The per-protocol effect is the effect that would have been observed in a randomized trial had everybody followed the protocol. Though obtaining a valid point estimate for the per-protocol effect requires assumptions that are unverifiable and often implausible, lower and upper bounds for the per-protocol effect may be estimated under more plausible assumptions. Strategies for obtaining bounds, known as "partial identification" methods, are especially promising in randomized trials.
We estimated bounds for the per-protocol effect of colorectal cancer screening in the Norwegian Colorectal Cancer Prevention trial, a randomized trial of one-time sigmoidoscopy screening in 98,792 men and women aged 50-64 years. The screening was not available to the control arm, while approximately two thirds of individuals in the treatment arm attended the screening. Study outcomes included colorectal cancer incidence and mortality over 10 years of follow-up. Without any assumptions, the data alone provide little information about the size of the effect. Under the assumption that randomization had no effect on the outcome except through screening, a point estimate for the risk under no screening and bounds for the risk under screening are achievable. Thus, the 10-year risk difference for colorectal cancer was estimated to be at least -0.6 % but less than 37.0 %. Bounds for the risk difference for colorectal cancer mortality (-0.2 to 37.4 %) and all-cause mortality (-5.1 to 32.6 %) had similar widths. These bounds appear helpful in quantifying the maximum possible effectiveness, but cannot rule out harm. By making further assumptions about the effect in the subpopulation who would not attend screening regardless of their randomization arm, narrower bounds can be achieved.
Bounding the per-protocol effect under several sets of assumptions illuminates our reliance on unverifiable assumptions, highlights the range of effect sizes we are most confident in, and can sometimes demonstrate whether to expect certain subpopulations to receive more benefit or harm than others.
Clinicaltrials.gov identifier NCT00119912 (registered 6 July 2005).
Effective breast cancer screening should detect early-stage cancer and prevent advanced disease.
To assess the association between screening and the size of detected tumors and to estimate overdiagnosis (detection of tumors that would not become clinically relevant).
Denmark from 1980 to 2010.
Women aged 35 to 84 years.
Screening programs offering biennial mammography for women aged 50 to 69 years beginning in different regions at different times.
Trends in the incidence of advanced (>20 mm) and nonadvanced (=20 mm) breast cancer tumors in screened and nonscreened women were measured. Two approaches were used to estimate the amount of overdiagnosis: comparing the incidence of advanced and nonadvanced tumors among women aged 50 to 84 years in screening and nonscreening areas; and comparing the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in screening and nonscreening areas.
Screening was not associated with lower incidence of advanced tumors. The incidence of nonadvanced tumors increased in the screening versus prescreening periods (incidence rate ratio, 1.49 [95% CI, 1.43 to 1.54]). The first estimation approach found that 271 invasive breast cancer tumors and 179 ductal carcinoma in situ (DCIS) lesions were overdiagnosed in 2010 (overdiagnosis rate of 24.4% [including DCIS] and 14.7% [excluding DCIS]). The second approach, which accounted for regional differences in women younger than the screening age, found that 711 invasive tumors and 180 cases of DCIS were overdiagnosed in 2010 (overdiagnosis rate of 48.3% [including DCIS] and 38.6% [excluding DCIS]).
Regional differences complicate interpretation.
Breast cancer screening was not associated with a reduction in the incidence of advanced cancer. It is likely that 1 in every 3 invasive tumors and cases of DCIS diagnosed in women offered screening represent overdiagnosis (incidence increase of 48.3%).
Improved understanding of the subsequent risk death from colorectal cancer (CRC) among individuals who had adenomas removed is needed. We aimed to quantify this risk using prospectively collected data from population-based cohorts.
Using Norwegian and Swedish registries, a cohort of 90,864 individuals with colorectal adenomas removed between 1980 and 2013 was identified. Surveillance was only recommended for high-risk adenomas. The validity of the registry data did not allow classification into low- and high-risk adenomas. Virtually complete follow-up was achieved through linkage to nationwide registers. We calculated incidence-based standardised mortality ratios (SMRs) with 95% confidence intervals (CI).
The median follow-up was 7.2 years; 48,058 individuals were followed for more than 10 years. We observed 819 deaths (0.9%) from CRC and expected 731 CRC deaths (0.8%), corresponding to an absolute excess risk of 88 cases (0.1%) and a relative risk of 12% (SMR 1.12; 95%CI 1.05-1.20). The relative risk of CRC death following adenoma removal was slightly higher in Sweden (SMR 1.22; 95%CI 1.11-1.34) than in Norway (SMR 1.03; 95%CI 0.93-1.14), and higher in women (SMR 1.24; 95%CI 1.12-1.36) than in men (SMR 1.02; 95%CI 0.93-1.13). Among individuals with more than 10 years of follow-up, the estimates were similar to the overall cohort, absolute excess risk 0.1% (SMR 1.15; 95%CI 1.06-1.24).
The excess risk of CRC death following adenoma removal is small. Optimal surveillance recommendations should be tested in randomised trials.
Norway and Sweden have similar populations and health care systems, but different reactions to the COVID-19 pandemic. Norway closed educational institutions, and banned sports and cultural activities; Sweden kept most institutions and training facilities open. We aimed to compare peoples' attitudes towards authorities and control measures, and perceived impact of the pandemic and implemented control measures on life in Norway and Sweden.
Anonymous web-based surveys for individuals age 15 or older distributed through Facebook using the snowball method, in Norway and Sweden from mid-March to mid-April, 2020. The survey contained questions about perceived threat of the pandemic, views on infection control measures, and impact on daily life. We performed descriptive analyses of the responses and compared the two countries.
3508 individuals participated in the survey (Norway 3000; Sweden 508). 79% were women, the majority were 30-49?years (Norway 60%; Sweden 47%), and about 45% of the participants in both countries had more than 4 years of higher education. Participants had high trust in the health services, but differed in the degree of trust in their government (High trust in Norway 17%; Sweden 37%). More Norwegians than Swedes agreed that school closure was a good measure (Norway 66%; Sweden 18%), that countries with open schools were irresponsible (Norway 65%; Sweden 23%), and that the threat from repercussions of the mitigation measures were large or very large (Norway 71%; Sweden 56%). Both countries had a high compliance with infection preventive measures (>?98%). Many lived a more sedentary life (Norway 69%; Sweden 50%) and ate more (Norway 44%; Sweden 33%) during the pandemic.
Sweden had more trust in the authorities, while Norwegians reported a more negative lifestyle during the pandemic. The level of trust in the health care system and self-reported compliance with preventive measures was high in both countries despite the differences in infection control measures.
Department of Medicine, Sorlandet Hospital Kristiansand, Kristiansand, Norway2Institute of Health and Society, University of Oslo, Oslo, Norway3Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts4Department of Biostatistics Harvard School of Public Health, Boston, Massachusetts.
Colorectal cancer is a major health burden. Screening is recommended in many countries.
To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial.
Randomized clinical trial of 100,210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry.
Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1:1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp =10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention.
Colorectal cancer incidence and mortality.
A total of 98,792 participants were included in the intention-to-screen analyses, of whom 78,220 comprised the control group and 20,572 comprised the screening group (10,283 randomized to receive a flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100,000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100,000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50- to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55- to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups.
In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups.
clinicaltrials.gov Identifier: NCT00119912.
Comment In: JAMA. 2014 Aug 13;312(6):601-225117127
A challenge in quantifying the effect of screening mammography on breast-cancer mortality is to provide valid comparison groups. The use of historical control subjects does not take into account chronologic trends associated with advances in breast-cancer awareness and treatment.
The Norwegian breast-cancer screening program was started in 1996 and expanded geographically during the subsequent 9 years. Women between the ages of 50 and 69 years were offered screening mammography every 2 years. We compared the incidence-based rates of death from breast cancer in four groups: two groups of women who from 1996 through 2005 were living in counties with screening (screening group) or without screening (nonscreening group); and two historical-comparison groups that from 1986 through 1995 mirrored the current groups.
We analyzed data from 40,075 women with breast cancer. The rate of death was reduced by 7.2 deaths per 100,000 person-years in the screening group as compared with the historical screening group (rate ratio, 0.72; 95% confidence interval [CI], 0.63 to 0.81) and by 4.8 deaths per 100,000 person-years in the nonscreening group as compared with the historical nonscreening group (rate ratio, 0.82; 95% CI, 0.71 to 0.93; P
Comment In: N Engl J Med. 2010 Sep 23;363(13):1276-820860510
Comment In: N Engl J Med. 2011 Jan 20;364(3):282-3; author reply 285-621247323
Comment In: N Engl J Med. 2011 Jan 20;364(3):283; author reply 285-621247322
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Comment In: N Engl J Med. 2011 Jan 20;364(3):281-2; author reply 285-621247324
Comment In: N Engl J Med. 2011 Jan 20;364(3):283; author reply 285-621247321
BACKGROUND Questionnaire surveys are important for surveying the health and disease behaviour of the population, but recent years have seen a fall in participation. Our study tested whether incentives can increase participation in these surveys.MATERIAL AND METHOD We sent a questionnaire on risk factors for colorectal cancer (height, weight, smoking, self-reported diagnoses, family medical history) to non-screened participants in a randomised colonoscopy screening study for colorectal cancer: participants who were invited but did not attend for colonoscopy examination (screening-invited) and persons who were not offered colonoscopy (control group). The persons were randomised to three groups: no financial incentive, lottery scratch cards included with the form, or a prize draw for a tablet computer when they responded to the form. We followed up all the incentive groups with telephone reminder calls, and before the prize draw for the tablet computer.RESULTS Altogether 3 705 of 6 795 persons (54.5??%) responded to the questionnaire; 43.5??% of those invited for screening and 65.6??% of the control group (p
The effect of modifying lifestyle at middle age on mortality has been sparsely examined.
Men and women aged 50-54 years randomised to the control group (no intervention) in the population-based Norwegian Colorectal Cancer Prevention trial were asked to fill in lifestyle questionnaires in 2001 and 2004. Lifestyle scores were estimated ranging from 0 (poorest) to 4 (best) based on health recommendations (non-smoking, daily physical activity, body mass index