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1.  Continuous Glucose Monitoring in the Subcutaneous Tissue over a 14-Day Sensor Wear Period 
Glucose monitoring systems using subcutaneously inserted sensors are currently labeled for up to 7 days of wear. In this study, we evaluated the feasibility of a 14-day wear duration using a modified version of the sensor found in the Freestyle Navigator™ continuous glucose monitoring system.
Sixty-two subjects with diabetes were enrolled in the study. One sensor per subject was inserted on the arm for a wear time of 14 days. Two different calibration algorithms were applied retrospectively, one that uses periodic sensor recalibrations and one without recalibrations. Sensor in vivo stability was determined by least square regression analysis using capillary blood glucose. Mean absolute relative difference (MARD) and mean relative difference were calculated. Consensus error grid analysis was performed by day and over the 14-day wear period to evaluate accuracy of both systems. The sensor insertion sites were inspected after sensor removal for skin reactions.
Sensor data from 55 subjects were used for the analysis. The accuracy metrics for the system with recalibration were calculated to MARD = 13.9% and 84.0% in zone A (error grid analysis). The system without recalibration performed significantly better, resulting in MARD of 12.2% and 88.0% in zone A (p < .0001). The maximum change of in vivo sensor sensitivity over the 14-day wear period was 2% per day. Two subjects reported pain during the first 5 days of sensor wear, and 1 subject reported itching at the sensor site. No further skin reactions were noticed.
The study shows that a 14-day sensor wear period is achievable. Moreover, sensors using “wired enzyme” technology showed excellent in vivo stability, with no significant sensitivity loss over the 14-day wear period.
PMCID: PMC3876365  PMID: 24124948
diabetes; glucose monitoring; sensor wear duration; subcutaneous
2.  Systematic identification of trans-eQTLs as putative drivers of known disease associations 
Nature genetics  2013;45(10):1238-1243.
Identifying the downstream effects of disease-associated single nucleotide polymorphisms (SNPs) is challenging: the causal gene is often unknown or it is unclear how the SNP affects the causal gene, making it difficult to design experiments that reveal functional consequences. To help overcome this problem, we performed the largest expression quantitative trait locus (eQTL) meta-analysis so far reported in non-transformed peripheral blood samples of 5,311 individuals, with replication in 2,775 individuals. We identified and replicated trans-eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Although we did not study specific patient cohorts, we identified trait-associated SNPs that affect multiple trans-genes that are known to be markedly altered in patients: for example, systemic lupus erythematosus (SLE) SNP rs49170141 altered C1QB and five type 1 interferon response genes, both hallmarks of SLE2-4. Subsequent ChIP-seq data analysis on these trans-genes implicated transcription factor IKZF1 as the causal gene at this locus, with DeepSAGE RNA-sequencing revealing that rs4917014 strongly alters 3’ UTR levels of IKZF1. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
PMCID: PMC3991562  PMID: 24013639
3.  A New-Generation Continuous Glucose Monitoring System: Improved Accuracy and Reliability Compared with a Previous-Generation System 
Diabetes Technology & Therapeutics  2013;15(10):881-888.
Use of continuous glucose monitoring (CGM) systems can improve glycemic control, but widespread adoption of CGM utilization has been limited, in part because of real and perceived problems with accuracy and reliability. This study compared accuracy and performance metrics for a new-generation CGM system with those of a previous-generation device.
Subjects and Methods
Subjects were enrolled in a 7-day, open-label, multicenter pivotal study. Sensor readings were compared with venous YSI measurements (blood glucose analyzer from YSI Inc., Yellow Springs, OH) every 15 min (±5 min) during in-clinic visits. The aggregate and individual sensor accuracy and reliability of a new CGM system, the Dexcom® (San Diego, CA) G4™ PLATINUM (DG4P), were compared with those of the previous CGM system, the Dexcom SEVEN® PLUS (DSP).
Both study design and subject characteristics were similar. The aggregate mean absolute relative difference (MARD) for DG4P was 13% compared with 16% for DSP (P<0.0001), and 82% of DG4P readings were within ±20 mg/dL (for YSI ≤80 mg/dL) or 20% of YSI values (for YSI >80 mg/dL) compared with 76% for DSP (P<0.001). Ninety percent of the DG4P sensors had an individual MARD ≤20% compared with only 76% of DSP sensors (P=0.015). Half of DG4P sensors had a MARD less than 12.5% compared with 14% for the DSP sensors (P=0.028). The mean absolute difference for biochemical hypoglycemia (YSI <70 mg/dL) for DG4P was 11 mg/dL compared with 16 mg/dL for DSP (P<0.001).
The performance of DG4P was significantly improved compared with that of DSP, which may increase routine clinical use of CGM and improve patient outcomes.
PMCID: PMC3781114  PMID: 23777402
4.  ATAQS: A computational software tool for high throughput transition optimization and validation for selected reaction monitoring mass spectrometry 
BMC Bioinformatics  2011;12:78.
Since its inception, proteomics has essentially operated in a discovery mode with the goal of identifying and quantifying the maximal number of proteins in a sample. Increasingly, proteomic measurements are also supporting hypothesis-driven studies, in which a predetermined set of proteins is consistently detected and quantified in multiple samples. Selected reaction monitoring (SRM) is a targeted mass spectrometric technique that supports the detection and quantification of specific proteins in complex samples at high sensitivity and reproducibility. Here, we describe ATAQS, an integrated software platform that supports all stages of targeted, SRM-based proteomics experiments including target selection, transition optimization and post acquisition data analysis. This software will significantly facilitate the use of targeted proteomic techniques and contribute to the generation of highly sensitive, reproducible and complete datasets that are particularly critical for the discovery and validation of targets in hypothesis-driven studies in systems biology.
We introduce a new open source software pipeline, ATAQS (Automated and Targeted Analysis with Quantitative SRM), which consists of a number of modules that collectively support the SRM assay development workflow for targeted proteomic experiments (project management and generation of protein, peptide and transitions and the validation of peptide detection by SRM). ATAQS provides a flexible pipeline for end-users by allowing the workflow to start or end at any point of the pipeline, and for computational biologists, by enabling the easy extension of java algorithm classes for their own algorithm plug-in or connection via an external web site.
This integrated system supports all steps in a SRM-based experiment and provides a user-friendly GUI that can be run by any operating system that allows the installation of the Mozilla Firefox web browser.
Targeted proteomics via SRM is a powerful new technique that enables the reproducible and accurate identification and quantification of sets of proteins of interest. ATAQS is the first open-source software that supports all steps of the targeted proteomics workflow. ATAQS also provides software API (Application Program Interface) documentation that enables the addition of new algorithms to each of the workflow steps. The software, installation guide and sample dataset can be found in
PMCID: PMC3213215  PMID: 21414234
5.  Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women 
The British journal of nutrition  2008;100(5):947-952.
Fructose consumption in the USA has increased over the past three decades. During this time, obesity, insulin resistance and the metabolic syndrome have also increased in prevalence. While diets high in fructose have been shown to promote insulin resistance and increase TAG concentrations in animals, there are insufficient data available regarding the long-term metabolic effects of fructose consumption in humans. The objective of the present study was to investigate the metabolic effects of 10-week consumption of fructose-sweetened beverages in human subjects under energy-balanced conditions in a controlled research setting. Following a 4-week weight-maintaining complex carbohydrate diet, seven overweight or obese (BMI 26.8–33.3 kg/m2) postmenopausal women were fed an isoenergetic intervention diet, which included a fructose-sweetened beverage with each meal, for 10 weeks. The intervention diet provided 15% of energy from protein, 30% from fat and 55% from carbohydrate (30% complex carbohydrate, 25% fructose). Fasting and postprandial glucose, insulin, TAG and apoB concentrations were measured. Fructose consumption increased fasting glucose concentrations and decreased meal-associated glucose and insulin responses (P=0.0002, P=0.007 and P=0.013, respectively). Moreover, after 10 weeks of fructose consumption, 14 h postprandial TAG profiles were significantly increased, with the area under the curve at 10 weeks being 141% higher than at baseline (P=0.04). Fructose also increased fasting apoB concentrations by 19% (P=0.043 v. baseline). In summary, consumption of fructose-sweetened beverages increased postprandial TAG and fasting apoB concentrations, and the present results suggest that long-term consumption of diets high in fructose could lead to an increased risk of CVD.
PMCID: PMC3038917  PMID: 18384705
Fructose; Glucose; Insulin; Hypertriacylglycerolaemia; Apolipoprotein-B
6.  Effects of a low-fat, high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance 
Journal of Clinical Investigation  1999;104(8):1087-1096.
Low-fat, high-carbohydrate (LF/HC) diets commonly elevate plasma triglyceride (TG) concentrations, but the kinetic mechanisms responsible for this effect remain uncertain. Subjects with low TG (normolipidemic [NL]) and those with moderately elevated TG (hypertriglyceridemic [HTG]) were studied on both a control and an LF/HC diet. We measured VLDL particle and TG transport rates, plasma nonesterified fatty acid (NEFA) flux, and sources of fatty acids used for the assembly of VLDL-TG. The LF/HC diet resulted in a 60% elevation in TG, a 37% reduction in VLDL-TG clearance, and an 18% reduction in whole-body fat oxidation, but no significant change in VLDL-apo B or VLDL-TG secretion rates. Significant elevations in fasting apo B-48 concentrations were observed on the LF/HC in HTG subjects. In both groups, fasting de novo lipogenesis was low regardless of diet. The NEFA pool contributed the great majority of fatty acids to VLDL-TG in NL subjects on both diets, whereas in HTG subjects, the contribution of NEFA was somewhat lower overall and was reduced further in individuals on the LF/HC diet. Between 13% and 29% of VLDL-TG fatty acids remained unaccounted for by the sum of de novo lipogenesis and plasma NEFA input in HTG subjects. We conclude that (a) whole-food LF/HC diets reduce VLDL-TG clearance and do not increase VLDL-TG secretion or de novo lipogenesis; (b) sources of fatty acids for assembly of VLDL-TG differ between HTG and NL subjects and are further affected by diet composition; (c) the presence of chylomicron remnants in the fasting state on LF/HC diets may contribute to elevated TG levels by competing for VLDL-TG lipolysis and by providing a source of fatty acids for hepatic VLDL-TG synthesis; and (d) the assembly, production, and clearance of elevated plasma VLDL-TG in response to LF/HC diets therefore differ from those for elevated TG on higher-fat diets.
PMCID: PMC408572  PMID: 10525047

Results 1-6 (6)