Curation of myeloma observational study MALIMAR using XNAT: solving the challenges posed by real-world data.

OBJECTIVES: MAchine Learning In MyelomA Response (MALIMAR) is an observational clinical study combining "real-world" and clinical trial data, both retrospective and prospective. Images were acquired on three MRI scanners over a 10-year window at two institutions, leading to a need for extensive curation. METHODS: Curation involved image aggregation, pseudonymisation, allocation between project phases, data cleaning, upload to an XNAT repository visible from multiple sites, annotation, incorporation of machine learning research outputs and quality assurance using programmatic methods. RESULTS: A total of 796 whole-body MR imaging sessions from 462 subjects were curated. A major change in scan protocol part way through the retrospective window meant that approximately 30% of available imaging sessions had properties that differed significantly from the remainder of the data. Issues were found with a vendor-supplied clinical algorithm for "composing" whole-body images from multiple imaging stations. Historic weaknesses in a digital video disk (DVD) research archive (already addressed by the mid-2010s) were highlighted by incomplete datasets, some of which could not be completely recovered. The final dataset contained 736 imaging sessions for 432 subjects. Software was written to clean and harmonise data. Implications for the subsequent machine learning activity are considered. CONCLUSIONS: MALIMAR exemplifies the vital role that curation plays in machine learning studies that use real-world data. A research repository such as XNAT facilitates day-to-day management, ensures robustness and consistency and enhances the value of the final dataset. The types of process described here will be vital for future large-scale multi-institutional and multi-national imaging projects. CRITICAL RELEVANCE STATEMENT: This article showcases innovative data curation methods using a state-of-the-art image repository platform; such tools will be vital for managing the large multi-institutional datasets required to train and validate generalisable ML algorithms and future foundation models in medical imaging. KEY POINTS: • Heterogeneous data in the MALIMAR study required the development of novel curation strategies. • Correction of multiple problems affecting the real-world data was successful, but implications for machine learning are still being evaluated. • Modern image repositories have rich application programming interfaces enabling data enrichment and programmatic QA, making them much more than simple "image marts".

Effects of obesity, and of weight loss following bariatric surgery, on methylation of DNA from the rectal mucosa and in cell-free DNA from blood.

BACKGROUND: DNA methylation is an epigenetic mechanism through which environmental factors including nutrition and inflammation influence health. Obesity is a major modifiable risk factor for many common diseases including cardiovascular diseases and cancer. In particular, obesity-induced inflammation resulting from aberrantly-methylated inflammatory genes may drive risk of several non-communicable diseases including colorectal cancer (CRC). This study is the first to investigate the effects of weight loss induced by bariatric surgery (BS) on DNA methylation in the rectum and in cell-free DNA (cfDNA) from blood. SUBJECTS AND METHODS: DNA methylation was quantified in rectal mucosal biopsies and cfDNA from serum of 28 participants with obesity before and 6 months after BS, as well as in 12 participants without obesity (control group) matched for age and sex from the Biomarkers Of Colorectal cancer After Bariatric Surgery (BOCABS) Study. DNA methylation of LEP, IL6, POMC, LINE1, MAPK7 and COX2 was quantified by pyrosequencing. RESULTS: BMI decreased significantly from 41.8 kg/m2 pre-surgery to 32.3 kg/m2 at 6 months after BS. Compared with the control group, obesity was associated with lower LEP methylation in both the rectal mucosa and in cfDNA from serum. BS normalised LEP methylation in DNA from the rectal mucosa but not in cfDNA. BS decreased methylation of some CpG sites of LINE1 in the rectal mucosal DNA and in cfDNA to levels comparable with those in participants without obesity. Methylation of POMC in rectal mucosal DNA was normalised at 6 months after BS. CONCLUSION: BS reversed LINE1, POMC and LEP methylation in the rectal mucosa of patients with obesity to levels similar to those in individuals without obesity. These findings support current evidence of effects of BS-induced weight loss on reversibility of DNA methylation in other tissues. The DNA methylation changes in the rectal mucosa shows promise as a biomarker for objective assessment of effects of weight loss interventions on risk of cancer and other diseases.

Repeatability and test-retest reproducibility of mean apparent diffusion coefficient measurements of focal and diffuse disease in relapsed multiple myeloma at 3T whole body diffusion-weighted MRI (WB-DW-MRI).

OBJECTIVE: To assess the test-retest reproducibility and intra/interobserver agreement of apparent diffusion coefficient (ADC) measurements of myeloma lesions using whole body diffusion-weighted MRI (WB-DW-MRI) at 3T MRI. METHODS: Following ethical approval, 11 consenting patients with relapsed multiple myeloma were prospectively recruited and underwent baseline WB-DW-MRI. For a single bed position, axial DWI was repeated after a short interval to permit test-retest measurements.Mean ADC measurement was performed by two experienced observers. Intra- and interobserver agreement and test-retest reproducibility were assessed, using coefficient of variation (CV) and interclass correlation coefficient (ICC) measures, for diffuse and focal lesions (small ≤10 mm and large >10 mm). RESULTS: 47 sites of disease were outlined (23 focal, 24 diffuse) in different bed positions (pelvis = 22, thorax = 20, head and neck = 5). For all lesions, there was excellent intraobserver agreement with ICC of 0.99 (0.98-0.99) and COV of 5%. For interobserver agreement, ICC was 0.89 (0.8-0.934) and COV was 17%. There was poor interobserver agreement for diffuse disease (ICC = 0.46) and small lesions (ICC = 0.54).For test-retest reproducibility, excellent ICC (0.916) and COV (14.5%) values for mean ADC measurements were observed. ICCs of test-retest were similar between focal lesions (0.83) and diffuse infiltration (0.80), while ICCs were higher in pelvic (0.95) compared to thoracic (0.81) region and in small (0.96) compared to large (0.8) lesions. CONCLUSION: ADC measurements of focal lesions in multiple myeloma are repeatable and reproducible, while there is more variation in ADC measurements of diffuse disease in patients with multiple myeloma. ADVANCES IN KNOWLEDGE: Mean ADC measurements are repeatable and reproducible in focal lesions in multiple myeloma, while the ADC measurements of diffuse disease in multiple myeloma are more subject to variation. The evidence supports the future potential role of ADC measurements as predictive quantitative biomarker in multiple myeloma.

Effects of bariatric surgery on DNA methylation in adults: a systematic review and meta-analysis.

BACKGROUND: DNA methylation is an epigenetic mechanism through which environmental factors, including obesity, influence health. Obesity is a major modifiable risk factor for many common diseases, including cardiovascular diseases and cancer. Obesity-induced metabolic stress and inflammation are key mechanisms that affect disease risk and that may result from changes in methylation of metabolic and inflammatory genes. OBJECTIVES: This review aims to report the effects of weight loss induced by bariatric surgery (BS) on DNA methylation in adults with obesity focusing on changes in metabolic and inflammatory genes. METHODS: A systematic review was performed using MEDLINE, EMBASE, and Scopus, to identify studies in adult humans that reported DNA methylation after BS. RESULTS: Of 15,996 screened titles, 15 intervention studies were identified, all of which reported significantly lower body mass index postsurgery. DNA methylation was assessed in 5 different tissues (blood = 7 studies, adipose tissues = 4, skeletal muscle = 2, liver, and spermatozoa). Twelve studies reported significant changes in DNA methylation after BS. Meta-analysis showed that BS increased methylation of PDK4 loci in skeletal muscle and blood in 2 studies, while the effects of BS on IL6 methylation levels in blood were inconsistent. BS had no overall effect on LINE1 or PPARGC1 methylation. CONCLUSION: The current evidence supports the reversibility of DNA methylation at specific loci in response to BS-induced weight loss. These changes are consistent with improved metabolic and inflammatory profiles of patients after BS. However, the evidence regarding the effects of BS on DNA methylation in humans is limited and inconsistent, which makes it difficult to combine and compare data across studies.

Effects of dietary interventions on DNA methylation in adult humans: systematic review and meta-analysis.

DNA methylation is a key component of the epigenetic machinery that is responsible for regulating gene expression and, therefore, cell function. Patterns of DNA methylation change during development and ageing, differ between cell types, are altered in multiple diseases and can be modulated by dietary factors. However, evidence about the effects of dietary factors on DNA methylation patterns in humans is fragmentary. This study was initiated to collate evidence for causal links between dietary factors and changes in DNA methylation patterns. We carried out a systematic review of dietary intervention studies in adult humans using Medline, EMBASE and Scopus. Out of 22 149 screened titles, sixty intervention studies were included, of which 65% were randomised (n 39). Most studies (53%) reported data from blood analyses, whereas 27% studied DNA methylation in colorectal mucosal biopsies. Folic acid was the most common intervention agent (33%). There was great heterogeneity in the methods used for assessing DNA methylation and in the genomic loci investigated. Meta-analysis of the effect of folic acid on global DNA methylation revealed strong evidence that supplementation caused hypermethylation in colorectal mucosa (P=0·009). Meta-regression analysis showed that the dose of supplementary folic acid was the only identified factor (P<0·001) showing a positive relationship. In summary, there is limited evidence from intervention studies of effects of dietary factors, other than folic acid, on DNA methylation patterns in humans. In addition, the application of multiple different assays and investigations of different genomic loci makes it difficult to compare, or to combine, data across studies.