, Canada.

0 1985 Alan R. Liss, Inc.

384 Sturgess et al

The purpose of this report is to describe the minimum incidence of cystic fibrosis in Ontario for the period 1966-1980 based on a database established at the Cystic Fibrosis Clinic of the Hospital for Sick Children, Toronto, Ontario [Corey, 19801 and from population statistics for the Province of Ontario [Vital Statistics, Province of Ontario, 1974, 1978, 19811. In addition, ages at diagnosis, sex ratios, and incidences of meconium ileus and mortality are presented for the early childhood period.

PATIENTS AND METHODS Cystic Fibrosis Cases

This survey included all cystic fibrosis subjects born in the Province of Ontario in the years 1966 to 1980 and registered in the Cystic Fibrosis Clinic at the Hospital for Sick Children, Toronto, Ontario during the period 1966 to 1984. The information included in this retrospective survey was ascertained from the Cystic Fibrosis Clinic database at the Hospital for Sick Children. The database documented all cystic fibrosis patients who attended the Hospital for Sick Children clinic and included statistical information on the birth, place of birth, date of confirmed diagnosis, and date of death where applicable; family data including sibships and ethnic origins; and clinical data including incidence of meconium ileus. All birth dates, diagnoses, and clinical and other data were confirmed from the original medical records for each patient. The occurrence of meconium ileus was confirmed from the clinical histories and from surgical and autopsy records from the Department of Pathology, Hospital for Sick Children. The clinical diagnosis of cystic fibrosis was confirmed in infants of 6 weeks or older by a sweat test.

The survey represented a total of 645 cystic fibrosis patients born in the Province of Ontario between 1966 and 1980, of whom 420 patients attended the Cystic Fibrosis Clinic at the Hospital for Sick Children.

Population Base

The number of live births in the Province of Ontario was ascertained from published statistical data [Vital Statistics, Province of Ontario, 1974, 1978, 19811. The number of live births ranged from approximately 121,000 to 135,000 per annum during the period 1966 to 1980 (see Table I).

On the basis of documentation and longitudinal data from the cystic fibrosis database [Corey, 19801 during the period 1966-1980, it was established that 65% of liveborn affected children in the Province of Ontario were referred to the Cystic Fibrosis Clinic at the Hospital for Sick Children; the remaining 35% were treated at other clinics in Ontario and reported to the Cystic Fibrosis Patient Registry [Cystic Fibrosis Foundation Report, 19791. The catchment population for calculation of incidence in this survey was defined as 65% of live births in the Province of Ontario.

The population of Ontario increased progressively during the period of this survey, although the annual birth rate declined significantly. The population included all ethnic origins but was predominantly Caucasian in origin and of European descent; in 1966 to 1970, 96.5% were Causasians, and at the end of the survey in 1980 the proportion of Caucasians was slightly lower, 94.2 % [Ontario Statistics, 1975; Census Statistics Canada, 19831.

Cystic Fibrosis in Ontario 385

TABLE I. Estimated Minimum Incidence of Cystic Fibrosis (CF) in Ontario, 1966-1980

No. of Catchment No. of CF Minimum incidence Years live births population patients of CF:live births

1966 131,942 85,762 28 1:3,063 1967 127,509 82,881 36 1 :2,302 1968 126,257 82,067 28 1:2,931 1969 130,398 84,759 38 1:2,231 1970 134,724 87,571 32 I :2,737 1966- 1970 650,830 423,040 162 1:2,611 1971 130,395 84,757 29 1:2,923 1972 125,060 81,289 35 1:2,323 1973 123,776 80,454 32 1:2,514 1974 124,229 80,749 21 1:3,845 1975 125,775 81,754 30 1:2,725 197 I - 1975 629,235 409,003 147 1:2,782 1976 122,700 79,755 30 1:2,659 1977 122,757 79,792 12 I :6,649 1978 120,964 78,627 26 I : 3,024 1979 12 1,655 79,076 21 1:3,766 1980 123,3 16 80,155 22 1:3,643 1976- I980 611,392 397,405 111 1:3,580 1966-1980 1,891,457 1,229,448 420 1:2,927a

“Mean incidence.

Incidence figures for cystic fibrosis were calculated for cystic fibrosis patients according to year of birth, in relation to the number of live births in the population for the corresponding year. Based on these data, incidence figures were derived exclusively for the Causasian population in Ontario (see Table 11). In addition, the incidence of cystic fibrosis in males and females was determined independently for male and female live births in Ontario for each year of the survey.

RESULTS Incidence of Cystic Fibrosis

The survey included a total of 420 patients (225 males, 195 females) born between January 1966 and December 1980 and confirmed to have cystic fibrosis in the period up to December 1984. The series included 367 families each having one affected child, 25 families each having two affected children, and one family having three affected children. In families with more than one affected child, the ages of diagnosis were likely to have been earlier on the basis of sibling history. However, the births of siblings were distributed throughout the period of this survey; when grouped by the year of birth of the oldest sibling in each family, ten were born in 1966-1970, ten in 1971-1975, and six in 1976-1980. Therefore, it was considered unlikely that these data influenced the overall estimates of incidence or average ages of diagnosis.

The mean incidence of cystic fibrosis in Ontario was calculated independently for each year from 1966 to 1980 from the ratio of the number of children born in each

386 Sturgess et al

TABLE 11. Minimum Incidence of Cystic Fibrosis in Live Births in the Caucasian Population of Ontario, 1966-1980

Estimated minimum incidence of

Catchment No. of CF CF:Caucasian No. of live births

Years Total Caucasian population patientsa live births

1966-1970 650,830 628,051 408,233 162 1:2,520 197 1 - 1975 629,235 599,661 389,780 146 1:2,670 1976-1980 611,392 575,931 374,355 108 1 : 3,466 Minimum 1,891,457 1,803,643 1,172,368 416 1:2,818

incidence (1966-1980)

aThe CF patients (416) were of Caucasian origin; four additional patients born in this period were diagnosed with CF but were not of Caucasian origin and were not included.

year who were ascertained to have cystic fibrosis to the total number of live births in that year. The mean incidence was calculated independently for each of three 5-year periods: 1966-1970, 1971-1975, and 1976-1980. During these periods, the total numbers of cystic fibrosis cases included in the survey were 162, 147, and 111, respectively. The minimal incidences of cystic fibrosis during these 5-year periods were one in 2,611; one in 2,782; and one in 3,580, respectively (Table I). The overall incidence in 1966-1980 was one in 2,927 live births. When adjusted for Caucasian live births, the average minimum incidence was one in 2,818 over the 15-year period (Table 11).

Sex Ratio

The incidences of boys and girls ascertained with cystic fibrosis were calculated in relation to the numbers of male and female live births for each year (Table 111). In the survey period, the numbers of live births with cystic fibrosis included 225 males (53.6%) and 195 females (46.4%). In the three consecutive 5-year periods the incidence of cystic fibrosis in live-born males was 1:2,585, 1:2,597 and 1:3,392, respectively, with an overall incidence of 1 :2,804. The incidence in liveborn females was 1:2,640, 1:3,010, and 1,3,801, with an overall incidence of 1:3,069. The higher

TABLE 111. Estimated Minimum Incidence of Cystic Fibrosis in Males and Females in Ontario, 1966-1980

No. of live births No. of Estimated minimum incidence - _ _ in catchment population - patients

Female ____ Male Female Male - Female Male ___ Ycars

1966- 19 70 2 17,137 205,902 84 78 1:2,585 1:2,640 197 1 .- I975 210,327 198,675 81 66 1:2,597 1:3,010 1976-1980 203,536 193,868 60 51 1:3,392 1:3,801 I966 - I9 80 63 1 ,OOO 598,445 225 I95 1:2,804 1:3,069


number of males with cystic fibrosis reflected in part a higher birth rate for males in the Province between 1966-1980. However, there was a consistent trend for a higher incidence of males with cystic fibrosis than females during the survey. The higher incidence of males reflected trends in other reports on cystic fibrosis, but the significance was unknown.

Age of Diagnosis During the entire survey period, 60% of children were diagnosed within the

first year of life, and an additional 14% were diagnosed by 2 years of age (Fig. 1). By age 5 years, 90% of all cases had a confirmed diagnosis. The percentage of cystic fibrosis patients diagnosed within the first year of life increased from 49% in 1966- 1970, to 63% in 1970-1975, and to 71% in 1976-1980. The incidence data for the year 1980 assumed that at least 85 % of the subjects born in that year were ascertained by the time of the analysis (1984). The age of diagnosis was analyzed separately for male and female infants with cystic fibrosis, and the results are shown in Figure 2. A greater proportion of males with cystic fibrosis was diagnosed during the first year of life (65 %) when compared with females (54 %), an observation that was consistent in each of the 5-year periods. By the age of 2 years, a similar proportion (74%) of males and females were ascertained.

5 L 6

0 1966-1970

0 1971 -1975

1975 - 1980

7 8 9 1 0

AGE AT DIAGNOSIS (years)

Fig. 1. Comparison of the ages of diagnosis of patients in Ontario with cystic fibrosis in three consecutive 5-year periods: 1966-1970, 1971-1975, 1976-1980. Values for the period 1976-1980 are limited within the time frame of this report by cases as yet undiagnosed. However, the data indicate a progressive trend to earlier diagnosis, within the first year of life.

388 Sturgess et al

70 1 I

.1 2 3 4 5 6 7 8 9 . 9

AGE AT DIAGNOSIS (years )

Fig. 2. Comparison of the ages of diagnosis of male and female patients with cystic fibrosis in Ontario. The data represent average values for the period 1966-1980. A significantly larger percentage of males were ascertained during the first year of life; this observation was consistent for each of the three 5-year time periods show in Figure 1.

Meconium lleus In this survey, of the 420 patients diagnosed with cystic fibrosis 65 newborn

infants had meconium ileus. The overall incidence of meconium ileus averaged 1:6 males (16.4%) and 1:7 females (14.4%) ascertained with cystic fibrosis, with no significant differences during the period of the survey. These data presumably reflected the maximum incidence of meconium ileus, since some cystic fibrosis cohorts may have been identified only at later ages.

Most deaths among cystic fibrosis patients ascertained from birth to 3 months of age were caused by meconium ileus and its sequelae. In the earlier periods of the survey mortality was significantly higher for male infants with meconium ileus than for females: considering only those patients with meconium ileus in the overall survey, ten of 37 males died at less than 1 year of age compared to two of 28 females (P < 0.05, Fisher Exact Test). Since the incidence of meconium ileus was not higher for males, the differences appeared to correlate with the earlier diagnosis in males and the greater number of deaths in affected males during the first year of life (Fig. 3). These observations suggested that the severity of disease in the neonatal period was greater for affected males than females.

Mortality Of the 420 cystic fibrosis patients in this survey, 58 have died (34 females and

24 males). Figure 3 shows the pattern of deaths by sex and age groups. A significantly


3mo 3mo -1 1-2

1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-5 5 -10 10

AGE AT DEATH (years)

Fig. 3. Mortality in cystic fibrosis patients in this survey born between 1966 and 1980. The number of deaths are compared for males and females according to age at time of death. During the neonatal period ( < 3 months) a significantly higher mortality was observed among males with cystic fibrosis. In contrast, cystic fibrosis patients surviving beyond the first year of life showed poorer survival among females than males.

larger number of males than females died in the first 3 months of life (P < 0.05). All female deaths and 11 of 12 male deaths under the age of 3 months had a clinical history of meconium ileus. After the age of 2 years, more females died than males. The latter trend of poorer survival for cystic fibrosis females persisted with increasing age.

The significantly higher mortality in males in the neonatal period and in the first 2 years of life has not been reported previously. The variation was significantly greater than the higher mortality reported for males in this age group in the general population [US. DHEW, 19531. This susceptibility of cystic fibrosis males in the neonatal period may have been attributed to a greater severity of disease from gastrointestinal complications or sequelae of meconium ileus. The basis for these observations is unknown and is of interest because from 4 years of age female children have a poorer prognosis with increased morbidity and mortality than males.

DISCUSSION Incidence of Cystic Fibrosis

The estimated average incidence reflects minimum incidences for Ontario. Not accounted for in these estimates are undiagnosed patients, patients who died before referral to a Cystic Fibrosis Clinic, patients who are treated outside the specialized

390 Sturgess et a1

Cystic Fibrosis Clinics in Ontario, and patients with milder forms of the disease who may be diagnosed only later in life.

Until a widespread screening program is established that is specific for cystic fibrosis, it will not be possible to determine the actual incidence in different regions of the world and among different ethnic groups. On the basis of limited ascertainment of cystic fibrosis cases and using statistical derivations from the United States Data Registry, Warwick [ 19801 has proposed that the actual incidence of cystic fibrosis may be two to three times greater than the minimal incidences, ie, 1:1,060 of the Caucasian population.

Based on reports of surveys that included more than 100 index cases (Table IV), the minimum incidence observed in Ontario resembles previous estimates from Europe, the United States, and Australasia. In the United States, the annual incidence of cystic fibrosis has been reported to increase in 10-year period from 1:4,800 live births in 1966 to 1:3,200 in 1975 [Cystic Fibrosis Foundation Report, 19791. In contrast, the data for Ontario have not changed significantly in the same period; the incidence is similar for the 10-year period from 1966-1975, and a trend to lower incidence is observed over the following 5-year period (1976-1980). The reason for the difference between the U.S. and Canadian data may be related to degree of ascertainment and to the scope of the Registry that, in Ontario, involves only a single center. Recognizing that milder forms of the disease do exist, it is likely that some cystic fibrosis subjects born in the 1976-1980 period have not been diagnosed, as yet, in the group. However, when estimates for cases as yet undiagnosed in the later birth

TABLE IV. Summary of Incidences of Cystic Fibrosis Reported in Large Surveys of Caucasian Live Births

Estimated No. of Population minimum

C F cases sampled incidence" Country [Reference] .

United States (Kramm et al, 19621 62 1 1,428,300 I :2,300 Australia [Allan et al, 19801 580 1,482,480 1:2,556 Denmark [Nielsen and Schiotz, 19821 490 1,390,620 1:2,838 Netherlands [Ten Kate, 19771 342 1,239,566 1:3,600

( I : 1,900- 1:5,000)

United States [Steinberg and Brown, 19601 198 742,163 1:3,700 Ireland [Nevin et al, 19791 195 362,224 1: 1,857 Czechoslovakia [Brunecky, 19721 147 490,000 I :3,300 Australia (Danks et al, 19651 138 362,732 1:2,448 United Kingdom [ h g h and Pickup, 19671 132 546,764 1 :4,142 Sweden [Kollberg, 19821 118 777,153 1 :2,200-

1:4,500 Ontario, Canada [present survey] 420 1,229,448 1:2,927

"Summarized here are published reports of incidence of cystic fibrosis based on surveys that include more than 100 ascertained and diagnosed cases: estimated minimum incidences were cited in the original reports.


cohorts are included in the data, extrapolation of incidence remain lower than in previous 5-year periods. The decline in incidence over the period of this survey may reflect, therefore, the effectiveness of early diagnosis followed by genetic counseling for families with affected children. The significance of this apparent trend remains to be evaluated.

The population statistics for Ontario do not allow for interpretation of immigra- tion and emigration in Ontario or for precise evaluation of the distribution of live births among different ethnic groups. The percentage of non-Caucasian ethnic groups in the Ontario population has increased from about 3.5% in 1971 to 5.8% in 1980 [Vital Statistics, Province of Ontario, 1975, 19811. When the incidence data are adjusted for the Caucasian population, it is clear that ethnic influences have not significantly changed the estimates of incidence of cystic fibrosis in the overall population. Comparison of longitudinal data for males and females with cystic fibrosis have identified a poorer prognosis for females [Corey, 1980; Cystic Fibrosis Foun- dation Report, 19791. In older children morbidity and mortality are significantly higher in affected females. The observation that clinical diagnosis in the first year of life in males with cystic fibrosis is significantly more common than in females is an interesting and unexplained finding that has not been reported previously. The earlier diagnosis does not reflect a predisposition to meconium ileus, since males and females appear equally affected. However, neonatal mortality in males is significantly higher than females. The findings suggest that the onset and course of the disease in cystic fibrosis males is earlier and more severe from birth and through the neonatal period until approximately age 1 year. By age 2 years, ascertainment, clinical status, and survival of males and females is similar; and, by age 4 years, the prognosis for males is better than for females.

The incidence of meconium ileus in cystic fibrosis patients registered in the Hospital for Sick Children averages 15.7%, with similar incidences in males (16.4%) and females (14.4%). Earlier reports describe the incidence of meconium ileus in a range from 7 to 25% of cystic fibrosis subjects (Table V). The average incidence calculated for all previous large surveys (15.3 %) closely resembles that among patients ascertained with cystic fibrosis in Ontario (15.7%). However, it is possible that these values reflect the maximum incidence for meconium ileus because it is likely that some cystic fibrosis patients with milder symptoms have not been ascertained as yet. A further consideration is that the need for medical or surgical treatment of newborn infants with meconium ileus may have referred disproportionately more cystic fibrosis patients with meconium ileus in Ontario to the Hospital for Sick Children.

In this survey, the cystic fibrosis patients were predominantly Caucasian and of European descent. In Canada [Cystic Fibrosis Patient Registry Report, 19811, the percentages of cystic fibrosis patients are 98.3 % white, 0.3% black, 0.4% Indian, and 1 % of other ethnic origin; these ethnic origins are similar to those reported in the United States Data Registry (97.2% white, 2.1 % black, 0.1 % Indian and 0.6% other). The incidences in relation to the population base have not been determined for different ethnic groups other than Caucasian. It is clearly evident that, while cystic fibrosis is considered predominantly a disorder of Caucasians of European descent, the cystic fibrosis gene is present in other ethnic groups.

392 Sturgess et al

TABLE V. Surveys of Meconium IIeus (MI) in Cystic Fibrosis (CF)

Survey - ~ ~ _ _

London, UK Toronto. Canada Baltimore, USA London, UK Connecticut, USA Boston, USA Leeds, UK New Zealand Wessex, UK Moscow, USSR Netherlands Israel Australia Denmark Total cases

~~~~l Patients with MI Survey CF

Reference period cases No. Percent

Bodian [I9521 MacDonald and Trusler [ 19601 Oppenheimer and Esterly [I9621 Holsclaw et al [ 19651 Honeyman and Siker [ 19651 Donnison et a1 [ 19661 Pugh and Pickup [I9671 Becroft [ 19681 Hall and Simpkiss [ 19681 Bochkova et al [I9741 Ten Kate 119771 Katznelson and Ben-Yishay 119781 Allan et al [I9801 Nielson and Schiotz [ 19821

1942- 1950 1949- 1959 1924-1961 19441964 1957- 1959 1952-1961 1952- 1962 1959- 1965 1960-1965 1960- 1973 1961- 1965 1946-1975 1955-1978 1945-1981

116” 18 429‘ 30

72 18 550” 109

721 99 132 12 57 13 80 16

312 55 140 19 580 104’ 490 72

3,834 588

5 3 b 8

102 15h

15.5 6.9

25.0‘ 19.8 15.1 13.7 9.1

22.8 20.0 14.7 17.6 13.6 17.9 14.7 15.3

Ontario, Canada Present survey [I9841 1966-1980 420 66 15.7

”Survey in 1965 includes some patients reviewed earlier by Bodian [1952]. kstimated figure. ‘A review of earlier case reports from this center indicated an approximately 15% incidence of meconium ileus (ie, 98 cases of meconium ileus in 636 reported cases of cystic fibrosis).

ACKNOWLEDGMENTS

This work was supported by the Medical Research Council of Canada and the Canadian Cystic Fibrosis Foundation.

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Report #37.

Edited by John M. Opitz and James F. Reynolds

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Cystic fibrosis in Ontario