•We compare performance for random forest variable selection methods.•VSURF or Jiang's method are preferable for most datasets.•varSelRF or Boruta perform well for data with >50 predictors.•Methods ...with conditional random forest usually have similar performance.•Type of methods, test- or performance-based, is not likely to impact performance.
Random forest classification is a popular machine learning method for developing prediction models in many research settings. Often in prediction modeling, a goal is to reduce the number of variables needed to obtain a prediction in order to reduce the burden of data collection and improve efficiency. Several variable selection methods exist for the setting of random forest classification; however, there is a paucity of literature to guide users as to which method may be preferable for different types of datasets. Using 311 classification datasets freely available online, we evaluate the prediction error rates, number of variables, computation times and area under the receiver operating curve for many random forest variable selection methods. We compare random forest variable selection methods for different types of datasets (datasets with binary outcomes, datasets with many predictors, and datasets with imbalanced outcomes) and for different types of methods (standard random forest versus conditional random forest methods and test based versus performance based methods). Based on our study, the best variable selection methods for most datasets are Jiang's method and the method implemented in the VSURF R package. For datasets with many predictors, the methods implemented in the R packages varSelRF and Boruta are preferable due to computational efficiency. A significant contribution of this study is the ability to assess different variable selection techniques in the setting of random forest classification in order to identify preferable methods based on applications in expert and intelligent systems.
Past research argues for an internal multidecadal (40- to 60-year) oscillation distinct from climate noise. Recent studies have claimed that this so-termed Atlantic Multidecadal Oscillation is ...instead a manifestation of competing time-varying effects of anthropogenic greenhouse gases and sulfate aerosols. That conclusion is bolstered by the absence of robust multidecadal climate oscillations in control simulations of current-generation models. Paleoclimate data, however, do demonstrate multidecadal oscillatory behavior during the preindustrial era. By comparing control and forced "Last Millennium" simulations, we show that these apparent multidecadal oscillations are an artifact of pulses of volcanic activity during the preindustrial era that project markedly onto the multidecadal (50- to 70-year) frequency band. We conclude that there is no compelling evidence for internal multidecadal oscillations in the climate system.
For several decades the existence of interdecadal and multidecadal internal climate oscillations has been asserted by numerous studies based on analyses of historical observations, paleoclimatic data ...and climate model simulations. Here we use a combination of observational data and state-of-the-art forced and control climate model simulations to demonstrate the absence of consistent evidence for decadal or longer-term internal oscillatory signals that are distinguishable from climatic noise. Only variability in the interannual range associated with the El Niño/Southern Oscillation is found to be distinguishable from the noise background. A distinct (40-50 year timescale) spectral peak that appears in global surface temperature observations appears to reflect the response of the climate system to both anthropogenic and natural forcing rather than any intrinsic internal oscillation. These findings have implications both for the validity of previous studies attributing certain long-term climate trends to internal low-frequency climate cycles and for the prospect of decadal climate predictability.
Phosphorothioate (PS)-modified antisense oligonucleotides (ASOs) have been extensively investigated over the past three decades as pharmacological and therapeutic agents. One second generation ASO, ...Kynamro™, was recently approved by the FDA for the treatment of homozygous familial hypercholesterolemia and over 35 second generation PS ASOs are at various stages of clinical development. In this report, we show that the Stabilin class of scavenger receptors, which were not previously thought to bind DNA, do bind and internalize PS ASOs. With the use of primary cells from mouse and rat livers and recombinant cell lines each expressing Stabilin-1 and each isoform of Stabilin-2 (315-HARE and 190-HARE), we have determined that PS ASOs bind with high affinity and these receptors are responsible for bulk, clathrin-mediated endocytosis within the cell. Binding is primarily dependent on salt-bridge formation and correct folding of the intact protein receptor. Increased internalization rates also enhanced ASO potency for reducing expression of the non-coding RNA Malat-1, in Stabilin-expressing cell lines. A more thorough understanding of mechanisms by which ASOs are internalized in cells and their intracellular trafficking pathways will aid in the design of next generation antisense agents with improved therapeutic properties.
The recent slowdown in global warming has brought into question the reliability of climate model projections of future temperature change and has led to a vigorous debate over whether this slowdown ...is the result of naturally occurring, internal variability or forcing external to Earth's climate system. To address these issues, we applied a semi-empirical approach that combines climate observations and model simulations to estimate Atlantic- and Pacific-based internal multidecadal variability (termed "AMO" and "PMO," respectively). Using this method, the AMO and PMO are found to explain a large proportion of internal variability in Northern Hemisphere mean temperatures. Competition between a modest positive peak in the AMO and a substantially negative-trending PMO are seen to produce a slowdown or "false pause" in warming of the past decade.
Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied ...carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP.
GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m
and cisplatin 50 mg/m
(day 1), followed by paclitaxel 160 mg/m
(day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m
and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints.
From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37
41 months, respectively; hazard ratio HR, 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13
14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (
= .40). More grade ≥ 3 thrombocytopenia (23%
12%), vomiting (7%
4%), diarrhea (6%
2%), and metabolic (14%
8%) toxicities were reported with TAP. Neutropenia (52%
80%) was more common with TC. Small HRQoL differences favored TC.
With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.
Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies
. Tumor complexity and ...heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient
. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies
. Several of these trials have been hindered by very low matching rates, often in the 5-10% range
, and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability, or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional prospective study (I-PREDICT, NCT02534675 ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multidrug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher 'matching score', was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.
Abstract The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk at the spine, hip, and other nonvertebral ...skeletal sites. Further, bisphosphonates have been associated with a significant decrease in morbidity and increase in survival. Following the use of bisphosphonates in millions of patients in clinical practice, some unexpected possible adverse effects have been reported, including osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer. Because bisphosphonates are incorporated into the skeleton and continue to exert an antiresorptive effect for a period of time after dosing is discontinued, the concept of a drug holiday has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from antifracture efficacy. Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for a drug holiday, while for those with bone mineral density in the osteoporosis range or previous history of fragility fracture, the benefits of continuing therapy probably far outweigh the risk of harm.
The Extended Distribution of Baryons around Galaxies Bregman, Joel N.; Anderson, Michael E.; Miller, Matthew J. ...
Astrophysical journal/The Astrophysical journal,
07/2018, Letnik:
862, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We summarize and reanalyze observations bearing on missing galactic baryons, where we propose a consistent picture for halo gas in L L* galaxies. The hot X-ray-emitting halos are detected to 50-70 ...kpc, where typically Mhot(<50 kpc) ∼ 5 × 109 M , and with density n ∝ r−3/2. When extrapolated to R200, the gas mass is comparable to the stellar mass, but about half of the baryons are still missing from the hot phase. If extrapolated to 1.7R200-3R200, the ratio of baryon to dark matter approaches the cosmic value. Significantly flatter density profiles are unlikely for R < 50 kpc, and they are disfavored but not ruled out for R > 50 kpc. For the Milky Way, the hot halo metallicity lies in the range 0.3-1 solar for R < 50 kpc. Planck measurements of the thermal Sunyaev-Zel'dovich (SZ) effect toward stacked luminous galaxies (primarily early type) indicate that most of their baryons are hot, are near the virial temperature, and extend beyond R200. This stacked SZ signal is nearly an order of magnitude larger than that inferred from the X-ray observations of individual (mostly spiral) galaxies with M* > 1011.3 M . This difference suggests that the hot halo properties are distinct for early- and late-type galaxies, possibly due to different evolutionary histories. For the cooler gas detected in UV absorption line studies, we argue that there are two absorption populations: extended halos, and disks extending to ∼50 kpc, containing most of this gas, and with masses a few times lower than the stellar masses. Such extended disks are also seen in 21 cm H i observations and in simulations.
Globally, one in five men aged >50 years is predicted to experience an osteoporotic fracture. Because of the treatment gap in osteoporosis and the paucity of bone-forming agents for men, new ...osteoporosis treatments are needed.
To evaluate the safety and efficacy of romosozumab in men with osteoporosis.
Phase III randomized BRIDGE study (placebo-controlled double-blind study evaluating the efficacy and safety of romosozumab in treating men with osteoporosis; ClinicalTrials.gov identifier, NCT02186171) for 12 months.
Thirty-one centers in Europe, Latin America, Japan, and North America.
Men aged 55 to 90 years with a baseline bone mineral density (BMD) T-score at the lumbar spine (LS), total hip (TH), or femoral neck of ≤-2.5 or ≤-1.5 with a history of a fragility nonvertebral or vertebral fracture.
The subjects were randomized 2:1 to receive romosozumab 210 mg subcutaneously monthly or placebo for 12 months.
The primary efficacy endpoint was percentage change from baseline in LS BMD at month 12.
In 245 subjects (163 romosozumab, 82 placebo), at month 12, the mean percentage change from baseline in the LS and TH BMD was significantly greater for the romosozumab group than for the placebo group (LS, 12.1% vs 1.2%; TH, 2.5% vs -0.5%; P < 0.001). Adverse events and serious adverse events were balanced between the two groups, with a numerical imbalance in the positively adjudicated cardiovascular serious adverse events romosozumab, 8 (4.9%) vs placebo, 2 (2.5%).
Treatment with romosozumab for 12 months increased the spine and hip BMD compared with placebo and was well tolerated in men with osteoporosis.
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