The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll‐out 2‐yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by ...2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost‐effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1‐Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10‐yearly, or once‐off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51–67(74–80)% in comparison with no screening; 2‐yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2‐yearly iFOBT screening was found to be cost‐effective in all scenarios in context of an indicative willingness‐to‐pay threshold of A$50,000/life‐year saved (LYS); this strategy was associated with an incremental cost‐effectiveness ratio of A$2,984/LYS–A$5,981/LYS (depending on adherence). The fully rolled‐out NBCSP is highly cost‐effective, and is also one of the most effective approaches for bowel cancer screening in Australia.
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The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll out biennial screening using the immunochemical Faecal Occult Blood Test (iFOBT) in people aged 50‐74 years by 2020. This is the first study to perform a comprehensive evaluation of the comparative health benefits, harms, and cost‐effectiveness of iFOBT versus other potential colorectal cancer screening strategies using alternative modalities, including pDNA, fDNA, sigmoidoscopy, CTC and colonoscopy within a nationally‐organised bowel cancer screening program. The findings support the rollout of the NBCSP, which was found to be cost‐effective and associated with a favourable benefits‐to‐harm balance when compared with the other strategies.
IMPORTANCE: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, ...the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. OBJECTIVE: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. MAIN OUTCOMES AND MEASURES: Diagnosis of Alzheimer disease. RESULTS: A total of 2784 individuals with Alzheimer disease (1944 female 69.8%) and 5222 controls (3743 female 71.7%) were analyzed (mean SD age at last evaluation, 74.2 13.6 years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10−7), near the immune response gene ALCAM (3q13; P = 9.3 × 10−7), within GPC6 (13q31; P = 4.1 × 10−7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10−7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10−9) and 6 additional loci with suggestive significance (P ≤ 5 × 10−7) such as API5 at 11p12 (P = 8.8 × 10−8) and RBFOX1 at 16p13 (P = 5.4 × 10−7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. CONCLUSIONS AND RELEVANCE: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
Colorectal cancer is the third most commonly diagnosed cancer in Australia. Emerging evidence from several countries suggests increasing incidence in people aged <50 years.
We assessed colon and ...rectal cancer incidence trends in people aged 20+ in Australia from 1982 to 2014. We used data on 375,008 incident cases (248,162 colon and 126,846 rectal). We quantified the annual percentage change (APC) in rates by age group using Joinpoint regression.
For people aged <50 years, colon cancer rates increased from the mid-2000s, with the increase in APCs ranging from 1.7% to 9.3% per annum (depending on specific age group); rectal cancer rates increased from the early 1990s, with APCs ranging from 0.9% to 7.1% per annum. For people aged 50 to 69 years, colon and rectal cancer rates decreased from the mid-1990s, with the decrease in APCs in specific age groups ranging from 0.8% to 4.8% per annum (except for colon cancer in those ages 65 to 69 years, where similar rate decreases were observed from 2007). An overall reduction in older persons (>70 years) was estimated at 1.9% to 4.9% per annum for colon cancer from 2010 onward and 1.1% to 1.8% per annum in rectal cancer from the early 2000s onward.
Colon and rectal cancer incidence has increased in people aged <50 years in Australia over the last two decades. However, colon and rectal cancer rates decreased in people aged 50+, likely due to
and organized bowel cancer screening.
Further research is needed to examine the cause of the increase and to quantify the impact of future trends on the cost-effectiveness of population-based screening for those <50 years.
The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population ...basis.
We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins.
Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%.
Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.
The Australian National Bowel Cancer Screening Program (NBCSP) is rolling out 2-yearly immunochemical fecal occult blood test screening in people aged 50 to 74 years. This study aimed to evaluate the ...benefits, harms, and cost-effectiveness of extending the NBCSP to younger and/or older ages.
A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate the fully rolled-out NBCSP and alternative strategies assuming screening starts at 40 or 45 years and/or ceases at 79 or 84 years given three scenarios: (i) perfect adherence (100%), (ii) high adherence (60%), and (ii) low adherence (40%, as currently achieved).
The current NBCSP will reduce colorectal cancer incidence (mortality) by 23% to 51% (36% to 74%) compared with no screening (range reflects participation); extending screening to younger or older ages would result in additional reductions of 2 to 6 (2 to 9) or 1 to 3 (3 to 7) percentage points, respectively. With an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS), only screening from 50 to 74 years incremental cost-effective ratio (ICER): A$2,984-5,981/LYS) or from 45 to 74 years (ICER: A$17,053-29,512/LYS) remained cost-effective in all participation scenarios. The number-needed-to-colonoscope to prevent a death over the lifetime of a cohort in the current NBCSP is 35 to 49. Starting screening at 45 years would increase colonoscopy demand for program-related colonoscopies by 3% to 14% and be associated with 55 to 170 additional colonoscopies per additional death prevented.
Starting screening at 45 years could be cost-effective, but it would increase colonoscopy demand and would be associated with a less favorable incremental benefits-to-harms trade-off than screening from 50 to 74 years.
The study underpins recently updated Australian colorectal cancer management guidelines that recommend that the NBCSP continues to offer bowel screening from 50 to 74 years.
No assessment of the National Bowel Screening Program (NBCSP) in Australia, which considers all downstream benefits, costs, and harms, has been done. We aimed to use a comprehensive natural history ...model and the most recent information about cancer treatment costs to estimate long-term benefits, costs, and harms of the NBCSP (2 yearly immunochemical faecal occult blood testing screening at age 50–74 years) and evaluate the incremental effect of improved screening participation under different scenarios.
In this modelling study, a microsimulation model, Policy1-Bowel, which simulates the development of colorectal cancer via both the conventional adenoma-carcinoma and serrated pathways was used to simulate the NBCSP in 2006–40, taking into account the gradual rollout of NBCSP in 2006–20. The base-case scenario assumed 40% screening participation (currently observed behaviour) and two alternative scenarios assuming 50% and 60% participation by 2020 were modelled. Aggregate year-by-year screening, diagnosis, treatment and surveillance-related costs, resource utilisation (number of screening tests and colonoscopies), and health outcomes (incident colorectal cancer cases and colorectal cancer deaths) were estimated, as was the cost-effectiveness of the NBCSP.
With current levels of participation (40%), the NBCSP is expected to prevent 92 200 cancer cases and 59 000 deaths over the period 2015–40; an additional 24 300 and 37 300 cases and 16 800 and 24 800 deaths would be prevented if participation was increased to 50% and 60%, respectively. In 2020, an estimated 101 000 programme-related colonoscopies will be done, associated with about 270 adverse events; an additional 32 500 and 49 800 colonoscopies and 88 and 134 adverse events would occur if participation was increased to 50% and 60%, respectively. The overall number needed to screen (NNS) is 647–788 per death prevented, with 52–59 colonoscopies per death prevented. The programme is cost-effective due to the cancer treatment costs averted (cost-effectiveness ratio compared with no screening at current participation, AUS$3014 95% uncertainty interval 1807–5583 per life-year saved) in the cost-effectiveness analysis. In the budget impact analysis, reduced annual expenditure on colorectal cancer control is expected by 2030, with expenditure reduced by a cumulative AUS$1·7 billion, AUS$2·0 billion, and AUS$2·1 billion (2015 prices) between 2030 and 2040, at participation rates of 40%, 50%, and 60%, respectively.
The NBCSP has potential to save 83 800 lives over the period 2015–40 if coverage rates can be increased to 60%. By contrast, the associated harms, although an important consideration, are at a smaller magnitude at the population level. The programme is highly cost-effective and within a decade of full roll-out, there will be reduced annual health systems expenditure on colorectal cancer control due to the impact of screening.
Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW.
Screening is an effective means for colorectal cancer prevention and early detection. Family history is strongly associated with colorectal cancer risk. We describe the rationale, evidence and ...recommendations for colorectal cancer screening by family history for people without a genetic syndrome, as reported in the 2017 revised Australian guidelines. Main recommendations: Based on 10-year risks of colorectal cancer, people at near average risk due to no or weak family history (category 1) are recommended screening by immunochemical faecal occult blood test (iFOBT) every 2 years from age 50 to 74 years. Individuals with moderate risk due to their family history (category 2) are recommended biennial iFOBT from age 40 to 49 years, then colonoscopy every 5 years from age 50 to 74 years. People with a high risk due to their family history (category 3) are recommended biennial iFOBT from age 35 to 44 years, then colonoscopy every 5 years from age 45 to 74 years. Changes in management as a result of the guidelines: By 2019, the National Bowel Cancer Screening Program will offer all Australians free biennial iFOBT screening from age 50 to 74 years, consistent with the recommendations in these guidelines for category 1. Compared with the 2005 guidelines, there are some minor changes in the family history inclusion criteria for categories 1 and 2; the genetic syndromes have been removed from category 3 and, as a consequence, colonoscopy screening is now every 5 years; and for categories 2 and 3, screening begins with iFOBT for people aged 40 and 35 years, respectively, before transitioning to colonoscopy after 10 years.
To examine the costs and cost-effectiveness of full implementation of biennial bowel cancer screening for Australian residents aged 50-74 years.
Identification of existing economic models from 1993 ...to 2010 through searches of PubMed and economic analysis databases, and by seeking expert advice; and additional modelling to determine the costs and cost-effectiveness of full implementation of biennial faecal occult blood test screening for the five million adults in Australia aged 50-74 years.
Estimated number of deaths from bowel cancer prevented, costs, and cost-effectiveness (cost per life-year gained LYG) of biennial bowel cancer screening.
We identified six relevant economic analyses, all of which found colorectal cancer (CRC) screening to be very cost-effective, with costs per LYG under $55,000 per year in 2010 Australian dollars. Based on our additional modelling, we conservatively estimate that full implementation of biennial screening for people aged 50-74 years would have gross costs of $150 million, reduce CRC mortality by 15%-25%, prevent 300-500 deaths from bowel cancer, and save 3600-6000 life-years annually, for an undiscounted cost per LYG of $25,000-$41,667, compared with no screening, and not taking cost savings as a result of treatment into consideration. The additional expenditure required, after accounting for reductions in CRC incidence, savings in CRC treatment costs, and existing ad-hoc colonoscopy use, is likely to be less than $50 million annually.
Full implementation of biennial faecal occult blood test screening in Australia can reduce bowel cancer mortality, and is an efficient use of health resources that would require modest additional government investment.
Several studies demonstrating that central line-associated bloodstream infections (CLABSIs) are preventable prompted a national initiative to reduce the incidence of these infections.
We conducted a ...collaborative cohort study to evaluate the impact of the national "On the CUSP: Stop BSI" program on CLABSI rates among participating adult intensive care units (ICUs). The program goal was to achieve a unit-level mean CLABSI rate of less than 1 case per 1,000 catheter-days using standardized definitions from the National Healthcare Safety Network. Multilevel Poisson regression modeling compared infection rates before, during, and up to 18 months after the intervention was implemented.
A total of 1,071 ICUs from 44 states, the District of Columbia, and Puerto Rico, reporting 27,153 ICU-months and 4,454,324 catheter-days of data, were included in the analysis. The overall mean CLABSI rate significantly decreased from 1.96 cases per 1,000 catheter-days at baseline to 1.15 at 16-18 months after implementation. CLABSI rates decreased during all observation periods compared with baseline, with adjusted incidence rate ratios steadily decreasing to 0.57 (95% confidence intervals, 0.50-0.65) at 16-18 months after implementation.
Coincident with the implementation of the national "On the CUSP: Stop BSI" program was a significant and sustained decrease in CLABSIs among a large and diverse cohort of ICUs, demonstrating an overall 43% decrease and suggesting the majority of ICUs in the United States can achieve additional reductions in CLABSI rates.
To estimate the impact of various expansion scenarios of the National Bowel Cancer Screening Program (NBCSP) on the number of bowel cancer deaths prevented; and to investigate the impact of the ...expansion scenarios on colonoscopy demand.
MISCAN-Colon, a well established, validated computer simulation model for bowel cancer screening, was adjusted to reflect the Australian situation. In July 2013, we simulated the effects of screening over a 50-year period, starting in 2006. The model parameters included rates of participation in screening and follow-up, rates of identification of cancerous and precancerous lesions, bowel cancer incidence, mortality and the outcomes of the NBCSP. Five implementation scenarios, based on biennial screening using an immunochemical faecal occult blood test, were developed and modelled. A sensitivity analysis that increased screening participation to 60% was also conducted.
Australian residents aged 50 to 74 years.
Comparison of the impact of five implementation scenarios on the number of bowel cancer deaths prevented and demand for colonoscopy.
MISCAN-Colon calculated that in its current state, the NBCSP should prevent 35 169 bowel cancer deaths in the coming 40 years. Accelerating the expansion of the program to achieve biennial screening by 2020 would prevent more than 70 000 deaths. If complete implementation of biennial screening results in a corresponding increase in participation to 60%, the number of deaths prevented will increase across all scenarios.
The findings strongly support the need for rapid implementation of the NBCSP. Compared with the current situation, achieving biennial screening by 2020 could result in 100% more bowel cancer deaths (about 35 000) being prevented in the coming 40 years.
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