Faster k-Medoids Clustering: Improving the PAM, CLARA, and CLARANS Algorithms

Clustering non-Euclidean data is difficult, and one of the most used algorithms besides hierarchical clustering is the popular algorithm Partitioning Around Medoids (PAM), also simply referred to as k-medoids. In Euclidean geometry the mean-as used in k-means-is a good estimator for the cluster center, but this does not hold for arbitrary dissimilarities. PAM uses the medoid instead, the object with the smallest dissimilarity to all others in the cluster. This notion of centrality can be used with any (dis-)similarity, and thus is of high relevance to many domains such as biology that require the use of Jaccard, Gower, or more complex distances. A key issue with PAM is its high run time cost. We propose modifications to the PAM algorithm to achieve an O(k)-fold speedup in the second SWAP phase of the algorithm, but will still find the same results as the original PAM algorithm. If we slightly relax the choice of swaps performed (at comparable quality), we can further accelerate the algorithm by performing up to k swaps in each iteration. With the substantially faster SWAP, we can now also explore alternative strategies for choosing the initial medoids. We also show how the CLARA and CLARANS algorithms benefit from these modifications. It can easily be combined with earlier approaches to use PAM and CLARA on big data (some of which use PAM as a subroutine, hence can immediately benefit from these improvements), where the performance with high k becomes increasingly important. In experiments on real data with k=100, we observed a 200-fold speedup compared to the original PAM SWAP algorithm, making PAM applicable to larger data sets as long as we can afford to compute a distance matrix, and in particular to higher k (at k=2, the new SWAP was only 1.5 times faster, as the speedup is expected to increase with k)

Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.Comment: 14 pages, 4 figure

Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

International audienceBACKGROUND:Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.METHODS AND FINDINGS:We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.CONCLUSIONS:An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine

Knowledge and behaviour of nurse/midwives in the prevention of vertical transmission of HIV in Owerri, Imo State, Nigeria: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Mother-to-Child Transmission (MTCT) of HIV remains the main mode of acquisition of HIV in children. Transmission of HIV may occur during pregnancy, delivery or breastfeeding. Studies have shown that some specific interventions help to reduce the transmission of the virus to the baby. In order to target safe, rational and effective intervention to reduce MTCT of HIV, it is necessary to ensure that the nurse/midwife has knowledge of the strategies for the prevention of vertical transmission of HIV.</p> <p>Method</p> <p>The cross-sectional design was utilized to determine the knowledge and behaviour of nurse/midwives in the prevention of vertical transmission of HIV in Owerri, Imo State, Nigeria. The study sample consisted of 155 nurse/midwives drawn from three selected hospitals through stratified random sampling method. Official permission was obtained from the institutions and consent from participants. Data was collected through the use of a self administered questionnaire. Information sought included respondents' demographic characteristics, knowledge about and behaviour of prevention of vertical transmission as well as factors influencing behaviour.</p> <p>Results</p> <p>Findings revealed that nurse/midwives had moderate level of knowledge with mean score of 51.4%. The mean score on behaviour was 52.5%, major factors that influence behaviour in these settings were mainly fear of getting infected, irregular supply of resources like gloves, goggles, sharp boxes, and water supply was not regular also. Hypotheses tested revealed that there is a positive relationship between knowledge and behaviour (r = 0.583, p = 0.00). Knowledge level of nurse/midwives who had educational exposure was not different from those who did not (t = 1.439, p = 0.152). There was a significant difference in the knowledge of nurse/midwives who had experience in managing pregnant women living with HIV/AIDS and those who did not (t = 2.142, p = 0.03). Also, there was a significant relationship between behaviour and availability of resources (r = 0.318, p = 0.000).</p> <p>Conclusion</p> <p>The study revealed that the nurse/midwives though moderately knowledgeable still had gaps in certain areas. Their behaviours were fairly appropriate. There is need for improved knowledge through structured educational intervention. Resources needed for practice should always be made available and the environment should be much more conducive for practice.</p

Strategies to overcome physician shortages in northern Ontario: A study of policy implementation over 35 years

<p>Abstract</p> <p>Background</p> <p>Shortages and maldistibution of physicians in northern Ontario, Canada, have been a long-standing issue. This study seeks to document, in a chronological manner, the introduction of programmes intended to help solve the problem by the provincial government over a 35-year period and to examine several aspects of policy implementation, using these programmes as a case study.</p> <p>Methods</p> <p>A programme analysis approach was adopted to examine each of a broad range of programmes to determine its year of introduction, strategic category, complexity, time frame, and expected outcome. A chronology of programme initiation was constructed, on the basis of which an analysis was done to examine changes in strategies used by the provincial government from 1969 to 2004.</p> <p>Results</p> <p>Many programmes were introduced during the study period, which could be grouped into nine strategic categories. The range of policy instruments used became broader in later years. But conspicuous by their absence were programmes of a directive nature. Programmes introduced in more recent years tended to be more complex and were more likely to have a longer time perspective and pay more attention to physician retention. The study also discusses the choice of policy instruments and use of multiple strategies.</p> <p>Conclusion</p> <p>The findings suggest that an examination of a policy is incomplete if implementation has not been taken into consideration. The study has revealed a process of trial-and-error experimentation and an accumulation of past experience. The study sheds light on the intricate relationships between policy, policy implementation and use of policy instruments and programmes.</p

Host genetics determine susceptibility to avian influenza infection and transmission dynamics

Host-genetic control of influenza virus infection has been the object of little attention. In this study we determined that two inbred lines of chicken differing in their genetic background, Lines 0 and C-B12, were respectively relatively resistant and susceptible to infection with the low pathogenicity influenza virus A/Turkey/England/647/77 as defined by substantial differences in viral shedding trajectories. Resistant birds, although infected, were unable to transmit virus to contact birds, as ultimately only the presence of a sustained cloacal shedding (and not oropharyngeal shedding) was critical for transmission. Restriction of within-bird transmission of virus occurred in the resistant line, with intra-nares or cloacal infection resulting in only local shedding and failing to transmit fully through the gastro-intestinal-pulmonary tract. Resistance to infection was independent of adaptive immune responses, including the expansion of specific IFNγ secreting cells or production of influenza-specific antibody. Genetic resistance to a novel H9N2 virus was less robust, though significant differences between host genotypes were still clearly evident. The existence of host-genetic determination of the outcome of influenza infection offers tools for the further dissection of this regulation and also for understanding the mechanisms of influenza transmission within and between birds

Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts

Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K+) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K+) hearts (P < 0.01): this was prevented by treatment with lidocaine (10 μM, P < 0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P < 0.05) maximal gradients (from 0.55 ± 0.14 to 2.35 ± 0.67 in the epicardium and from 0.67 ± 0.13 to 1.87 ± 0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from −2.14 ± 0.52 ms to 50.93 ± 14.45 ms in the epicardium and from 8.14 ± 1.49 ms to 44.64 ± 5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P > 0.05) on either maximal gradients (0.78 ± 0.27 in the epicardium and 0.83 ± 0.45 in the endocardium) or critical DIs (6.06 ± 2.10 ms and 7.04 ± 3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P < 0.05) both these parameters (1.05 ± 0.30 in the epicardium and 0.89 ± 0.36 in the endocardium and 30.38 ± 8.88 ms in the epicardium and 31.65 ± 4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings

A proposed method to investigate reliability throughout a questionnaire

<p>Abstract</p> <p>Background</p> <p>Questionnaires are used extensively in medical and health care research and depend on validity and reliability. However, participants may differ in interest and awareness throughout long questionnaires, which can affect reliability of their answers. A method is proposed for "screening" of systematic change in random error, which could assess changed reliability of answers.</p> <p>Methods</p> <p>A simulation study was conducted to explore whether systematic change in reliability, expressed as changed random error, could be assessed using unsupervised classification of subjects by cluster analysis (CA) and estimation of intraclass correlation coefficient (ICC). The method was also applied on a clinical dataset from 753 cardiac patients using the Jalowiec Coping Scale.</p> <p>Results</p> <p>The simulation study showed a relationship between the systematic change in random error throughout a questionnaire and the slope between the estimated ICC for subjects classified by CA and successive items in a questionnaire. This slope was proposed as an awareness measure - to assessing if respondents provide only a random answer or one based on a substantial cognitive effort. Scales from different factor structures of Jalowiec Coping Scale had different effect on this awareness measure.</p> <p>Conclusions</p> <p>Even though assumptions in the simulation study might be limited compared to real datasets, the approach is promising for assessing systematic change in reliability throughout long questionnaires. Results from a clinical dataset indicated that the awareness measure differed between scales.</p

Mobility, Balance and Falls in Persons with Multiple Sclerosis

BACKGROUND: There is a lack of information concerning the relation between objective measures of gait and balance and fall history in persons with MS (PwMS). This investigation assessed the relation between demographic, clinical, mobility and balance metrics and falls history in persons with multiple sclerosis (MS). METHODS: 52 ambulatory persons with MS (PwMS) participated in the investigation. All persons provided demographic information including fall history over the last 12 months. Disease status was assessed with Expanded Disability Status Scale (EDSS). Walking speed, coordination, endurance and postural control were quantified with a multidimensional mobility battery. RESULTS: Over 51% of the participants fell in the previous year with 79% of these people being suffering recurrent falls. Overall, fallers were older, had a greater prevalence of assistive devices use, worse disability, decreased walking endurance, and greater postural sway velocity with eyes closed compared to non-fallers. Additionally, fallers had greater impairment in cerebellar, sensory, pyramidal, and bladder/bowel subscales of the EDSS. CONCLUSIONS: The current observations suggest that PwMS who are older, more disabled, utilize an assistive device, have decreased walking coordination and endurance and have diminished balance have fallen in the previous year. This suggests that individuals who meet these criteria need to be carefully monitored for future falls. Future research is needed to determine a prospective model of falls specific to PwMS. Additionally, the utility of interventions aimed at reducing falls and fall risk in PwMS needs to be established

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible