231 research outputs found
Analysis and design of randomised clinical trials involving competing risks endpoints
<p>Abstract</p> <p>Background</p> <p>In randomised clinical trials involving time-to-event outcomes, the failures concerned may be events of an entirely different nature and as such define a classical competing risks framework. In designing and analysing clinical trials involving such endpoints, it is important to account for the competing events, and evaluate how each contributes to the overall failure. An appropriate choice of statistical model is important for adequate determination of sample size.</p> <p>Methods</p> <p>We describe how competing events may be summarised in such trials using cumulative incidence functions and Gray's test. The statistical modelling of competing events using proportional cause-specific and subdistribution hazard functions, and the corresponding procedures for sample size estimation are outlined. These are illustrated using data from a randomised clinical trial (SQNP01) of patients with advanced (non-metastatic) nasopharyngeal cancer.</p> <p>Results</p> <p>In this trial, treatment has no effect on the competing event of loco-regional recurrence. Thus the effects of treatment on the hazard of distant metastasis were similar via both the cause-specific (unadjusted <it>csHR </it>= 0.43, 95% CI 0.25 - 0.72) and subdistribution (unadjusted <it>subHR </it>0.43; 95% CI 0.25 - 0.76) hazard analyses, in favour of concurrent chemo-radiotherapy followed by adjuvant chemotherapy. Adjusting for nodal status and tumour size did not alter the results. The results of the logrank test (<it>p </it>= 0.002) comparing the cause-specific hazards and the Gray's test (<it>p </it>= 0.003) comparing the cumulative incidences also led to the same conclusion. However, the subdistribution hazard analysis requires many more subjects than the cause-specific hazard analysis to detect the same magnitude of effect.</p> <p>Conclusions</p> <p>The cause-specific hazard analysis is appropriate for analysing competing risks outcomes when treatment has no effect on the cause-specific hazard of the competing event. It requires fewer subjects than the subdistribution hazard analysis for a similar effect size. However, if the main and competing events are influenced in opposing directions by an intervention, a subdistribution hazard analysis may be warranted.</p
Causarum Investigatio and the Two Bell's Theorems of John Bell
"Bell's theorem" can refer to two different theorems that John Bell proved,
the first in 1964 and the second in 1976. His 1964 theorem is the
incompatibility of quantum phenomena with the joint assumptions of Locality and
Predetermination. His 1976 theorem is their incompatibility with the single
property of Local Causality. This is contrary to Bell's own later assertions,
that his 1964 theorem began with the assumption of Local Causality, even if not
by that name. Although the two Bell's theorems are logically equivalent, their
assumptions are not. Hence, the earlier and later theorems suggest quite
different conclusions, embraced by operationalists and realists, respectively.
The key issue is whether Locality or Local Causality is the appropriate notion
emanating from Relativistic Causality, and this rests on one's basic notion of
causation. For operationalists the appropriate notion is what is here called
the Principle of Agent-Causation, while for realists it is Reichenbach's
Principle of common cause. By breaking down the latter into even more basic
Postulates, it is possible to obtain a version of Bell's theorem in which each
camp could reject one assumption, happy that the remaining assumptions reflect
its weltanschauung. Formulating Bell's theorem in terms of causation is
fruitful not just for attempting to reconcile the two camps, but also for
better describing the ontology of different quantum interpretations and for
more deeply understanding the implications of Bell's marvellous work.Comment: 24 pages. Prepared for proceedings of the "Quantum [Un]speakables II"
conference (Vienna, 2014), to be published by Springe
Realism and Objectivism in Quantum Mechanics
The present study attempts to provide a consistent and coherent account of
what the world could be like, given the conceptual framework and results of
contemporary quantum theory. It is suggested that standard quantum mechanics
can, and indeed should, be understood as a realist theory within its domain of
application. It is pointed out, however, that a viable realist interpretation
of quantum theory requires the abandonment or radical revision of the classical
conception of physical reality and its traditional philosophical
presuppositions. It is argued, in this direction, that the conceptualization of
the nature of reality, as arising out of our most basic physical theory, calls
for a kind of contextual realism. Within the domain of quantum mechanics,
knowledge of 'reality in itself', 'the real such as it truly is' independent of
the way it is contextualized, is impossible in principle. In this connection,
the meaning of objectivity in quantum mechanics is analyzed, whilst the
important question concerning the nature of quantum objects is explored.Comment: 20 pages. arXiv admin note: substantial text overlap with
arXiv:0811.3696, arXiv:quant-ph/0502099, arXiv:0904.2702, arXiv:0904.2859,
arXiv:0905.013
Relative Necessity Reformulated
This paper discusses some serious difficulties for what we shall call the standard account of various kinds of relative necessity, according to which any given kind of relative necessity may be defined by a strict conditional - necessarily, if C then p - where C is a suitable constant proposition, such as a conjunction of physical laws. We argue, with the help of Humberstone (1981), that the standard account has several unpalatable consequences. We argue that Humberstone's alternative account has certain disadvantages, and offer another - considerably simpler - solution
Effectiveness of temozolomide for primary glioblastoma multiforme in routine clinical practice
Temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiforme since 2005. To assess the effectiveness of temozolomide in routine clinical practice, we conducted an observational study at Maastricht University Medical Centre (MUMC). Data of patients receiving radiotherapy and temozolomide between January 2005 and January 2008 were retrieved from a clinical database (radiochemotherapy group), as were data of patients in a historical control group from the period before 2005 treated with radiotherapy only (radiotherapy group). The primary endpoint was overall survival. A total of 125 patients with GBM were selected to form the study cohort. Median survival benefit was 4 months: the median overall survival was 12 months (95% CI, 9.7–14.3) in the group with radiochemotherapy with temozolomide, versus 8 months (95% CI, 5.3–10.7) in the group with only radiotherapy. Progression-free survival was 7 months (95% CI, 5.5–8.5) in the radiochemotherapy group and 4 months (95% CI, 2.9-5.1) in the group with only radiotherapy. The two-year survival rate was 18% with radiochemotherapy with temozolomide against 4% with radiotherapy alone. Concomitant treatment with radiotherapy and temozolomide followed by adjuvant temozolomide resulted in grade III or IV haematological toxic effects in 9% of patients. The addition of temozolomide to radiotherapy in routine clinical practice for newly diagnosed glioblastoma resulted in a clinically meaningful survival benefit with minimal haematological toxicity, which confirms the experience of previous trials and justifies the continued use of temozolomide in routine clinical practice
Growth Hormone Improves Growth Retardation Induced by Rapamycin without Blocking Its Antiproliferative and Antiangiogenic Effects on Rat Growth Plate
Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis
Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo
We use data from the second science run of the LIGO gravitational-wave
detectors to search for the gravitational waves from primordial black hole
(PBH) binary coalescence with component masses in the range 0.2--.
The analysis requires a signal to be found in the data from both LIGO
observatories, according to a set of coincidence criteria. No inspiral signals
were found. Assuming a spherical halo with core radius 5 kpc extending to 50
kpc containing non-spinning black holes with masses in the range 0.2--, we place an observational upper limit on the rate of PBH coalescence
of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.
Surprisingly High Specificity of the PPD Skin Test for M. tuberculosis Infection from Recent Exposure in The Gambia
BACKGROUND: Options for intervention against Mycobacterium tuberculosis infection are limited by the diagnostic tools available. The Purified Protein Derivative (PPD) skin test is thought to be non-specific, especially in tropical settings. We compared the PPD skin test with an ELISPOT test in The Gambia. METHODOLOGY/PRINCIPAL FINDINGS: Household contacts over six months of age of sputum smear positive TB cases and community controls were recruited. They underwent a PPD skin test and an ELISPOT test for the T cell response to PPD and ESAT-6/CFP10 antigens. Responsiveness to M. tuberculosis exposure was analysed according to sleeping proximity to an index case using logistic regression. 615 household contacts and 105 community controls were recruited. All three tests assessed increased significantly in positivity with increasing M. tuberculosis exposure, the PPD skin test most dramatically (OR 15.7; 95% CI 6.6–35.3). While the PPD skin test positivity continued to trend downwards in the community with increasing distance from a known case (61.9% to 14.3%), the PPD and ESAT-6/CFP-10 ELISPOT positivity did not. The PPD skin test was more in agreement with ESAT-6/CFP-10 ELISPOT (75%, p = 0.01) than the PPD ELISPOT (53%, p<0.0001). With increasing M. tuberculosis exposure, the proportion of ESAT-6/CFP-10 positive contacts who were PPD skin test positive increased (p<0.0001), and the proportion of ESAT-6/CFP-10 negative contacts that were PPD skin test negative decreased (p<0.0001); the converse did not occur. CONCLUSIONS/SIGNIFICANCE: The PPD skin test has surprisingly high specificity for M. tuberculosis infection from recent exposure in The Gambia. In this setting, anti-tuberculous prophylaxis in PPD skin test positive individuals should be revisited
Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa
<p>Abstract</p> <p>Background</p> <p>Antibody serology is an important tool in the investigation of celiac disease (CD), but does not always correlate with mucosal appearance in the small intestine. Patients with positive CD serology but normal mucosa (Marsh 0) are at increased risk of future CD. In this study we describe a model for identifying and characterizing individuals with normal mucosa but positive CD serology. Such individuals are sometimes referred to as having latent CD.</p> <p>Methods</p> <p>The records of ten Swedish pathology departments were used to identify individuals with biopsies indicating normal duodenal/jejunal mucosa. Using the national personal identification number, these data were linked with CD serology data (antigliadin, antiendomysial and tissue transglutaminase antibodies); and we thereby identified 3,736 individuals with normal mucosa but positive CD serology. Two independent reviewers then manually reviewed their biopsy reports to estimate comorbidity. We also randomly selected 112 individuals for validation through patient chart review.</p> <p>Results</p> <p>The majority of the 3,736 individuals were females (62%). Children (0–15 years) made up 21.4%. The median number of biopsy specimen was 3. Our review of biopsy reports found that other gastrointestinal comorbidity was rare (inflammatory bowel disease: 0.4%; helicobacter pylori infection: 0.2%). Some 22% individuals selected for patient chart review had a relative with CD. The most common symptoms among these individuals were diarrhea (46%) and abdominal pain (45%), while 26% had anemia. Although 27% of the individuals selected for validation had been informed about gluten-free diet, only 13% were adhering to a gluten-free diet at the end of follow-up.</p> <p>Conclusion</p> <p>Individuals with positive CD serology but normal mucosa often have CD-like symptoms and a family history of CD.</p
A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment
BACKGROUND: The prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty. METHODS: Two retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women. RESULTS: Genotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68). CONCLUSION: BRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up
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