The Philosopher"s Garden: Scepticism within (and from without) Wittgenstein

I am sitting with a philosopher in the garden; he says again and again "I know that that"s a tree�, pointing to a tree that is near us. Someone else arrives and hears this, and I tell him: "This fellow isn"t insane. We are only doing philosophy.� On Certainty § 467 If philosophy is disease, the sceptic must surely have a terminal case. There seems to be no relief for one so ill. However, in On Certainty Wittgenstein offers us a new way to examine the problem, a new treatment, as it were. As Wittgenstein"s methodology is so uniquely multi-faceted, so too is his attack on the sceptic, and as it has been said before, Wittgenstein has a marvelous capacity, not for solving problems, but dissolving them. We should not therefore be surprised that the die-hard sceptic remains unconvinced by Wittgenstein"s attack; it is not the sort of maneuver the sceptic is used to. Indeed, at times it does not seem like an attack at all. The sceptic must beware however; behind Wittgenstein"s oblique style there lies an assault of such subtlety and caliber that only a master of could deliver it. But really, for all his mastery, for all his philosophical poignancy, how effective is Wittgenstein"s criticism? It is certainly of a very different order than those we have seen in the past, but can Wittgenstein ultimately avoid the charge of "question begging� that have plagued so many before him? The question is somewhat complicated in the case of Wittgenstein, not only by his philosophical position, but also by his methodology

Using philosophy to improve the coherence and interoperability of applications ontologies: A field report on the collaboration of IFOMIS and L&C

The collaboration of Language and Computing nv (L&C) and the Institute for Formal Ontology and Medical Information Science (IFOMIS) is guided by the hypothesis that quality constraints on ontologies for software ap-plication purposes closely parallel the constraints salient to the design of sound philosophical theories. The extent of this parallel has been poorly appreciated in the informatics community, and it turns out that importing the benefits of phi-losophical insight and methodology into application domains yields a variety of improvements. L&C’s LinKBase® is one of the world’s largest medical domain ontologies. Its current primary use pertains to natural language processing ap-plications, but it also supports intelligent navigation through a range of struc-tured medical and bioinformatics information resources, such as SNOMED-CT, Swiss-Prot, and the Gene Ontology (GO). In this report we discuss how and why philosophical methods improve both the internal coherence of LinKBase®, and its capacity to serve as a translation hub, improving the interoperability of the ontologies through which it navigates

Ontological theory for ontological engineering: Biomedical systems information integration

Software application ontologies have the potential to become the keystone in state-of-the-art information management techniques. It is expected that these ontologies will support the sort of reasoning power required to navigate large and complex terminologies correctly and efficiently. Yet, there is one problem in particular that continues to stand in our way. As these terminological structures increase in size and complexity, and the drive to integrate them inevitably swells, it is clear that the level of consistency required for such navigation will become correspondingly difficult to maintain. While descriptive semantic representations are certainly a necessary component to any adequate ontology-based system, so long as ontology engineers rely solely on semantic information, without a sound ontological theory informing their modeling decisions, this goal will surely remain out of reach. In this paper we describe how Language and Computing nv (L&C), along with The Institute for Formal Ontology and Medical Information Sciences (IFOMIS), are working towards developing and implementing just such a theory, combining the open software architecture of L&C’s LinkSuiteTM with the philosophical rigor of IFOMIS’s Basic Formal Ontology. In this way we aim to move beyond the more or less simple controlled vocabularies that have dominated the industry to date

Review of the Role of EBUS-TBNA for the Pulmonologist, Including Lung Cancer Staging

This review focuses on the role of endobronchial ultrasound-guided transbronchial needle aspiration in day-to-day pulmonology practice. Case examples are given of the common indications for endobronchial ultrasound-guided transbronchial needle aspiration which are: (i) lung cancer staging; (ii) confirming a diagnosis of malignancy in thoracic lymph nodes; (iii) diagnosing central pulmonary masses; (iv) sarcoidosis; and (v) inflammatory/benign thoracic lymph nodes. The technique is widely used, and after appropriate training by experienced bronchoscopists can be easily integrated into a bronchoscopy service

The optimal design of stepped wedge trials with equal allocation to sequences and a comparison to other trial designs.

Background/Aims We sought to optimise the design of stepped wedge trials with an equal allocation of clusters to sequences and explored sample size comparisons with alternative trial designs. Methods We developed a new expression for the design effect for a stepped wedge trial, assuming that observations are equally correlated within clusters and an equal number of observations in each period between sequences switching to the intervention. We minimised the design effect with respect to (1) the fraction of observations before the first and after the final sequence switches (the periods with all clusters in the control or intervention condition, respectively) and (2) the number of sequences. We compared the design effect of this optimised stepped wedge trial to the design effects of a parallel cluster-randomised trial, a cluster-randomised trial with baseline observations, and a hybrid trial design (a mixture of cluster-randomised trial and stepped wedge trial) with the same total cluster size for all designs. Results We found that a stepped wedge trial with an equal allocation to sequences is optimised by obtaining all observations after the first sequence switches and before the final sequence switches to the intervention; this means that the first sequence remains in the control condition and the last sequence remains in the intervention condition for the duration of the trial. With this design, the optimal number of sequences is [Formula: see text], where [Formula: see text] is the cluster-mean correlation, [Formula: see text] is the intracluster correlation coefficient, and m is the total cluster size. The optimal number of sequences is small when the intracluster correlation coefficient and cluster size are small and large when the intracluster correlation coefficient or cluster size is large. A cluster-randomised trial remains more efficient than the optimised stepped wedge trial when the intracluster correlation coefficient or cluster size is small. A cluster-randomised trial with baseline observations always requires a larger sample size than the optimised stepped wedge trial. The hybrid design can always give an equally or more efficient design, but will be at most 5% more efficient. We provide a strategy for selecting a design if the optimal number of sequences is unfeasible. For a non-optimal number of sequences, the sample size may be reduced by allowing a proportion of observations before the first or after the final sequence has switched. Conclusion The standard stepped wedge trial is inefficient. To reduce sample sizes when a hybrid design is unfeasible, stepped wedge trial designs should have no observations before the first sequence switches or after the final sequence switches

Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals.

OBJECTIVE: To assess the adequacy of reporting of non-inferiority trials alongside the consistency and utility of current recommended analyses and guidelines. DESIGN: Review of randomised clinical trials that used a non-inferiority design published between January 2010 and May 2015 in medical journals that had an impact factor >10 (JAMA Internal Medicine, Archives Internal Medicine, PLOS Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet and New England Journal of Medicine). DATA SOURCES: Ovid (MEDLINE). METHODS: We searched for non-inferiority trials and assessed the following: choice of non-inferiority margin and justification of margin; power and significance level for sample size; patient population used and how this was defined; any missing data methods used and assumptions declared and any sensitivity analyses used. RESULTS: A total of 168 trial publications were included. Most trials concluded non-inferiority (132; 79%). The non-inferiority margin was reported for 98% (164), but less than half reported any justification for the margin (77; 46%). While most chose two different analyses (91; 54%) the most common being intention-to-treat (ITT) or modified ITT and per-protocol, a large number of articles only chose to conduct and report one analysis (65; 39%), most commonly the ITT analysis. There was lack of clarity or inconsistency between the type I error rate and corresponding CIs for 73 (43%) articles. Missing data were rarely considered with (99; 59%) not declaring whether imputation techniques were used. CONCLUSIONS: Reporting and conduct of non-inferiority trials is inconsistent and does not follow the recommendations in available statistical guidelines, which are not wholly consistent themselves. Authors should clearly describe the methods used and provide clear descriptions of and justifications for their design and primary analysis. Failure to do this risks misleading conclusions being drawn, with consequent effects on clinical practice

Effectiveness and safety of misoprostol distributed to antenatal women to prevent postpartum haemorrhage after child-births: a stepped-wedge cluster-randomized trial.

BACKGROUND: Oral misoprostol, administered by trained health-workers is effective and safe for preventing postpartum haemorrhage (PPH). There is interest in expanding administration of misoprostol by non-health workers, including task-shifting to pregnant women themselves. However, the use of misoprostol for preventing PPH in home-births remains controversial, due to the limited evidence to support self-administration or leaving it in the hands of non-health workers. This study aimed to determine if antenatally distributing misoprostol to pregnant women to self-administer at home birth reduces PPH. METHODS: Between February 2013 and March 2014, we conducted a stepped-wedge cluster-randomized trial in six health facilities in Central Uganda. Women at 28+ weeks of gestation attending antenatal care were eligible. Women in the control-arm received the standard-of-care; while the intervention-arm were offered 600 mcg of misoprostol to swallow immediately after birth of baby, when oxytocin was not available. The primary outcome (PPH) was a drop in postpartum maternal haemoglobin (Hb) by ≥ 2 g/dl, lower than the prenatal Hb. Analysis was by intention-to-treat at the cluster level and we used a paired t-tests to assess whether the mean difference between the control and intervention groups was statistically significant. RESULTS: 97% (2466/2545) of eligible women consented to participate; 1430 and 1036 in the control and intervention arms respectively. Two thousand fifty-seven of the participants were successfully followed up and 271 (13.2%) delivered outside a health facility. There was no significant difference between the study group in number of women who received a uterotonic at birth (control 80.4% vs intervention 91.4%, mean difference = -11.0%, 95% confidence interval [CI] -25.7% to 3.6%, p = 0.11). No woman took misoprostol before their baby's birth. Shivering and fever were 14.9% in the control arm compared to 22.2% in the intervention arm (mean difference = -7.2%, 95% CI -11.1% to -3.7%), p = 0.005). There was a slight, but non-significant, reduction in the percentage of women with Hb drop ≥ 2g/dl from 18.5% in the control arm to 11.4% in the intervention arm (mean difference = 7.1%, 95% CI -3.1% to 17.3%, p = 0.14). Similarly, there was no significant difference between the groups in the primary outcome in the women who delivered at home (control 9.6% vs intervention 14.5%, mean difference -4.9; 95% CI -12.7 to 2.9), p = 0.17). CONCLUSION: This study was unable to detect a significant reduction in PPH following the antenatal distribution of misoprostol. The study was registered with Pan-African Clinical Trials Network ( PACTR201303000459148, on 19/11/2012)

How important is randomisation in a stepped wedge trial?

In cluster randomised trials, randomisation increases internal study validity. If enough clusters are randomised, an unadjusted analysis should be unbiased. If a smaller number of clusters are included, stratified or matched randomisation can increase comparability between trial arms. In addition, an adjusted analysis may be required; nevertheless, randomisation removes the possibility for systematically biased allocation and increases transparency. In stepped wedge trials, clusters are randomised to receive an intervention at different start times ('steps'), and all clusters eventually receive it. In a recent study protocol for a 'modified stepped wedge trial', the investigators considered randomisation of the clusters (hospital wards), but decided against it for ethical and logistical reasons, and under the assumption that it would not add much to the rigour of the evaluation. We show that the benefits of randomisation for cluster randomised trials also apply to stepped wedge trials. The biggest additional issue for stepped wedge trials in relation to parallel cluster randomised trials is the need to control for secular trends in the outcome. Analysis of stepped wedge trials can in theory be based on 'horizontal' or 'vertical' comparisons. Horizontal comparisons are based on measurements taken before and after the intervention is introduced in each cluster, and are unbiased if there are no secular trends. Vertical comparisons are based on outcome measurements from clusters that have switched to the intervention condition and those from clusters that have yet to switch, and are unbiased under randomisation since at any time point, which clusters are in intervention and control conditions will have been determined at random. Secular outcome trends are a possibility in many settings. Many stepped wedge trials are analysed with a mixed model, including a random effect for cluster and fixed effects for time period to account for secular trends, thereby combining both vertical and horizontal comparisons of intervention and control clusters. The importance of randomisation in a stepped wedge trial is that the effects of time can be estimated from the data, and bias from secular trends that would otherwise arise can be controlled for, provided the trends are correctly specified in the model