Could the clinical interpretability of subgroups detected using clustering methods be improved by using a novel two-stage approach?

Background: Recognition of homogeneous subgroups of patients can usefully improve prediction of their outcomes and the targeting of treatment. There are a number of research approaches that have been used to recognise homogeneity in such subgroups and to test their implications. One approach is to use statistical clustering techniques, such as Cluster Analysis or Latent Class Analysis, to detect latent relationships between patient characteristics. Influential patient characteristics can come from diverse domains of health, such as pain, activity limitation, physical impairment, social role participation, psychological factors, biomarkers and imaging. However, such 'whole person' research may result in data-driven subgroups that are complex, difficult to interpret and challenging to recognise clinically. This paper describes a novel approach to applying statistical clustering techniques that may improve the clinical interpretability of derived subgroups and reduce sample size requirements. Methods: This approach involves clustering in two sequential stages. The first stage involves clustering within health domains and therefore requires creating as many clustering models as there are health domains in the available data. This first stage produces scoring patterns within each domain. The second stage involves clustering using the scoring patterns from each health domain (from the first stage) to identify subgroups across all domains. We illustrate this using chest pain data from the baseline presentation of 580 patients. Results: The new two-stage clustering resulted in two subgroups that approximated the classic textbook descriptions of musculoskeletal chest pain and atypical angina chest pain. The traditional single-stage clustering resulted in five clusters that were also clinically recognisable but displayed less distinct differences. Conclusions: In this paper, a new approach to using clustering techniques to identify clinically useful subgroups of patients is suggested. Research designs, statistical methods and outcome metrics suitable for performing that testing are also described. This approach has potential benefits but requires broad testing, in multiple patient samples, to determine its clinical value. The usefulness of the approach is likely to be context-specific, depending on the characteristics of the available data and the research question being asked of it

Measuring enteric methane emissions from individual ruminant animals in their natural environment

Ruminant livestock are an important source of meat, milk, fiber, and labor for humans. The process by which ruminants digest plant material through rumen fermentation into useful product results in the loss of energy in the form of methane gas from consumed organic matter. The animal removes the methane building up in its rumen by repeated eructations of gas through its mouth and nostrils. Ruminant livestock are a notable source of atmospheric methane, with an estimated 17% of global enteric methane emissions from livestock. Historically, enteric methane was seen as an inefficiency in production and wasted dietary energy. This is still the case, but now methane is seen more as a pollutant and potent greenhouse gas. The gold standard method for measuring methane production from individual animals is a respiration chamber, which is used for metabolic studies. This approach to quantifying individual animal emissions has been used in research for over 100 years; however, it is not suitable for monitoring large numbers of animals in their natural environment on commercial farms. In recent years, several more mobile monitoring systems discussed here have been developed for direct measurement of enteric methane emissions from individual animals. Several factors (diet composition, rumen microbial community, and their relationship with morphology and physiology of the host animal) drive enteric methane production in ruminant populations. A reliable method for monitoring individual animal emissions in large populations would allow (1) genetic selection for low emitters, (2) benchmarking of farms, and (3) more accurate national inventory accounting

The Prevalence of Natural Health Product Use in Patients with Acute Cardiovascular Disease

Background: Natural health products (NHP) use may have implications with respect to adverse effects, drug interactions and adherence yet the prevalence of NHP use by patients with acute cardiovascular disease and the best method to ascertain this information is unknown. Objective: To identify the best method to ascertain information on NHP, and the prevalence of use in a population with acute cardiovascular disease. Methods: Structured interviews were conducted with a convenience sample of consecutive patients admitted with acute cardiovascular disease to the University of Alberta Hospital during January 2009. NHP use was explored using structured and open-ended questions based on Health Canada’s definition of NHP. The medical record was reviewed, and documentation of NHP use by physicians, nurses, and pharmacists, compared against the gold-standard structured interview. Results: 88 patients were interviewed (mean age 62 years, standard deviation [SD 14]; 80 % male; 41 % admitted for acute coronary syndromes). Common co-morbidities included hypertension (59%), diabetes (26%) and renal impairment (19%). NHP use was common (78 % of patients) and 75 % of NHP users reported daily use. The category of NHP most commonly used was vitamins and minerals (73%) followed by herbal products (20%), traditional medicines including Chines

Turbulent flow as a cause for underestimating coronary flow reserve measured by Doppler guide wire

BACKGROUND: Doppler-tipped coronary guide-wires (FW) are well-established tools in interventional cardiology to quantitatively analyze coronary blood flow. Doppler wires are used to measure the coronary flow velocity reserve (CFVR). The CFVR remains reduced in some patients despite anatomically successful coronary angioplasty. It was the aim of our study to test the influence of changes in flow profile on the validity of intra-coronary Doppler flow velocity measurements in vitro. It is still unclear whether turbulent flow in coronary arteries is of importance for physiologic studies in vivo. METHODS: We perfused glass pipes of defined inner diameters (1.5 – 5.5 mm) with heparinized blood in a pulsatile flow model. Laminar and turbulent flow profiles were achieved by varying the flow velocity. The average peak velocity (APV) was recorded using 0.014 inch FW. Flow velocity measurements were also performed in 75 patients during coronary angiography. Coronary hyperemia was induced by intra-coronary injection of adenosine. The APV maximum was taken for further analysis. The mean luminal diameter of the coronary artery at the region of flow velocity measurement was calculated by quantitative angiography in two orthogonal planes. RESULTS: In vitro, the measured APV multiplied with the luminal area revealed a significant correlation to the given perfusion volumes in all diameters under laminar flow conditions (r(2 )> 0.85). Above a critical Reynolds number of 500 – indicating turbulent flow – the volume calculation derived by FW velocity measurement underestimated the actual rate of perfusion by up to 22.5 % (13 ± 4.6 %). In vivo, the hyperemic APV was measured irrespectively of the inherent deviation towards lower velocities. In 15 of 75 patients (20%) the maximum APV exceeded the velocity of the critical Reynolds number determined by the in vitro experiments. CONCLUSION: Doppler guide wires are a valid tool for exact measurement of coronary flow velocity below a critical Reynolds number of 500. Reaching a coronary flow velocity above the velocity of the critical Reynolds number may result in an underestimation of the CFVR caused by turbulent flow. This underestimation of the flow velocity may reach up to 22.5 % compared to the actual volumetric flow. Cardiologists should consider this phenomena in at least 20 % of patients when measuring CFVR for clinical decision making

Neighborhood built environment and physical activity of Japanese older adults: results from the Aichi Gerontological Evaluation Study (AGES)

<p>Abstract</p> <p>Background</p> <p>Although many studies have reported the association between neighborhood built environment (BE) and physical activity (PA), less is known about the associations for older populations or in countries besides the US and Australia. The aim of this paper is to examine the associations for older adult populations in Japan.</p> <p>Methods</p> <p>Our analyses were based on cross-sectional data from the Aichi Gerontological Evaluation Study (AGES), conducted in 2003. The respondents were older adults, aged 65 years or over (n = 9,414), from 8 municipalities across urban, suburban, and rural areas. The frequency of leisure time sports activity and total walking time were used as the outcome variables. Using geographic information systems (GIS), we measured residential density, street connectivity, number of local destinations, access to recreational spaces, and land slope of the respondents' neighborhoods, based on network distances with multiple radii (250 m, 500 m, 1,000 m). An ordinal logistic regression model was used to analyze the association between PA and BE measures.</p> <p>Results</p> <p>Population density and presence of parks or green spaces had positive associations with the frequency of sports activity, regardless of the selected buffer zone. The analysis of total walking time, however, showed only a few associations.</p> <p>Conclusions</p> <p>Our findings provide mixed support for the association between PA and the characteristics of BE measures, previously used in Western settings. Some characteristics of the neighborhood built environment may facilitate leisure time sports activity, but not increase the total walking time for Japanese older adults.</p

From papers to practices: district level priority setting processes and criteria for family planning, maternal, newborn and child health interventions in Tanzania

Contains fulltext : 97928.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Successful priority setting is increasingly known to be an important aspect in achieving better family planning, maternal, newborn and child health (FMNCH) outcomes in developing countries. However, far too little attention has been paid to capturing and analysing the priority setting processes and criteria for FMNCH at district level. This paper seeks to capture and analyse the priority setting processes and criteria for FMNCH at district level in Tanzania. Specifically, we assess the FMNCH actor's engagement and understanding, the criteria used in decision making and the way criteria are identified, the information or evidence and tools used to prioritize FMNCH interventions at district level in Tanzania. METHODS: We conducted an exploratory study mixing both qualitative and quantitative methods to capture and analyse the priority setting for FMNCH at district level, and identify the criteria for priority setting. We purposively sampled the participants to be included in the study. We collected the data using the nominal group technique (NGT), in-depth interviews (IDIs) with key informants and documentary review. We analysed the collected data using both content analysis for qualitative data and correlation analysis for quantitative data. RESULTS: We found a number of shortfalls in the district's priority setting processes and criteria which may lead to inefficient and unfair priority setting decisions in FMNCH. In addition, participants identified the priority setting criteria and established the perceived relative importance of the identified criteria. However, we noted differences exist in judging the relative importance attached to the criteria by different stakeholders in the districts. CONCLUSIONS: In Tanzania, FMNCH contents in both general development policies and sector policies are well articulated. However, the current priority setting process for FMNCH at district levels are wanting in several aspects rendering the priority setting process for FMNCH inefficient and unfair (or unsuccessful). To improve district level priority setting process for the FMNCH interventions, we recommend a fundamental revision of the current FMNCH interventions priority setting process. The improvement strategy should utilize rigorous research methods combining both normative and empirical methods to further analyze and correct past problems at the same time use the good practices to improve the current priority setting process for FMNCH interventions. The suggested improvements might give room for efficient and fair (or successful) priority setting process for FMNCH interventions

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

OBJECTIVE: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. METHODS: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. RESULTS: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. CONCLUSIONS: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant

Gemcitabine twice weekly as a radiosensitiser for the treatment of brain metastases in patients with carcinoma: a phase I study

Conventional treatment for brain metastases (BM) is whole-brain radiotherapy (WBRT). Efficacy is poor. It might be increased by a potent radiosensitiser such as gemcitabine which is believed to cross the disrupted blood–brain barrier. Primary objective of this study was to determine the maximum tolerated dose (MTD) of twice weekly gemcitabine given concurrently with WBRT. Patients with BM from carcinoma were included. The dose of WBRT was 30 Gys (10 daily fractions). Gemcitabine was given 2–4 h prior to WBRT on days 1 and 8 for the first cohort of patients and then on days 1, 4, 8 and 11. Starting dose was 25 mg m−2, escalated by 12.5 mg m−2 increments. At least three patients were included per level. Dose limiting toxicity (DLT) was defined as grade 4 haematological or grade ⩾3 nonhaematological toxicity. A total of 25 patients were included; 74% had a PS 1 (ECOG). In all, 23 had non-small-cell lung cancer, six colorectal, four breast, two renal cell and one oesophageal carcinoma. A total of 92% had concurrent extracranial disease. Six had single BM, 13 had two or three BM and six multiple. Up to 50 mg m−2 (level 4) no DLT was observed. At 62.5 mg m−2, one out of six patients developed DLT (thrombocytopenia-bleeding). The next dose level (75 mg m−2) was abandoned after grade 4 bone marrow toxicity (fatal neutropenic sepsis) was seen in one out of two patients. So that the dose of 50 mg m−2 will be taken forward for further study

Ethics and Nanopharmacy: Value Sensitive Design of New Drugs

Although applications are being developed and have reached the market, nanopharmacy to date is generally still conceived as an emerging technology. Its concept is ill-defined. Nanopharmacy can also be construed as a converging technology, which combines features of multiple technologies, ranging from nanotechnology to medicine and ICT. It is still debated whether its features give rise to new ethical issues or that issues associated with nanopharma are merely an extension of existing issues in the underlying fields. We argue here that, regardless of the alleged newness of the ethical issues involved, developments occasioned by technological advances affect the roles played by stakeholders in the field of nanopharmacy to such an extent that this calls for a different approach to responsible innovation in this field. Specific features associated with nanopharmacy itself and features introduced to the associated converging technologies- bring about a shift in the roles of stakeholders that call for a different approach to responsibility. We suggest that Value Sensitive Design is a suitable framework to involve stakeholders in addressing moral issues responsibly at an early stage of development of new nanopharmaceuticals