An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life

Mucopolysaccharidosis type I (MPS I) is a progressive multisystem lysosomal storage disease caused by deficiency of the enzyme α-L-iduronidase (IDUA). Patients present with a continuous spectrum of disease severity, and the most severely affected patients (Hurler phenotype; MPS I-H) develop progressive cognitive impairment. The treatment of choice for MPS I-H patients is haematopoietic stem cell transplantation, while patients with the more attenuated phenotypes benefit from enzyme replacement therapy. Thirty patients were included in this study. Genotypes were collected from all patients and all patients were phenotypically categorized at an age of > 18 months based on the clinical course of the disease. In 18 patients, IDUA activity in fibroblast cultures was measured using an optimized IDUA assay. Clinical characteristics from the first month of life were collected from 23 patients. Homozygosity or compound heterozygosity for specific mutations which are associated with MPS I-H, discriminated a subset of patients with MPS I-H from patients with more attenuated phenotypes (specificity 100%, sensitivity 82%). Next, we found that enzymatic analysis of IDUA activity in fibroblasts allowed identification of patients affected by MPS I-H. Therefore, residual IDUA activity in fibroblasts was introduced as second step in the algorithm. Patients with an IDUA activity of < 0.32 nmol x mg(-1) × hr(-1) invariably were MPS I-H patients, while an IDUA activity of > 0.66 nmol × mg(-1) × hr(-1) was only observed in more attenuated patients. Patients with an intermediate IDUA activity could be further classified by the presence of differentiating clinical characteristics, resulting in a model with 100% sensitivity and specificity for this cohort of patients. Using genetic, biochemical and clinical characteristics, all potentially available in the newborn period, an algorithm was developed to predict the MPS I phenotype, allowing timely initiation of the optimal treatment strategy after introduction of NB

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles

Objective: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. Design: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. Results: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test’s ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. Conclusion: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact

Optimizing colorectal cancer screening using fecal immunochemical tests

Colorectal cancer (CRC) screening using fecal occult blood tests has been shown to lower CRC incidence and CRC-related mortality and CRC incidence by the removal of precancerous polyps and the detection of CRC in an early stage. At present, the recommended method for organised CRC screening is the fecal immunochemical test (FIT), followed by a colonoscopy if the FIT result is positive. Multiple different brands of FITs are available but their accuracy is not perfect. FIT misses 1/4 of participants with CRC and 2/3 of participants with advanced neoplasia (AN: CRC and/or advanced adenoma) when used for a single screening round. Additionally, in 40-70% of the participants with a positive FIT who undergo a colonoscopy no AN is detected. A better understanding of the factors influencing FIT’s accuracy as well as strategies to optimize CRC FIT screening effectiveness are therefore warranted. The studies described in this thesis were performed to contribute to these goals

Participant-Related Risk Factors for False-Positive and False-Negative Fecal Immunochemical Tests in Colorectal Cancer Screening: Systematic Review and Meta-Analysis

Objectives: Colorectal cancer (CRC) screening using fecal immunochemical tests (FIT) may reduce CRC-related mortality but its effectiveness is influenced by the limited accuracy of FIT. Identifying individuals at increased risk of a false FIT result could improve screening, but the available evidence is conflicting. We performed a systematic review and meta-analysis on risk factors for false-positive and false-negative FIT results in CRC screening. Methods: A systematic search in MEDLINE, EMBASE, and Cochrane Library identified publications (before 29 January 2017) on risk factors (known at time of FIT invitation) associated with false FIT results (presence/absence of advanced neoplasia) in a CRC screening setting. Risk of bias was assessed using QUIPS. In meta-analysis, summary relative risk ratios and corresponding 95% confidence intervals were calculated for each risk factor. Results: Of 518 records identified, 14 studies with 54,499 participants in total were included for analysis. In meta-analysis, male sex was associated with a significantly lower risk of false-positivity (RR 0.84, CI 0.74–0.94), whereas participants using non-steroidal anti-inflammatory drugs (NSAIDs) had a higher risk (RR 1.16, CI 1.06–1.27). The use of anticoagulants was most frequently studied, without a significant effect on FIT positivity. Males (RR 1.83, CI 1.53–2.19), participants with a family history for CRC (RR 1.61, CI 1.19–2.15), hyperglycemia (RR 1.29, CI 1.02–1.65), hypertension (RR 1.50, CI 1.14–1.98), obesity (RR 1.38, CI 1.11–1.71), and (former) smokers (RR 1.93, CI 1.52–2.45) were all at significantly higher risk for false-negative results. Age was not found to have a systematic effect on either FIT false-positivity or false-negativity in meta-analysis. Conclusions: Multiple risk factors, known at time of FIT invitation, are associated with false FIT results in CRC screening. This information can be used to identify populations risking false reassurance after a negative result or unnecessary colonoscopy after a positive result, and to further optimize CRC screening effectiveness

Screening for colorectal cancer with fecal immunochemical testing with and without postpolypectomy surveillance colonoscopy: A cost-effectiveness analysis

Background: Population-based screening to prevent colorectal cancer (CRC) death is effective, but the effectiveness of postpolypectomy surveillance is unclear. Objective: To evaluate the additional benefit in terms of costeffectiveness of colonoscopy surveillance in a screening setting. Design: Microsimulation using the ASCCA (Adenoma and Serrated pathway to Colorectal CAncer) model. Data Sources: Dutch CRC screening program and published literature. Target Population: Asymptomatic persons aged 55 to 75 years without a prior CRC diagnosis. Time Horizon: Lifetime. Perspective: Health care payer. Intervention: Fecal immunochemical test (FIT) screening with colonoscopy surveillance performed according to the Dutch guideline was simulated. The comparator was no screening or surveillance. FIT screening without colonoscopy surveillance and the effect of extending surveillance intervals were also evaluated. Outcome Measures: CRC burden, colonoscopy demand, lifeyears, and costs. Results of Base-Case Analysis: FIT screening without surveillance reduced CRC mortality by 50.4% compared with no screening or surveillance. Adding surveillance to FIT screening reduced mortality by an additional 1.7% to 52.1% but increased lifetime colonoscopy demand by 62% (from 335 to 543 colonoscopies per 1000 persons) at an additional cost of €68 000, for an increase of 0.9 life-year. Extending the surveillance intervals to 5 years reduced CRC mortality by 51.8% and increased colonoscopy demand by 42.7% compared with FIT screening without surveillance. In an incremental analysis, incremental costeffectiveness ratios (ICERs) for screening plus surveillance exceeded the Dutch willingness-to-pay threshold of €36 602 per life-year gained. Results of Sensitivity Analysis: When using a parameter set representing low colorectal lesion prevalence or when colonoscopy costs were halved or colorectal lesion incidence was doubled, screening plus surveillance became cost-effective compared with screening without surveillance. Limitation: Limited data on FIT performance and background CRC risk in the surveillance population. Conclusion: Adding surveillance to FIT screening is not costeffective based on the Dutch ICER threshold and substantially increases colonoscopy demand. Extending surveillance intervals to 5 years would decrease colonoscopy demand without substantial loss of effectiveness. Primary Funding Source: Alpe d'HuZes, Dutch Cancer Society, and Stand Up To Cancer

Screening for Colorectal Cancer With Fecal Immunochemical Testing With and Without Postpolypectomy Surveillance Colonoscopy A Cost-Effectiveness Analysis

Background: Population-based screening to prevent colorectal cancer (CRC) death is effective, but the effectiveness of post-polypectomy surveillance is unclear. Objective: To evaluate the additional benefit in terms of costeffectiveness of colonoscopy surveillance in a screening setting. Design: Microsimulation using the ASCCA (Adenoma and Serrated pathway to Colorectal CAncer) model. Data Sources: Dutch CRC screening program and published literature. Target Population: Asymptomatic persons aged 55 to 75 years without a prior CRC diagnosis. Time Horizon: Lifetime. Perspective: Health care payer. Intervention: Fecal immunochemical test (FIT) screening with colonoscopy surveillance performed according to the Dutch guideline was simulated. The comparator was no screening or surveillance. FIT screening without colonoscopy surveillance and the effect of extending surveillance intervals were also evaluated. Outcome Measures: CRC burden, colonoscopy demand, life-years, and costs. Results of Base-Case Analysis: FIT screening without surveillance reduced CRC mortality by 50.4% compared with no screening or surveillance. Adding surveillance to FIT screening reduced mortality by an additional 1.7% to 52.1% but increased lifetime colonoscopy demand by 62% (from 335 to 543 colono-scopies per 1000 persons) at an additional cost of (sic)68 000, for an increase of 0.9 life-year. Extending the surveillance intervals to 5 years reduced CRC mortality by 51.8% and increased colonoscopy demand by 42.7% compared with FIT screening without surveillance. In an incremental analysis, incremental cost-effectiveness ratios (ICERs) for screening plus surveillance exceeded the Dutch willingness-to-pay threshold of (sic)36 602 per life-year gained. Results of Sensitivity Analysis: When using a parameter set representing low colorectal lesion prevalence or when colonoscopy costs were halved or colorectal lesion incidence was doubled, screening plus surveillance became cost-effective compared with screening without surveillance. Limitation: Limited data on FIT performance and background CRC risk in the surveillance population. Conclusion: Adding surveillance to FIT screening is not cost-effective based on the Dutch ICER threshold and substantially increases colonoscopy demand. Extending surveillance intervals to 5 years would decrease colonoscopy demand without substantial loss of effectivenes

A Quarter of Participants With Advanced Neoplasia Have Discordant Results From 2-Sample Fecal Immunochemical Tests for Colorectal Cancer Screening

Background & Aims: Some colorectal cancer (CRC) screening programs use 2-sample fecal immunochemical tests (FITs). We aimed to assess advanced neoplasia (AN) yield of 2 different FIT assays performed on the same bowel movement and have discordant results. Methods: We conducted a large prospective comparative accuracy study within the Dutch national CRC screening program to evaluate 2 quantitative FIT assays (FOB-Gold, Sentinel, Italy and OC-Sensor, Eiken, Japan) with comparable performance characteristics. We asked 42,179 screening-naïve individuals, 55–75 years old, to perform both tests on the same bowel movement, from May 2016 through March 2017. Participants with ≥1 positive test result (≥15 μg hemoglobin/gram feces) were invited for colonoscopy examination. Detection of AN by colonoscopy was the reference standard. Results: A total of 21,078 participants (50% participation rate) were included. FIT results were both negative for 19,032 participants (90%), both positive for 1163 participants (5.5%), and discordant for 883 participants (4.2%). AN was detected in 500 participants with 2 positive FIT results (43%) compared to 187 with discordant FIT results (21%) (p <.001). Of the 687 participants found to have AN by colonoscopy, 187 had only 1 positive FIT result (27%). Conclusion: In a large 2-sample FIT-based CRC screening study, more than a quarter of participants in whom AN was detected by colonoscopy in the first screening round had discordant FIT results. AN was detected in one-fifth of those with FIT discordance. Participants with discordant results from 2 FITs should undergo colonoscopy. (www.trialregister.nl; no. NTR5874)

Performance of two faecal immunochemical tests for the detection of advanced neoplasia at different positivity thresholds: a cross-sectional study of the Dutch national colorectal cancer screening programme

Background: Faecal immunochemical tests (FITs) are recommended for colorectal cancer screening. Two frequently used FIT methods (FOB-Gold, Sentinel Diagnostics, Milan, Italy and OC-Sensor, Eiken Chemical, Tokyo, Japan) perform similarly in detecting advanced neoplasia (ie, colorectal cancer and advanced adenoma) at a fixed positivity cutoff for faecal haemoglobin concentration. It is unclear whether the performance of the two methods is also comparable at other thresholds. We compared the accuracy of the two assays in detecting advanced neoplasia across various thresholds. Methods: In a cross-sectional study in the Dutch national screening programme, individuals who were screening naive in 2016 (aged 55–75 years) living in the southwest region of the Netherlands were invited to use two different FIT assays on the same bowel movement. Eligible participants were randomly selected from municipal registers. Participants were referred for colonoscopy if either FIT assay result met the predefined positivity threshold (≥15 μg haemoglobin per g faeces). We compared the respective distributions of reported haemoglobin concentration and positivity rates with various FIT positivity thresholds. The performance of each FIT for identifying advanced neoplasia at colonoscopy in FIT-positive assays was compared with the area under the receiver operating characteristic curve. Findings: 21 078 (50·0%) of 42 179 invitees completed both FIT assays. The distribution of haemoglobin concentrations differed significantly between the two FITs (p<0·0001), with higher positivity rates for OC-Sensor at FIT thresholds of 5 and 10 μg haemoglobin per g faeces, similar positivity rates at 15 and 20 μg haemoglobin per g faeces, and higher rates for FOB-Gold at FIT thresholds of 25–150 μg haemoglobin per g faeces. 2046 (9·7%) of 21 078 participants had at least one FIT assay that was positive and of these, 1724 (84·3%) attended colonoscopy. The accuracy of results in individuals undergoing colonoscopy did not significantly differ between the FITs, with an area under the receiver operating characteristic curve of 0·675 (95% CI 0·649 to 0·702) for FOB-Gold and 0·686 (0·661 to 0·712) for OC-Sensor (p=0·40). At identical positivity rates, the positive predictive value of the two FIT assays was similar (difference varying from 0·5% [95% CI −2·6 to 3·7] at a positivity rate of 3·5% to 2·4% [–2·5 to 7·3] at a positivity rate of 2·0%). Interpretation: The two widely used FITs have significantly different distributions of reported haemoglobin concentration and yield different positivity rates at equal thresholds. However, they perform similarly in detecting advanced neoplasia at a preset positivity rate. When implementing either FIT in a screening programme, the desired positivity rate that identifies participants to be referred for colonoscopy should first be set, guided by available resources and feasibility. Funding: The Netherlands Organisation for Health Research and Development

Urban density differences in colorectal cancer screening participation and screening yield in The Netherlands

Lower socioeconomic status has been associated with higher colorectal cancer incidence and lower participation in population-based screening with faecal immunochemical testing (FIT) but regional variations in participation may also exist. We analysed differences in participation and yield in colorectal cancer screening by urban density level. Data of all invitees to the Dutch colorectal cancer screening programme in 2014–2015 were included. Primary outcomes were participation (returning FIT), FIT positive predictive value, and screening yield (advanced neoplasia detected in invitees). Differences were explored across five levels of urban density. In total 1,873,639 screening invitees were included. FIT participation was 77.3% in the lowest versus 62.8% in the highest urban areas (RR 1.23; 95%CI 1.23–1.24). FIT positive predictive value was 58.6% in the lowest versus 55.2% in the highest urban areas (RR 1.06; 95% CI 1.04–1.09). Screening yield was also higher in the lowest (2.1%-2.3%) compared to the highest urban areas (1.8%). Compared to socioeconomic status, differences in urban density were associated with larger differences in screening participation. In conclusion, participation is lower and fewer cases of advanced neoplasia are detected in areas with a high urban density in the Dutch colorectal cancer screening programme. Differences in urban density could be used in tailoring regional strategies to target barriers in colorectal cancer screening