Summarizing probe levels of Affymetrix arrays taking into account day-to-day variability
ABSTRACT: Day-to-day variability in microarray experiments is a recognized source of variation that can impede the analysis of large microarray studies where samples are processed on different days. In this study, we have applied an algorithm, called D2Dsum, which is based on a log-linear fixed effect model to cope with this kind of issues on a data set of 45 microarrays. Keywords: time course Overall design: A2780 human ovarian cancer cell lines have been treated (TRT) with two different chemical compounds (A and B) or left untreated (CTRL). RNA was collected form 1 to 6 hour every hour. For each time point a technical duplicate or triplicate has been performed. Samples were subjected to complete randomisation experimental design and the effect of hybridisation day has been evaluated. processed on 4 different days
Project description:Day-to-day variability in microarray experiments is a recognized source of variation that can impede the analysis of large microarray studies where samples are processed on different days. In this study, we have applied an algorithm, called D2Dsum, which is based on a log-linear fixed effect model to cope with this kind of issues on a data set of 45 microarrays. Experiment Overall Design: A2780 human ovarian cancer cell lines have been treated (TRT) with two different chemical compounds (A and B) or left untreated (CTRL). RNA was collected form 1 to 6 hour every hour. For each time point a technical duplicate or triplicate has been performed. Samples were subjected to complete randomisation experimental design and the effect of hybridisation day has been evaluated. Experiment Overall Design: processed on 4 different days
Project description:BACKGROUND:In 2015, 162,877 persons sought asylum in Sweden, 35,369 of whom were unaccompanied refugee minors (URMs). Refugee children, especially URMs, have often experienced traumas and are at significant risk of developing mental health problems, such as symptoms of post-traumatic stress disorder (PTSD), depression and anxiety, which can continue years after resettlement. The Swedish UnaccomPanied yOuth Refugee Trial (SUPpORT) aims to evaluate a community-based intervention, called Teaching Recovery Techniques (TRT), for refugee youth experiencing PTSD symptoms. METHODS/DESIGN:A randomised controlled trial will be conducted in which participants will be randomly allocated to one of two possible arms: the intervention arm (n?=?109) will be offered the TRT programme, and the waitlist-control arm (n?=?109) will receive services as usual, followed by the TRT programme around 20?weeks later. Outcome data will be collected at three points: pre-intervention (T1), post-intervention (T2; about 8?weeks after randomisation) and follow-up (T3; about 20?weeks after randomisation). DISCUSSION:This study will provide knowledge about the effect and efficiency of a group intervention for URMs reporting symptoms of PTSD in Sweden. TRIAL REGISTRATION:ISRCTN, ISRCTN47820795. Prospectively registered on 20 December 2018.
Project description:AIM:To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes. MATERIALS AND METHODS:In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period. RESULTS:Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P < .0001). The distribution of glucose-lowering effect was stable across 6-hour intervals (24%-26%) for IDeg, while IGlar-U300 had greater effects in the first (35%) and last (28%) intervals compared with 6 to 12 hours (20%) and 12 to 18 hours (17%). Within-day variability (relative fluctuation) was 37% lower with IDeg than with IGlar-U300 (estimated ratio IDeg/IGlar-U300: 0.63, 95% CI 0.54; 0.73; P < .0001). The day-to-day variability in glucose-lowering effect with IDeg was approximately 4 times lower than IGlar-U300 (variance ratio IGlar-U300/IDeg: 3.70, 95% CI 2.42; 5.67; P < .0001). The day-to-day variability in glucose-lowering effect assessed in 2-hour intervals was consistently low with IDeg over 24 hours, but steadily increased with IGlar-U300 to a maximum at 10 to 12 hours and 12 to 14 hours after dosing (variance ratios 12.4 and 11.4, respectively). CONCLUSION:IDeg has lower day-to-day and within-day variability than IGlar-U300 and a more stable glucose-lowering effect, which might facilitate titration and enable tighter glycaemic control with a reduced risk of hypoglycaemia.
Project description:To determine whether favorable changes to lean tissue mass (LTM), resting energy expenditure (REE), and testosterone (T) that occurred with 12 months of physiological testosterone replacement therapy (TRT) were retained 6 months after discontinuing treatment.Prospective, open-label, controlled drug intervention trial.Metropolitan area hospitals.Eugonadal (n = 11) and hypogonadal (n = 13) men with chronic spinal cord injury (SCI).Hypogonadal subjects received a 5 or 10 mg transdermal T patch daily for 12 months, with adjustment of the dose to normalize the serum T concentration; TRT was discontinued after 12 months (TRT-12M) and subjects were followed for an additional 6 months and re-evaluated (Post-TRT). Total body dual energy X-ray absorptiometry and blood draws were performed at baseline (BL) prior to TRT, TRT-12M, and Post-TRT. Eugonadal subjects did not receive treatment and were evaluated at comparable time points.There were no significant differences between groups prior to TRT at BL for any of the study endpoints. In the hypogonadal group, a significant increase in LTM was observed from BL to TRT-12M (50.2 ± 7.4 vs. 52.9 ± 6.8 kg, P < 0.01), which persisted Post-TRT compared to BL (52.2 ± 7.8 kg, P < 0.05). The increase in REE from BL to TRT-12M (1283 ± 246 vs. 1410 ± 250 kcal/day) was also retained at Post-TRT (1393 ± 220 kcal/day). These sustained improvements in LTM and REE after termination of anabolic hormonal therapy may be associated with persistent beneficial effects on health and physical function of hypogonadal men with chronic SCI.
Project description:The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0).Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome.ClinicalTrials.gov: NCT00589693.
Project description:STUDY DESIGN:Secondary analysis of a clinical trial. OBJECTIVES:To perform a secondary analysis on the effects of neuromuscular electrical stimulation resistance training (RT) combined with testosterone replacement therapy (TRT) compared with TRT on the untrained muscles after spinal cord injury (SCI). SETTING:Medical research center. METHODS:Twenty-two men with chronic motor complete SCI were randomized into TRT?+?RT group (n?=?11) or TRT group (n?=?11). Both groups received 16 weeks of TRT (2-6?mg/day) via testosterone patches. The TRT?+?RT group received twice weekly progressive RT of the knee extensor muscles using electrical stimulation and ankle weights. Magnetic resonance images were captured to measure cross-sectional areas (CSAs) of trunk, glutei, and leg muscles. RESULTS:Total and absolute gluteus maximus m. (14%, P?=?0.003 and 16%, P?=?0.001), gluteus medius m. (10%; P?=?0.008 and 14%; P?=?0.02), and total glutei m. (8%, P?=?0.01 and 11%, P?=?0.005) CSAs increased overtime for the TRT?+?RT group. Mean between-group differences of 2.86 (95% CI: 0.30, 5.4), 1.89 (95% CI: 0.23, 3.58) and 5.27 (95% CI: 0.90, 9.69) cm2 were noted for absolute gluteus maximus, total gluteus medius and total glutei CSAs, respectively (P?<?0.05). Trunk muscle CSAs showed a trend towards an interaction between groups. CONCLUSIONS:RT combined with low-dose TRT results in significant hypertrophy compared with TRT only on the adjacent untrained glutei muscles. Trunk muscles may require direct stimulation to evoke hypertrophy. These exploratory findings may be of clinical relevance in the reduction of incidence and severity of pelvic pressure injuries.
Project description:Students starting at university tend to adopt unhealthy behaviors. With students expected to sit during classes, their academic schedule may be responsible for their activity patterns. The aim of the current study was to investigate the relationship between university students' academic schedule and day-to-day variations in sedentary behavior (SB) and physical activity (PA). The activity of 317 first-year undergraduate students (mean age 19.6 ± 1.4 years, 69.4% female, 30.0% male, and 0.6% other) was measured with the activPAL3™ triaxial monitor for seven consecutive days. Each class hour was found to be associated with 9.0 additional minutes of SB (95% CI [4.9, 13.1]), 54 additional seconds of moderate-to-vigorous PA (MVPA; 95% CI [12, 96]), and 12.2 min less time in bed (95% CI [-16.6, -7.8]). Active SB ratio (total duration of SB bouts < 30 min divided by total SB duration) decreased by 0.011 per hour of class scheduled for the students (95% CI [-0.016, -0.006]). Light PA (LPA) was not significantly associated with class duration. Students tend to cycle more on days with classes. Seated transportation was not significantly related to whether the students had classes or not. Overall, the academic schedule is associated with SB and PA in students.
Project description:BACKGROUND:Hypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules. METHODS:Eligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or <60 years if unsuitable for intensive chemotherapy with an anthracycline plus cytarabine). The first 40 patients were allocated equally to the two treatment groups by computer-generated block randomisation (block size 40), after which a response-adaptive randomisation algorithm used all previous patients' treatment and response data to decide the allocation of each following patient favouring the group with superior response. Patients were assigned to receive 20 mg/m2 decitabine intravenously for 5 or 10 consecutive days as induction therapy, every 4-8 weeks for up to three cycles. Responding patients received decitabine as consolidation therapy on a 5-day schedule for up to 24 cycles. We assessed a composite primary endpoint of complete remission, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete haematological recovery (CRi) achieved at any time and assessed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01786343. FINDINGS:Between Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26-60, and 17 [40%] of 43 in the 10-day schedule group, 26-54, p=0·78; difference 3%, -21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1-11·7) in the 5-day group and 6·0 months (1·9-11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3-4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups. INTERPRETATION:In older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule. FUNDING:University of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.
Project description:Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton-pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradication of Helicobacter pylori infection than are 5-day concomitant and 10-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses than do three-drug regimens and thus could be suitable for eradication programmes in low-resource settings. Few studies in Latin America have been done, where the burden of H pylori-associated diseases is high. We therefore did a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy.Between September, 2009, and June, 2010, we did a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori in seven Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites). Participants aged 21-65 years who tested positive for H pylori by a urea breath test were randomly assigned by a central computer using a dynamic balancing procedure to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by urea breath test 6-8 weeks after randomisation. The trial was not masked. Our primary outcome was probablity of H pylori eradication. Our analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, registration number NCT01061437.1463 participants aged 21-65 years were randomly allocated a treatment: 488 were treated with 14-day standard therapy, 489 with 5-day concomitant therapy, and 486 with 10-day sequential therapy. The probability of eradication with standard therapy was 82·2% (401 of 488), which was 8·6% higher (95% adjusted CI 2·6-14·5) than with concomitant therapy (73·6% [360 of 489]) and 5·6% higher (-0·04% to 11·6) than with sequential therapy (76·5% [372 of 486]). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites.Standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empiric therapy for H pylori infection in diverse Latin American populations.Bill & Melinda Gates Foundation, US National Institutes of Health.
Project description:Graph-based computational network analysis has proven a powerful tool to quantitatively characterize functional architectures of the brain. However, the test-retest (TRT) reliability of graph metrics of functional networks has not been systematically examined. Here, we investigated TRT reliability of topological metrics of functional brain networks derived from resting-state functional magnetic resonance imaging data. Specifically, we evaluated both short-term (<1 hour apart) and long-term (>5 months apart) TRT reliability for 12 global and 6 local nodal network metrics. We found that reliability of global network metrics was overall low, threshold-sensitive and dependent on several factors of scanning time interval (TI, long-term>short-term), network membership (NM, networks excluding negative correlations>networks including negative correlations) and network type (NT, binarized networks>weighted networks). The dependence was modulated by another factor of node definition (ND) strategy. The local nodal reliability exhibited large variability across nodal metrics and a spatially heterogeneous distribution. Nodal degree was the most reliable metric and varied the least across the factors above. Hub regions in association and limbic/paralimbic cortices showed moderate TRT reliability. Importantly, nodal reliability was robust to above-mentioned four factors. Simulation analysis revealed that global network metrics were extremely sensitive (but varying degrees) to noise in functional connectivity and weighted networks generated numerically more reliable results in compared with binarized networks. For nodal network metrics, they showed high resistance to noise in functional connectivity and no NT related differences were found in the resistance. These findings provide important implications on how to choose reliable analytical schemes and network metrics of interest.