Lennarth Nyström

Long-term effects of mammography screening: updated overview of the Swedish randomised trials

BACKGROUND There has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malmö trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods The trials (n=247010, invited group 129750, control group 117260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure. FINDINGS The median trial time-the time from randomisation until the first round was completed for the control group or if the control group was not invited, until end of follow-up-was 6.5 years (range 3.0-18.1). The median follow-up time, the time from randomisation, to the end of follow-up, was 15.8 years (5.8-20.2). There were 511 breast cancer deaths in 1864770 women-years in the invited groups and 584 breast cancer deaths in 1688440 women-years in the control groups, a significant 21% reduction in breast cancer mortality (RR=0.79, 95% CI 0.70-0.89). The reduction was greatest in the age group 60-69 years at entry (33%). Looking at 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64, and 65-69 years (RR=0.76, 0.68, and 0.69, respectively). There was a small effect in women 50-54 years at randomisation (RR=0.95). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years after randomisation and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation. The age-adjusted relative risk for the total mortality was 0.98 (0.96-1.00). INTERPRETATION The advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up. The recent criticism against the Swedish randomised controlled trials is misleading and scientifically unfounded.

Epidemic of coeliac disease in Swedish children.

Coeliac disease has emerged as a public health problem. The aim of the present study was to analyse trends in the occurrence of symptomatic coeliac disease in Swedish children from 1973 to 1997, and to explore any temporal relationship to changes in infant dietary patterns. We established a population‐based prospective incidence register of coeliac disease in 1991, and, in addition, retrospective data from 1973 were collected. A total of 2151 cases fulfilled the diagnostic criteria. Furthermore, we collected national data on a yearly basis on duration of breastfeeding, intake of gluten‐containing cereals and recommendations on when and how to introduce gluten into the diet of infants. From 1985 to 1987 the annual incidence rate in children below 2 y of age increased fourfold to 200‐240 cases per 100 000 person years, followed from 1995 by a sharp decline to the previous level of 50‐60 cases per 100 000 person years. This epidemic pattern is quite unique for a chronic disease of immunological pathogenesis, suggesting that prevention could be possible. The ecological observations made in this study are compatible with the epidemic being the result, at least in part, of a change in and an interplay among three factors within the area of infant feeding, i.e. amount of gluten given, age at introduction of gluten, and whether breastfeeding was ongoing or not when gluten was introduced. Other factor(s) may also have contributed, and the search for these should be intensified.

The Gothenburg Breast Screening Trial

Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects.

An altered immune response to Epstein-Barr virus in multiple sclerosis: A prospective study

Objective: To investigate the association between human herpesviruses and multiple sclerosis (MS), as well as between measles virus and MS. Methods: The authors identified prospectively collected serum samples from 73 MS cases and retrospective sera from 161 MS cases in two population-based serum bank registers. Analyses of IgG antibody responses in cases and matched referents were performed for Epstein-Barr virus (EBV [EBNA-1 and VCA]), human herpesvirus 6 (HHV-6), herpes simplex virus (HSV), varicella zoster virus (VZV), and measles. Results: All cases showed signs of past EBV infection. High activity to EBNA-1 and HHV-6 significantly (borderline significance for HHV-6) increased the risk for MS in prospective sera. A discrepancy between activities to EBNA-1 and VCA was striking in MS samples collected less than 5 years before relapsing-remitting MS onset, where high activity to EBNA-1 significantly increased, and high VCA activity significantly decreased the risk for MS. There was no support for major causal roles for HSV, VZV, or measles. Conclusion: Individuals who will develop MS exhibit an altered immune response against the EBV virus characterized by a high IgG activity to EBNA-1 in the absence of high activity to VCA, this being most pronounced in the 5-year period preceding MS onset.

The impact of mammographic screening on breast cancer mortality in Europe: a review of observational studies

Objectives To assess the impact of population-based mammographic screening on breast cancer mortality in Europe, considering different methodologies and limitations of the data. Methods We conducted a systematic literature review of European trend studies (n = 17), incidence-based mortality (IBM) studies (n = 20) and case-control (CC) studies (n = 8). Estimates of the reduction in breast cancer mortality for women invited versus not invited and/or for women screened versus not screened were obtained. The results of IBM studies and CC studies were each pooled using a random effects meta-analysis. Results Twelve of the 17 trend studies quantified the impact of population-based screening on breast cancer mortality. The estimated breast cancer mortality reductions ranged from 1% to 9% per year in studies reporting an annual percentage change, and from 28% to 36% in those comparing post- and prescreening periods. In the IBM studies, the pooled mortality reduction was 25% (relative risk [RR] 0.75, 95% confidence interval [CI] 0.69–0.81) among invited women and 38% (RR 0.62, 95% CI 0.56–0.69) among those actually screened. The corresponding pooled estimates from the CC studies were 31% (odds ratio [OR] 0.69, 95% CI 0.57–0.83), and 48% (OR 0.52, 95% CI 0.42–0.65) adjusted for self-selection. Conclusions Valid observational designs are those where sufficient longitudinal individual data are available, directly linking a womans screening history to her cause of death. From such studies, the best ‘European’ estimate of breast cancer mortality reduction is 25–31% for women invited for screening, and 38–48% for women actually screened. Much of the current controversy on breast cancer screening is due to the use of inappropriate methodological approaches that are unable to capture the true effect of mammographic screening.

Reduction in breast cancer mortality from organized service screening with mammography : 1. Further confirmation with extended data.

Background: In an earlier publication, our evaluation of data from breast cancer screening programs in seven Swedish counties suggested a 40% reduction in incidence-based breast cancer mortality among women actually screened. In the current study, we expand the previous analysis from seven counties to 13 large areas within nine counties, including six of the original counties and seven additional areas, examine a longer period of follow-up (20-44 years), apply new analytic methods for the evaluation of incidence-based breast cancer mortality, and estimate the number needed to screen to save one life. Methods: Data from six of the original counties (one being excluded as it does not yet have 10 years of follow-up after the initiation of screening), with increased follow-up, and seven additional large areas, within three counties, representing ∼45% of Swedish women, provide information about age at diagnosis, age at death, and screening history for 542,187 women in the prescreening and 566,423 women in the screening epochs. Regardless of year of diagnosis, there were a total of 6,231 deaths due to breast cancer in the period of study as a whole. Of these, 4,778 were incidence-based deaths in the two epochs, i.e., death among cases diagnosed within either the prescreening or screening period. Data were analyzed using Poisson regression and adjusted, when necessary, for self-selection bias, contemporaneous changes in incidence, and changes in mortality independent of screening. Results: Attendance was uniformly high, averaging 75% in the screening epochs. Recall rates for assessment varied from 4% to 5% at the first round of screening and ∼3% at later rounds. Detection rates averaged five breast cancers per 1,000 women screened in the first round, and four breast cancers per 1,000 women screened in subsequent rounds. There was a significant 45% reduction in incidence-based breast cancer mortality among screened women in the screening epoch relative to incidence-based breast cancer mortality in the prescreening epoch (relative risk, 0.55; 95% confidence intervals, 0.51-0.59). After adjusting for self-selection bias, there still was a significant 43% reduction in incidence-based breast cancer mortality associated with screening (relative risk, 0.57; 95% confidence intervals, 0.53-0.62). Conclusions: These results indicate a reduction in breast cancer mortality of between 40% and 45% in association with screening, after adjustment for self-selection bias. These results were obtained with modest human costs: the number needed to screen to save one life was estimated as 472. (Cancer Epidemiol Biomarkers Prev 2006;15(1):45–51)

Effectiveness of Population-Based Service Screening With Mammography for Women Ages 40 to 49 Years Evaluation of the Swedish Mammography Screening in Young Women (SCRY) Cohort

The effectiveness of mammography screening for women ages 40 to 49 years still is questioned, and few studies of the effectiveness of service screening for this age group have been conducted.

The Swedish childhood diabetes study — results from a nine year case register and a one year case-referent study indicating that Type 1 (insulin-dependent) diabetes mellitus is associated with both Type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders

SummaryFrom July 1, 1977 to July 1, 1986, 3,503 incident cases of Type 1 (insulin-dependent) diabetes mellitus were registered in the Swedish childhood diabetes study. Using data from this register and from a case-referent study, including all incident Type 1 diabetic children in Sweden during one year and, for each patient, two referent children matched according to age, sex and county, we have studied the associations between Type 1 diabetes and familial Type 1 and Type 2 (non-insulin-dependent) diabetes, thyroid, adrenal, allergic, rheumatic, heart and bowel disease. The mean annual incidence per 100,000 during the nine year period was 25.1 for boys and 23.5 for girls. In 8.5% of the patients, one parent had Type 1 diabetes, 73% of whom were fathers. Fifty-six of the patients (1.7%) had a parent with Type 2 diabetes. The prevalence of parental Type 1 diabetes tended to be higher in patients with younger age at onset; whereas, the opposite was found for patients with parental Type 2 diabetes. In the case-referent study, the age-adjusted odds ratio for Type 1 diabetes when a first and/or second degree relative had Type 1 diabetes was 5.5 (95% confidence limits 4.0–7.7), and in accordance with the findings of the case register, the odds ratio tended to be highest in patients with the youngest age at onset. Season at onset of the patients was not associated with parental Type 1 diabetes. The odds ratio for Type 1 diabetes was significantly increased 3.3 (95% confidence limits: 2.3–4.6) when Type 2 diabetes was reported in relatives (three generations). Odds ratios were also significantly increased (p(0.05) when thyroid or rheumatic diseases were reported among relatives.It is concluded that although the majority of incident Type 1 diabetic children lack family history, parental Type 1 diabetes may influence the age at onset of the disease but has no effect on sex distribution of these children. An increased risk for Type 1 diabetes in children is also indicated when Type 2 diabetes, (non-insulin-treated) thyroid or rheumatic disease is reported in relatives.

Obesity increases the risk of incident asthma among adults

The annual incidence of asthma in adults in northern Sweden has been estimated at 2.3 per thousand population. Risk factors for incident asthma among adults were studied in a case–referent study based on incident cases of asthma during 1995–1999. The healthcare providers reported suspected cases of incident asthma. After clinical examination, 309 (65% female) of 473 reported subjects were included. Inclusion criteria were a history of incident asthma (onset <12 months) and verified bronchial variability. Referents were randomly selected and stratified by age, sex and area of residence. The significant risk factors were hay fever, a family history of asthma, ex-smoking status and elevated body mass index (25.0–29.9 and ≥30). The risk factor pattern was similar for females and males, and increased body mass index was a significant risk factor for both males and females, as well as for allergic and nonallergic subjects. In conclusion, in addition to hay fever, a family history of asthma, allergic sensitisation and ex-smoking status, increased body mass index was a significant risk factor for incident asthma independent of sex and allergic status.

Randomised controlled trial of a reduced-visits programme of antenatal care in Harare, Zimbabwe

BACKGROUND Many of the individual components of antenatal care have been studied in randomised controlled trials, but few studies have compared whole programmes of antenatal care. Our aim was to test the hypothesis that a new programme of antenatal care with fewer goal-oriented visits would give an equivalent or better result in the outcomes associated with pregnancy and delivery. METHODS In a randomised clinical trial in Harare, Zimbabwe, we compared a new programme of antenatal care with the standard programme. The new programme consisted of fewer but more objectively oriented visits and fewer procedures per visit. Seven primary care clinics were randomly assigned to the two programmes-three to the standard programme and four to the new programme. FINDINGS Over a 2-year period, 15,994 women were recruited into the study at the time they booked antenatal care. 97% of the women were followed up, 9,394 who had followed the new programme, and 6,138 from clinics with the standard one. Women allocated to the new programme made, as planned, fewer visits than those in the standard programme (median 4 vs 6 visits, respectively). The proportion of antenatal referrals was also lower (13.6 vs 15.3%; odds ratio 0.87 [95% CI 0.79-0.95]) because of significantly fewer referrals for pregnancy-induced hypertension (2.5 vs 3.8%; 0.66 [0.55-0.79]). Nevertheless, there were significantly fewer labour referrals for severe hypertension or eclampsia (2.1 vs 2.6%; 0.81 [0.66-1.00]). The risk for preterm (< 37 weeks) delivery was significantly lower for women on the new programme (10.1 vs 11.5%; 0.86 [0.78-0.96]). There were no other significant differences between the programmes in other major indices of pregnancy outcome, including antenatal referrals for other causes, labour referrals, obstetric interventions, low birthweight, and perinatal and maternal mortality and morbidity. INTERPRETATION An antenatal care programme with fewer more objectively oriented visits can be introduced without adverse effects on the main intermediate outcome pregnancy variables.