The purpose of this communication is to estimate the expected magnitude of error produced by uncontrolled confounding from health behaviors in observational medical record-based studies evaluating effectiveness of screening colonoscopy.
We used data from the prospective NIH-AARP Diet and Health Study to assess the impact of health behavior related factors (lifestyle, education, and use of non-steroidal anti-inflammatory drugs [NSAID]) on the association between colonoscopy and CRC mortality. We first examined the difference between adjusted and unadjusted results within the cohort data, and then estimated a broader range of likely confounding errors based on the Breslow-Day approach that uses prevalence of confounders among persons with and without exposure, and the rate ratio reflecting the association between these confounders and the outcome of interest. As dietary factors and habits are often inter-correlated, we combined these variables (physical activity, body mass index, waist-to-hip ratio, alcohol consumption, and intakes of red meat, processed meat, fiber, milk, and calcium) into a “healthy lifestyle score” (HLS).
The estimated error (a ratio of biased-to-true result) attributable to confounding by HLS was 0.959–0.997 indicating less than 5% departure from the true effect of colonoscopy on CRC mortality. The corresponding errors ranged from 0.970 to 0.996 for NSAID, and from 0.974 to 1.006 for education (all ≤3% difference). The results for other CRC screening tests were similar.
Health behavior-related confounders, either alone or in combination, seem unlikely to strongly affect the association between colonoscopy and CRC mortality in observational studies of CRC screening.
(i) To document the current state of the English, Scottish, Welsh, Northern Irish and Australian bowel cancer screening programmes, according to seven key characteristics, and (ii) To explore the policy trade-offs resulting from inadequate funding.
United Kingdom and Australia.
A comparative case study design using document and key informant interview analysis. Data was collated for each national jurisdiction on seven key programme characteristics: screening frequency, population coverage, quality of test, programme model, quality of follow-up, quality of colonoscopy and quality of data collection. A list of optimal features for each of the seven characteristics was compiled, based on the FOBT screening literature and our detailed examination of each programme.
Each country made different implementation choices or trade-offs intended to conserve costs and/or manage limited and expensive resources. The overall outcome of these trade-offs was probable lower programme effectiveness as a result of compromises such as reduced screening frequency, restricted target age range, the use of less accurate tests, the deliberate setting of low programme positivity rates, or increased inconvenience to participants from retesting.
Insufficient funding has forced programme administrators to make trade-offs that may undermine the potential net population benefits achieved in randomized controlled trials. Such policy compromise contravenes the principle of evidence-based practice which is dependent on adequate funding being made available.
Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain.
To estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance.
All births in areas of high ethnic minority prevalence in England.
Prospective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain).
Approximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71–83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]).
One baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.
The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50–70 years regularly screened over a ten-year period.
To determine the proportion of emergency department (ED) patients who have been tested for human immunodeficiency virus (HIV) infection and assess if patient history of HIV testing varies according to patient demographic characteristics.
From July 2005–July 2006, a random sample of 18–55-year-old English-speaking patients being treated for sub-critical injury or illness at a northeastern US ED were interviewed on their history of HIV testing. Logistic regression models were created to compare patients by their history of being tested for HIV according to their demography. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated.
Of 2107 patients surveyed who were not known to be HIV-infected, the median age was 32 years; 54% were male, 71% were white, and 45% were single/never married; 49% had private health-care insurance and 45% had never been tested for HIV. Of the 946 never previously tested for HIV, 56.1% did not consider themselves at risk for HIV. In multivariable logistic regression analyses, those less likely to have been HIV tested were male (OR: 1.32 [1.37–2.73]), white (OR: 1.93 [1.37–2.73]), married (OR: 1.53 [1.12–2.08]), and had private health-care insurance (OR: 2.10 [1.69–2.61]). There was a U-shaped relationship between age and history of being tested for HIV; younger and older patients were less likely to have been tested. History of HIV testing and years of formal education were not related.
Almost half of ED patients surveyed had never been tested for HIV. Certain demographic groups are being missed though HIV diagnostic testing and screening programmes in other settings. These groups could potentially be reached through universal screening.
Offering antenatal sickle cell and thalassaemia (SCT) screening early in pregnancy can maximize the range of post-screening choices available, however these benefits should not be obtained at the expense of informed choice. This study examined whether offering this screening in primary care at the time of pregnancy confirmation compromises women making informed choices.
Partial factorial, cluster randomized controlled trial.
25 general practices in two socially deprived UK areas.
464 pregnant women offered antenatal SCT screening.
Practices were randomly allocated to offer pregnant women screening: i) in primary care at time of pregnancy confirmation, with parallel partner testing (n = 191), ii) in primary care at time of pregnancy confirmation, with sequential partner testing (n = 158), or iii) in secondary care by midwives, with sequential partner testing (standard care, n = 115).
Informed choice – a classification based on attitudes, knowledge and test uptake.
91% of woman underwent screening. About a third (30.6%) made an informed choice to accept or decline screening: 34% in primary care parallel group; 23.4% in primary care sequential and 34.8% in secondary care sequential. Allowing for adjustments, rates of informed choice did not vary by intervention group: secondary care versus primary care with parallel partner testing OR 1.07 (95% CI 0.56 to 2.02); secondary care versus primary care with sequential partner testing OR 0.67 (95% CI 0.36 to 1.25). Uninformed choices were generally attributable to poor knowledge (65%).
Offering antenatal SCT screening in primary care did not reduce the likelihood that women made informed choices. Rates of informed choice were low and could be increased by improving knowledge.
The UK Human Papillomavirus (HPV) vaccination programme was introduced in 2008 for girls aged 12–13. The vaccine offers protection against HPV types 16 and 18, which together cause about 70% of cervical cancers. Vaccinated girls will receive future invitations to the NHS Cervical Screening Programme, to prevent cancers associated with HPV types not included in the vaccine, and in case of prior infection with HPV 16 or 18. Little is known about parents' and girls' understandings of the protection offered by the vaccine, or the need for future screening.
Qualitative interviews with twenty-six parents, and nine girls aged 12–13 who were offered HPV vaccination through a Primary Care Trust (PCT) in the South-east of England, UK.
Thirty-nine schools, and four general practices.
Uncertainty about the level of protection offered by the HPV vaccine was evident among parents, and to a lesser extent among vaccination-aged girls. There was a lack of understanding among parents and girls that cervical screening would be required irrespective of vaccination status; some parental decisions to accept the vaccine were made on the misunderstanding that vaccination provided complete protection against cervical cancer.
Sufficient awareness of the issues related to screening is necessary for informed decision-making about whether or not to accept the HPV vaccine. Clearer information is needed concerning the incomplete protection offered by the vaccine, and that cervical screening will still be required. Future invitations for cervical screening should stress the necessity to attend regardless of HPV vaccination status, to ensure that high levels of prevention of cervical cancer through screening are maintained.
A mixture model of crown–rump length (CRL)-dependent and CRL-independent nuchal translucency (NT) measurements has been proposed for antenatal screening for Down's syndrome. We here compare the efficacy of the mixture model method with the standard method, which uses NT multiple of the median (MoM) values in a single distribution.
A routine antenatal screening programme for Down's syndrome comprising 104 affected and 22,284 unaffected pregnancies.
The ability of NT to distinguish between affected and unaffected pregnancies was compared using the mixture model method and the standard MoM method by using published distribution parameters for the mixture model of NT and parameters derived from these for the standard MoM method. The accuracy of the two methods was compared for NT and maternal age by comparing the median estimated risk with the prevalence of Down's syndrome in different categories of estimated risk.
Using NT alone observed estimates of discrimination using the two methods are similar; at a 70% detection rate the false-positive rates were 12% using the mixture model method and 10% using the MoM method. Risk estimation was marginally (but not statistically significantly) more accurate using the standard MoM method.
The mixture model method offers no advantage over the standard MoM method in antenatal screening for Down's syndrome, is more complicated and less generalizable to other data-sets. The standard MoM method remains the method of choice.
To determine whether the standard deviation of nuchal translucency (NT) measurements has decreased over time and if so to revise the estimate and assess the effect of revising the estimate of the standard deviation on the performance of antenatal screening for Down's syndrome.
Data from a routine antenatal screening programme for Down's syndrome comprising 106 affected and 22,640 unaffected pregnancies.
NT measurements were converted into multiple of the median (MoM) values and standard deviations of log10 MoM values were calculated in affected and unaffected pregnancies. The screening performance of the Combined and Integrated tests (that include NT measurement) were compared using previous and revised estimates of the standard deviation.
The standard deviation of NT in unaffected pregnancies has reduced over time (from 1998 to 2008) (e.g. from 0.1329 to 0.1105 [log10 MoM] at 12–13 completed weeks of pregnancy, reducing the variance by about 30%). This was not observed in affected pregnancies. Compared with results from the serum, urine and ultrasound screening study (SURUSS), use of the revised NT standard deviations in unaffected pregnancies resulted in an approximate 20% decrease in the false-positive rate for a given detection rate; for example, from 2.1% to 1.7% (a 19% reduction) at a 90% detection rate using the Integrated test with first trimester markers measured at 11 completed weeks' gestation and from 4.4% to 3.5% (a 20% reduction) at an 85% detection rate using the Combined test at 11 completed weeks.
The standard deviation of NT has declined over time and using the revised estimates improves the screening performance of tests that incorporate an NT measurement.
To estimate the absolute numbers of breast cancer deaths prevented and the absolute numbers of tumours overdiagnosed in mammographic screening for breast cancer at ages 50–69 years.
The Swedish Two-County randomized trial of mammographic screening for breast cancer, and the UK Breast Screening Programme in England, ages 50–69 years.
We estimated the absolute numbers of deaths avoided and additional cases diagnosed in the study group (active study population) of the Swedish Two-County Trial, by comparison with the control group (passive study population). We estimated the same quantities for the mortality and incidence rates in England (1974–2004 and 1974–2003, respectively). We used Poisson regression for statistical inference.
A substantial and significant reduction in breast cancer mortality was associated with screening in both the Two-County Trial (P < 0.001) and the screening programme in England (P < 0.001). The absolute benefits were estimated as 8.8 and 5.7 breast cancer deaths prevented per 1000 women screened for 20 years starting at age 50 from the Two-County Trial and screening programme in England, respectively. The corresponding estimated numbers of cases overdiagnosed per 1000 women screened for 20 years were, respectively, 4.3 and 2.3 per 1000.
The benefit of mammographic screening in terms of lives saved is greater in absolute terms than the harm in terms of overdiagnosis. Between 2 and 2.5 lives are saved for every overdiagnosed case.
To assess uptake of once-only flexible sigmoidoscopy (FS) in a community sample to determine whether FS would be viable as a method of population-based screening for colorectal cancer.
All adults aged 60–64 years registered at three General Practices in North West London, UK (510 men and women) were sent a letter of invitation to attend FS screening carried out by an experienced nurse, followed by a reminder if they did not make contact to confirm or decline the invitation. The primary outcome was attendance at the endoscopy unit for a FS test.
Of the 510 people invited to attend, 280 (55%) underwent FS. Among non-attenders, 91 (18%) were ineligible for screening or did not receive the invitation, 19 (4%) accepted the offer of screening but were unable to attend during the study period, 52 (10%) declined the offer, 41 (8%) did not respond to the invitation, and 27 (5%) accepted the offer of screening but did not attend. Attendance among those eligible to be screened, who had received the invitation, was 67%. People from more socioeconomically deprived neighbourhoods were less likely to attend (odds ratio [OR] = 0.90; confidence interval [CI] = 0.84–0.96; P = 0.003). Women were more likely to attend than men (OR = 1.44; CI = 1.01–2.05; P = 0.041).
Attendance rates in this pilot for nurse-led, population-based FS screening were higher than those reported in other FS studies, and comparable with adherence to fecal occult blood testing (FOBT) in the UK FOBT pilot. Having a female nurse endoscopist may have been responsible for increasing female uptake rates but this warrants confirmation in a larger study.
Outcomes in an episodic care setting like an Emergency Department (ED) are traditionally evaluated with comparison to the number of visits as opposed to the number of unique patients, yet it is common for a patient to present to the ED multiple times. We examined the differences in HIV screening programmatic outcomes that would occur if the analysis were conducted at the patient-level rather than the traditional visit-level. We hypothesized that while our ED-based HIV testing program does test some patients repeatedly, the primary programmatic outcome of percent positive is not substantially altered by the unit of analysis.
We reviewed the clinical database of an ED HIV testing program at a large, urban, teaching hospital from 2003–2007. Data were analyzed descriptively. The main outcome measure was the rate of positive test results computed with either the visit or the patient as the unit of analysis.
HIV testing was provided at 9,629 visits, representing 8,450 unique patients. For patient-level analysis, the proportion of patients found to be positive was 0.91%. For visit-level analysis, the proportion of tests with positive results was 0.83%. Of the 910 patients with repeat testing, 7 (0.77%) were identified as positive at a repeat test. The median time between tests was 383 days (range 1–1742).
Results changed little regardless of whether unique patients or unique visits were used as the unit of analysis. Any differences in positive rates were mitigated by the contribution of repeat testing to the identification of newly infected patients. Given these findings, and the difficulty of tracking repeat testing over time, visit-level analysis are appropriate for comparing programmatic outcomes when detailed modeling of epidemiology, cost, and/or outcomes is not required.
Emergency Service, Hospital; Communicable Disease Control; Mass Screening; Preventive Health Services; Risk Factors; HIV seropositivity
To estimate the risk of radiation-induced lung cancer mortality from three annual low-dose lung CT screens before age 55 years and the mortality reduction from screening (i.e. the efficacy) needed to outweigh these risks for never and current-smokers. The risk of radiation-induced breast cancer was also estimated for women.
The Biological Effectiveness of Ionizing Radiation VII committee’s risk models were used to estimate radiation risk. Lung cancer mortality rates (based on the Bach model for current and the Cancer Prevention Study for never-smokers) were used to estimate the mortality reduction needed to outweigh this risk.
For never-smokers the estimated excess lifetime risk of radiation-induced lung cancer mortality from annual screening age 40-42 was 1/10,000 (90% credibility interval:0.4-3) for males and 3/10,000 (2-6) for females. For current-smokers the estimated risks were approximately 2-fold higher, with wider credibility intervals. Risks from screening age 30-32 or 50-52 years were of similar magnitude. The mortality reduction required to outweigh these risks was, for male never-smokers:125%(40%-300%) age 30-32 years, 70%(30%-190%) age 40-42 years and 25%(10%-70%) age 50-52 years, and for male current-smokers:70%(20%-120%) age 30-32 years, 10%(3%-20%) age 40-42 years and 2%(1%-4%) age 50-52 years. These figures were 2-3 times higher for females because of the higher radiation risks. The risk of radiation-induced breast cancer was in the range of 3-6 cases/10,000 females screened.
Before age 50 the mortality reduction from lung CT screening that is required to outweigh the radiation risk may be substantial, and in some cases unattainable (i.e.>100%).
This paper aims to investigate whether the stage shift (where more cancers are detected at an earlier stage) in PSA-detected cancers differs by Gleason score.
Between 2002 and 2005, 1,514 men 50-69 years were identified with prostate cancer following community-based PSA testing as part of the ProtecT study. In the same period, 2021 men 50-69 years with clinically diagnosed prostate cancer were registered at a population based cancer registry in East of England. Using logistic regression analysis and controlling for age, the odds ratio (OR) for advanced stage (TNM stage T3 and above) prostate cancer among the PSA detected group was compared to the clinically diagnosed tumours. The evidence that stage shift differs by Gleason score was assessed using the likelihood ratio test for interaction.
Advanced stage disease among the PSA detected cancers was less common than among the clinically detected cancers (OR = 0.47, 95% CI 0.39-0.56). PSA detected tumours had a substantial shift to earlier stage disease where the Gleason score was <7 (OR=0.52; 95%CI 0.36-0.77, P<0.001) but showed no such shift where the Gleason score was 7 or more (OR=0.84; 95% CI 0.66-1.07, P=0.1). There was evidence of interaction between detection mode and Gleason score (p=0.03).
The observed stage shift could be partially explained by length bias or overdiagnosis. These findings may have implications on understanding pathways of prostate cancer progression and on identifying potential targets for screening, pending further investigation of complexities of associations between PSA testing, Gleason score, and stage.
Prostate cancer; PSA testing; Stage shift; Gleason score; Effect modification
Many cancer screening trials involve a screening programme of one or more screenings with follow-up after the last screening. Usually a maximum follow-up time is selected in advance. However, during the follow-up period there is an opportunity to report the results of the trial sooner than planned. Early reporting of results from a randomized screening trial is important because obtaining a valid result sooner translates into health benefits reaching the general population sooner. The health benefits are reduction in cancer deaths if screening is found to be beneficial and more screening is recommended, or avoidance of unnecessary biopsies, work-ups and morbidity if screening is not found to be beneficial and the rate of screening drops.
Our proposed method for deciding if results from a cancer screening trial should be reported earlier in the follow-up period is based on considerations involving postscreening noise. Postscreening noise (sometimes called dilution) refers to cancer deaths in the follow-up period that could not have been prevented by screening: (1) cancer deaths in the screened group that occurred after the last screening in subjects whose cancers were not detected during the screening program and (2) cancer deaths in the control group that occurred after the time of the last screening and whose cancers would not have been detected during the screening programme had they been randomized to screening (the number of which is unobserved). Because postscreening noise increases with follow-up after the last screening, we propose early reporting at the time during the follow-up period when postscreening noise first starts to overwhelm the estimated effect of screening as measured by a z-statistic. This leads to a confidence interval, adjusted for postscreening noise, that would not change substantially with additional follow-up. Details of the early reporting rule were refined by simulation, which also accounts for multiple looks.
For the re-analysis of the Health Insurance Plan trial for breast cancer screening and the Mayo Lung Project for lung cancer screening, estimates and confidence intervals for the effect of screening on cancer mortality were similar on early reporting and later.
The proposed early reporting rule for a cancer screening trial with post-screening follow-up is a promising method for making results from the trial available sooner, which translates into health benefits (reduction in cancer deaths or avoidance of unnecessary morbidity) reaching the population sooner.
To measure whether uptake of breast cancer screening was affected by the publication of the Marmot Review and associated press coverage.
Eight NHS breast screening centres in the West Midlands of the UK.
Uptake of breast cancer screening invitations was compared in the week before and after the Marmot review publication. All 12,023 women invited for screening between 23 October 2012 and 5 November 2012 were included. A mixed effects model of the predictors of screening uptake (on date invited, or within 21 days) was created. Predictors considered for inclusion were whether the allocated screening appointment was before or after publication of the review, population factors (age, index of multiple deprivation income domain by quintile, previous attendance), and interaction terms.
Uptake decreased after publication of the review from 65% to 62% (OR = 0.87 95%CI = 0.80–0.94), but a similar decrease was seen for the same dates on the previous year (OR = 0.85 95%CI = 0.78–0.93). Odds of attending screening were lower for women in the most deprived (uptake = 49%, OR = 0.54, 95%CI = 0.46–0.62) in comparison with the least deprived quintile (uptake = 71%). Odds of attendance also increased if the woman had ever previously attended (OR 3.9 95% CI 3.5–4.4), and decreased with each year of increasing age (OR 0.96 95% CI 0.96–0.97). There were no interactions between any of the other predictors and whether the appointment was before or after publication of the Marmot review.
No change in uptake of breast cancer screening above normal seasonal variation was detected after publication of the Marmot review.
In August 2008 the British reality TV star Jade Goody made public her diagnosis of cervical cancer. In February 2009 it was announced that she was terminally ill and she died a few weeks later. A surge in cervical screening attendances associated with these events was widely reported. This paper aims to quantify the size of that effect across England, its duration, and whether it affected some groups of women more than others.
The Cervical Screening Programme in England.
Routinely collected statistics for the months around Jade Goody's diagnosis and death were compared with those for other periods.
About half a million extra cervical screening attendances occurred in England between mid-2008 and mid-2009, the period during which Jade Goody was diagnosed and died; among these were 370 attendances where the test result was suspected neoplasia. At its peak in March 2009, attendance was 70% higher than expected. Increases were seen in both initial and follow-up screening attendances and in colposcopy attendances, and at all ages, though the magnitude was greater for women aged under 50. A substantially greater proportion of the extra attendances of women aged 25–49 on routine recall occurred in women whose attendance was overdue (28% occurred at 60 months or more) and relatively little represented over-screening (8% had been screened within the last 30 months).
The pattern of increased attendance mirrored the pattern of media coverage of Jade Goody's diagnosis and death. It is likely that the increased screening resulted in a number of lives saved.