Nonparametric Bounds and Sensitivity Analysis of Treatment Effects

This paper considers conducting inference about the effect of a treatment (or exposure) on an outcome of interest. In the ideal setting where treatment is assigned randomly, under certain assumptions the treatment effect is identifiable from the observable data and inference is straightforward. However, in other settings such as observational studies or randomized trials with noncompliance, the treatment effect is no longer identifiable without relying on untestable assumptions. Nonetheless, the observable data often do provide some information about the effect of treatment, that is, the parameter of interest is partially identifiable. Two approaches are often employed in this setting: (i) bounds are derived for the treatment effect under minimal assumptions, or (ii) additional untestable assumptions are invoked that render the treatment effect identifiable and then sensitivity analysis is conducted to assess how inference about the treatment effect changes as the untestable assumptions are varied. Approaches (i) and (ii) are considered in various settings, including assessing principal strata effects, direct and indirect effects and effects of time-varying exposures. Methods for drawing formal inference about partially identified parameters are also discussed.Comment: Published in at http://dx.doi.org/10.1214/14-STS499 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Growth and form of the mound in Gale Crater, Mars: Slope wind enhanced erosion and transport

Ancient sediments provide archives of climate and habitability on Mars. Gale Crater, the landing site for the Mars Science Laboratory (MSL), hosts a 5-km-high sedimentary mound (Mount Sharp/Aeolis Mons). Hypotheses for mound formation include evaporitic, lacustrine, fluviodeltaic, and aeolian processes, but the origin and original extent of Gale’s mound is unknown. Here we show new measurements of sedimentary strata within the mound that indicate ∼3° outward dips oriented radially away from the mound center, inconsistent with the first three hypotheses. Moreover, although mounds are widely considered to be erosional remnants of a once crater-filling unit, we find that the Gale mound’s current form is close to its maximal extent. Instead we propose that the mound’s structure, stratigraphy, and current shape can be explained by growth in place near the center of the crater mediated by wind-topography feedbacks. Our model shows how sediment can initially accrete near the crater center far from crater-wall katabatic winds, until the increasing relief of the resulting mound generates mound-flank slope winds strong enough to erode the mound. The slope wind enhanced erosion and transport (SWEET) hypothesis indicates mound formation dominantly by aeolian deposition with limited organic carbon preservation potential, and a relatively limited role for lacustrine and fluvial activity. Morphodynamic feedbacks between wind and topography are widely applicable to a range of sedimentary and ice mounds across the Martian surface, and possibly other planets

Nonparametric binary instrumental variable analysis of competing risks data

In both observational studies and randomized trials with noncompliance, unmeasured confounding may exist which may bias treatment effect estimates. Instrumental variables (IV) are a popular technique for addressing such confounding, enabling consistent estimation of causal effects. This paper proposes nonparametric IV estimators for censored time to event data that may be subject to competing risks. A simple, plug-in estimator is introduced using nonparametric estimators of the cumulative incidence function, with confidence intervals derived using asymptotic theory. To provide an overall test of the treatment effect, an integrated weighted difference statistic is suggested, which is applicable to data with and without competing risks. Simulation studies demonstrate that the methods perform well with realistic samples sizes. The methods are applied to assess the effect of infant or maternal antiretroviral therapy on transmission of HIV from mother to child via breastfeeding using data from a large, recently completed randomized trial in Malawi where noncompliance with assigned treatment may confound treatment effect estimates

Differences in experiences of care between patients diagnosed with metastatic cancer of known and unknown primaries: mixed-method findings from the 2013 cancer patient experience survey in England.

OBJECTIVES: To explore differences in experiences of care reported in the Cancer Patient Experience Survey (CPES) between patients with cancer of unknown primary (CUP) and those with metastatic disease of known primary (non-CUP); to determine insights pertaining to the experiences of care for CUP respondents from free-text comments. DESIGN: Two separate, but related, studies, involving secondary analysis of existing data. Using frequency matching of CUP and non-CUP patients, statistical comparisons of responses to CPES questions were conducted. Free-text comments from CUP respondents were analysed thematically. SETTING AND PARTICIPANTS: The CPES questionnaire comprises 63 closed questions measuring 8 areas that relate to experience of care and 3 free-text questions. Questionnaires were mailed to all adult patients (aged ≥16 years) in England with cancer admitted to hospital between 1 September 2013 and 30 November 2013. RESULTS: Matched analysis of closed response items from 2992 patients found significant differences between CUP (n=1496) and non-CUP patients (n=1496): CUP patients were more likely to want more written information about their type of cancer and tests received, to receive their diagnosis from a general practitioner (GP) and have seen allied health professionals, but less likely to have understood explanations of their condition or had surgery. Freetext responses (n=3055) were coded into 17 categories and provided deeper insight regarding patient information and interactions with GPs. CPES data may include a preponderance of patients with favourable CUP subtypes and patients initially identified as CUP but whose primary was subsequently identified. CONCLUSIONS: These are the first large-scale studies to explore the experiences of care of CUP patients. The significant differences identified between the experiences of CUP and non-CUP patients suggest CUP patients require more psychosocial support and specific interventions to manage diagnostic uncertainty and the multiple investigations many CUP patients face. Substantial limitations were identified with the CPES data, emphasising the need for prospective studies

The X-ray Remnant of SN1987A

We present high resolution Chandra observations of the remnant of SN1987A in the Large Magellanic Cloud. The high angular resolution of the Chandra X-ray Observatory (CXO) permits us to resolve the X-ray remnant. We find that the remnant is shell-like in morphology, with X-ray peaks associated with some of the optical hot spots seen in HST images. The X-ray light curve has departed from the linear flux increase observed by ROSAT, with a 0.5-2.0 keV luminosity of 1.5 x 10^35 erg/s in January 2000. We set an upper limit of 2.3 x 10^34 ergs/s on the luminosity of any embedded central source (0.5 - 2 keV). We also present a high resolution spectrum, showing that the X-ray emission is thermal in origin and is dominated by highly ionized species of O, Ne, Mg, and Si.Comment: 16 pages, 3 figures, Accepted for publication in ApJ Letter

Two- and three-input TALE-based AND logic computation in embryonic stem cells

Biological computing circuits can enhance our ability to control cellular functions and have potential applications in tissue engineering and medical treatments. Transcriptional activator-like effectors (TALEs) represent attractive components of synthetic gene regulatory circuits, as they can be designed de novo to target a given DNA sequence. We here demonstrate that TALEs can perform Boolean logic computation in mammalian cells. Using a split-intein protein-splicing strategy, we show that a functional TALE can be reconstituted from two inactive parts, thus generating two-input AND logic computation. We further demonstrate three-piece intein splicing in mammalian cells and use it to perform three-input AND computation. Using methods for random as well as targeted insertion of these relatively large genetic circuits, we show that TALE-based logic circuits are functional when integrated into the genome of mouse embryonic stem cells. Comparing construct variants in the same genomic context, we modulated the strength of the TALE-responsive promoter to improve the output of these circuits. Our work establishes split TALEs as a tool for building logic computation with the potential of controlling expression of endogenous genes or transgenes in response to a combination of cellular signals

Improving classification of epileptic and non-epileptic EEG events by feature selection

This is the Accepted Manuscript version of the following article: E. Pippa, et al, “Improving classification of epileptic and non-epileptic EEG events by feature selection”, Neurocomputing, Vol. 171: 576-585, July 2015. The final published version is available at: http://www.sciencedirect.com/science/article/pii/S0925231215009509?via%3Dihub Copyright © 2015 Elsevier B.V.Correctly diagnosing generalized epileptic from non-epileptic episodes, such as psychogenic non epileptic seizures (PNES) and vasovagal or vasodepressor syncope (VVS), despite its importance for the administration of appropriate treatment, life improvement of the patient, and cost reduction for patient and healthcare system, is rarely tackled in the literature. Usually clinicians differentiate between generalized epileptic seizures and PNES based on clinical features and video-EEG. In this work, we investigate the use of machine learning techniques for automatic classification of generalized epileptic and non-epileptic events based only on multi-channel EEG data. For this purpose, we extract the signal patterns in the time domain and in the frequency domain and then combine all features across channels to characterize the spatio-temporal manifestation of seizures. Several classification algorithms are explored and evaluated on EEG epochs from 11 subjects in an inter-subject cross-validation setting. Due to large number of features feature ranking and selection is performed prior to classification using the ReliefF ranking algorithm within two different voting strategies. The classification models using feature subsets, achieved higher accuracy compared to the models using all features reaching 95% (Bayesian Network), 89% (Random Committee) and 87% (Random Forest) for binary classification (epileptic versus non-epileptic). The results demonstrate the competitiveness of this approach as opposed to previous methods.Peer reviewe

Frozen section analysis and sentinel lymph node biopsy in well differentiated thyroid cancer

BACKGROUND: The aim of this study is to prospectively review the role of sentinel lymph node (SLN) biopsy in the management of well differentiated thyroid carcinoma (WDTC), and to determine the efficacy of intraoperative frozen section analysis at detecting SLN metastasis and central compartment involvement. METHODS: The SLN biopsy protocol using 1% methylene blue was performed in 300 patients undergoing thyroidectomy for WDTC. A limited pretracheal central compartment neck dissection (CCND) was performed on all patients. Lymph nodes staining blue were considered as SLN’s. Both frozen and permanent section analyses were performed. RESULTS: SLN’s with metastasis were found in 14.3% (43/300) of cases. Of this, 11% (33/300) were positive on intraoperative frozen section analysis. Frozen section results failed in predicting central compartment involvement in 15 cases (5%) whereas central neck compartment involvement was missed in 5 cases (1.7%) when based on permanent section results. On frozen section analysis, the sensitivity, specificity, positive predictive value and negative predictive value (95% CI) of our SLN biopsy technique aiming to remove all disease from the central compartment was 68.8% (53.6-80.9), 100% (98.1-100), 100% (87.0-100) and 94.4% (90.7-96.7) respectively with P < 0.0001. On permanent section analysis, the values were 89.6% (76.6-96.1), 100% (98.1-100), 100% (89.8-100), and 98.1% (95.3-99.3) with P < 0.0001. CONCLUSION: This data series demonstrates that patients with WDTC have positive SLN’s in 14.3% of cases. Moreover, when the SLN’s are negative for metastasis on frozen section, the central compartment was disease-free in 94.4% of cases. Finally, this study shows that 23.3% of positive SLN’s were false negatives on intraoperative frozen section. According to this data, SLN involvement is an accurate predictor of central compartment metastasis, however surgeons should use caution when relying on intraoperative frozen section to determine whether to perform a CCND