Search PubMed⌕ Search

Biomedical subjects

Brian D M Tom

Publications and source records attributed to Brian D M Tom.

12 recordsLinked to original sources
PubMed2024

Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.

OBJECTIVES: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis. METHODS: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis. RESULTS: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space. CONCLUSIONS: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.

Humans↗
PubMed2005

Quality determination and the repair of poor quality spots in array experiments.

BACKGROUND: A common feature of microarray experiments is the occurrence of missing gene expression data. These missing values occur for a variety of reasons, in particular, because of the filtering of poor quality spots and the removal of undefined values when a logarithmic transformation is applied to negative background-corrected intensities. The efficiency and power of an analysis performed can be substantially reduced by having an incomplete matrix of gene intensities. Additionally, most statistical methods require a complete intensity matrix. Furthermore, biases may be introduced into analyses through missing information on some genes. Thus methods for appropriately replacing (imputing) missing data and/or weighting poor quality spots are required. RESULTS: We present a likelihood-based method for imputing missing data or weighting poor quality spots that requires a number of biological or technical replicates. This likelihood-based approach assumes that the data for a given spot arising from each channel of a two-dye (two-channel) cDNA microarray comparison experiment independently come from a three-component mixture distribution--the parameters of which are estimated through use of a constrained E-M algorithm. Posterior probabilities of belonging to each component of the mixture distributions are calculated and used to decide whether imputation is required. These posterior probabilities may also be used to construct quality weights that can down-weight poor quality spots in any analysis performed afterwards. The approach is illustrated using data obtained from an experiment to observe gene expression changes with 24 hr paclitaxel (Taxol) treatment on a human cervical cancer derived cell line (HeLa). CONCLUSION: As the quality of microarray experiments affect downstream processes, it is important to have a reliable and automatic method of identifying poor quality spots and arrays. We propose a method of identifying poor quality spots, and suggest a method of repairing the arrays by either imputation or assigning quality weights to the spots. This repaired data set would be less biased and can be analysed using any of the appropriate statistical methods found in the microarray literature.

Algorithms↗
PubMed2005

Fusing microarray experiments with multivariate regression.

MOTIVATION: It is widely acknowledged that microarray data are subject to high noise levels and results are often platform dependent. Therefore, microarray experiments should be replicated several times and in several laboratories before the results can be relied upon. To make the best use of such extensive datasets, methods for microarray data fusion are required. Ideally, the fused data should distil important aspects of the data while suppressing unwanted sources of variation and be amenable to further informal and formal methods of analysis. Also, the variability in the quality of experimentation should be taken into account. RESULTS: We present such an approach to data fusion, based on multivariate regression. We apply our methodology to data from a previous study on cell-cycle control in Schizosaccharomyces pombe. AVAILABILITY: The algorithm implemented in R is freely available from the authors on request.

Algorithms↗
PubMed2005

Conservation of unique cell-surface CD antigen mosaics in HIV-1-infected individuals.

Cluster of differentiation (CD) antigens are expressed on cells of myeloid and lymphoid lineages. As most disease processes involve immune system activation or suppression, these antigens offer unique opportunities for monitoring host responses. Immunophenotyping using limited numbers of CD antigens enables differentiation states of immune system cells to be determined. Extended phenotyping involving parallel measurement of multiple CD antigens may help identify expression pattern signatures associated with specific disease states. To explore this possibility we have made a CD monoclonal antibody array and scanner, enabling the parallel immunophenotyping of leukocyte cell suspensions in a single and rapid analysis. To demonstrate this approach, we used the specific example of patients infected with human immunodeficiency virus type-1 (HIV-1). An invariant HIV-induced CD antigen signature has been defined that is both robust and independent of clinical outcome, composed of a unique profile of CD antigen expression levels that are both increased and decreased relative to internal controls. The results indicate that HIV-induced changes in CD antigen expression are disease specific and independent of outcome. Their invariant nature indicates an irreversible component to retroviral infection and suggests the utility of CD antigen expression patterns in other disease settings.

Antibodies, Monoclonal↗
PubMed2004

Is there disparity between risk and incidence of cardiovascular disease after liver transplant?

BACKGROUND: Hypertension and hypercholesterolemia are recognized complications of liver transplantation, but whether they contribute to the development of cardiovascular disease is uncertain. We aimed first to determine the prevalence of risk factors for coronary heart disease (CHD) after liver transplantation and second to study the effect of liver transplantation on the predicted 10-year risk of developing CHD and the incidence of cardiovascular events in comparison with a matched local population. METHODS: Data on blood pressure, serum lipids, weight, diabetes mellitus, smoking, and incidence of myocardial infarction (MI) and stroke were obtained retrospectively from the case notes of 181 consecutive adult liver transplant recipients (median follow-up 54 months). The Framingham coronary risk equations were used to calculate the 10-year probability of developing CHD. RESULTS: The prevalences of hypertension and hypercholesterolemia after transplantation were 77% and 62%, respectively. The predicted 10-year risk of CHD increased from 6.9% before transplantation to 11.5% at 1 year after transplantation, whereas that of a matched local population was 7%. Compared with a matched nontransplant population, the incidence ratios for MI and stroke were 0.55 (95% confidence interval, 0.01-3.06 ) and 1.45 (95% confidence interval, 0.18-5.22), respectively. No patients died from MI or stroke. CONCLUSIONS: Liver transplant recipients have a high prevalence of risk factors for cardiovascular disease, exceeding that of the general population, and have a higher predicted risk of developing CHD. Despite this, there were no deaths from CHD or stroke during the study period.

Adolescent↗
PubMed2004

Ectopic pregnancy diagnosis and the pseudo-sac.

OBJECTIVE: To evaluate the impact of an ultrasound finding of a pseudo-sac (PS), a uterine sac without a double decidual ring or a yolk sac, on the management of cases with possible ectopic pregnancy. DESIGN: A retrospective review of a series of cases. SETTING: A general hospital. PATIENT(S): Seventy-seven patients who had a diagnostic laparoscopy over a period of 3 years for suspected ectopic pregnancy. MAIN OUTCOME MEASURE(S): A logistic regression analysis was conducted to evaluate the effect of the ultrasound finding of a PS on predicting a negative finding at laparoscopy. RESULT(S): The report of a PS is significantly associated with a false-positive diagnosis of ectopic pregnancy. CONCLUSION(S): A diagnosis of PS should not be interpreted as indicative of an ectopic pregnancy because radiological differentiation between an early intrauterine pregnancy failure and an ectopic pregnancy is not possible.

False Positive Reactions↗
PubMed2004

Variation in thresholds for reporting mobility disability between national population subgroups and studies.

BACKGROUND: Disability questions require older people to report difficulties with everyday activities, using broad categorical responses. Relatively little is known about population group differences in the thresholds for reporting difficulty or inability with medium-distance mobility against tested mobility-related performance. We aimed to estimate the thresholds on tested performance at which self-reports change from one category to another, across a range of sociodemographic subgroups. We also aimed to compare reported and tested performance across two national population studies. METHODS: The samples were from the third U.S. National Health and Nutrition Examination Study (NHANES III) and the Longitudinal Aging Study Amsterdam (LASA). Measures of gait speed, chair stands, and peak expiratory flow rate in both studies yielded the validated index of mobility-related physical limitations (MOBLI). Latent probit models were used to estimate cutpoints (thresholds) on the index for reporting difficulty or inability to walk a medium distance. RESULTS: Thresholds for reporting difficulty or inability were studied by age, sex, race, educational level, and income in NHANES III. In models adjusting for the other factors, performance thresholds for reporting disability categories varied by age and income. The younger elderly persons in NHANES III on average reported difficulties or inabilities only when they reached a more severe level of tested limitation compared with older old persons. A similar pattern exists for those on higher incomes. For race, differences in threshold were present only for reporting inability, but not difficulty. Significant differences in thresholds were not present between groups defined by sex or for years of education. Comparisons between the NHANES and LASA studies show that lower reported mobility difficulty or inability prevalence in the Dutch sample is attributable both to reporting at higher levels of limitation and to better functioning. CONCLUSIONS: There is evidence of differences in thresholds for reporting mobility disability, especially across age and income groups in older Americans. Further work is needed to understand the perceptual, attitudinal, or environmental factors that cause these reporting differences.

Activities of Daily Living↗
PubMed2003

Endothelial cells preparing to die by apoptosis initiate a program of transcriptome and glycome regulation.

The protein-based changes that underlie the cell biology of apoptosis have been extensively studied. In contrast, mRNA- and polysaccharide-based changes have received relatively little attention. We have combined transcriptome and glycome analyses to show that apoptotic endothelial cell cultures undergo programmed changes to RNA transcript abundance and cell surface polysaccharide profiles. Although a few of the transcriptome changes were protective, most appeared to prepare cells for apoptosis by decreasing the reception and transduction of pro-survival signals, increasing pro-death signals, increasing abundance of apoptotic machinery, inhibiting cellular proliferation, recruiting phagocytes to regions of cell death, and promoting phagocytosis. Additional transcriptomal changes appeared to alter the synthesis and modification of cell surface glycosaminoglycans. The resultant reduced abundance of sulphated cell surface glycosaminoglycans may further promote cell death by inhibiting the presentation of extracellular matrix-tethered survival factors to their receptors on dying cells. We propose that the transcriptome and glycome regulation presented here synergize with previously described protein-based changes to guide the apoptotic program.

Apoptosis↗
PubMed2003

Antiangiogenic agents are effective inhibitors of endometriosis.

Endometriosis is a disease in which the lining of the uterus (endometrium), shed at the time of menstruation, becomes established at sites such as the peritoneum and ovaries. These explants develop a rich blood supply that enables them to survive and grow. We hypothesized that inhibitors of angiogenesis would prevent this growth by disrupting sensitive vessels supplying endometriotic lesions. Vessels sensitive to angiogenic antagonism have few associations with pericyte cells. The vessels supplying human endometriotic lesions were immunohistochemically characterized and found to be predominantly pericyte free. A model in which human endometrium is implanted into nude mice was used to test the effects of two antagonists of the angiogenic growth factor, vascular endothelial cell growth factor A. Soluble truncated receptor (flt-1; P = 0.002) and an affinity-purified antibody to human vascular endothelial cell growth factor A (P = 0.03) significantly inhibited the growth of nude mouse explants. Pericyte-free vessels were shown to supply endometrial lesions in nude mice and were disrupted in lesions taken from soluble flt-1-treated mice. In summary, antiangiogenic agents inhibited the growth of explants in an in vivo model of endometriosis by disrupting the vascular supply, and this effect is likely to apply to the human disease. These findings suggest that antiangiogenic agents may provide a novel therapeutic approach for the treatment of endometriosis.

Angiogenesis Inhibitors↗
PubMed2002

Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation.

BACKGROUND/AIMS: Increased rates of bone loss and fracture have been reported after liver transplantation. The aim of this study was to investigate the effects of a pre-transplant infusion of pamidronate on fracture incidence and bone loss during the first year after transplantation. METHODS: Ninety-nine adults awaiting orthotopic liver transplantation (OLT) were randomised to pamidronate or no treatment. Spinal X-rays were obtained at baseline and after 12 months. Bone mineral density (BMD) was measured at the lumbar spine (L1-4) and femoral neck at baseline, and 3, 6, and 12 months after OLT. RESULTS: The incidence of fractures in the first year after OLT was 8%, four patients within the pamidronate treated group and two in the untreated group developing fractures (P=0.40). No significant spinal bone loss occurred in either group during the first year. However, significant and sustained bone loss occurred at the femoral neck in both groups. No significant differences were seen between pamidronate treated or untreated groups at either site. CONCLUSIONS: Pamidronate in the regimen used had no significant effect on fracture rate or BMD post-transplant. The low incidence of fracture and absence of spinal bone loss indicate that bone disease after liver transplantation may be less common than previously reported.

Adult↗
PubMed2002

Performance tests and disability: developing an objective index of mobility-related limitation in older populations.

BACKGROUND: Disability reflects physiological limitations, social and environmental barriers, and "sickness" behavior. Being able to measure these influences separately would greatly assist interpretation of disability comparisons over time or between populations. This study aimed to identify an index of mobility-related limitations composed of physiological measures that are most closely associated with reported mobility disability in elders. METHODS: Data from the Third National Health and Nutrition Examination Survey (NHANES III) were used. Participants aged 60 and older were included in this analysis. Participants included 6596 respondents who were interviewed in their homes, and 5724 (87%) of these attended a further examination. Domains of measurements included body measurements, bone densitometry, physical examination, spirometry, fundus photography, and physical performance measures. Multivariate models were developed on a random half subsample of the data and were validated on the other half. Receiver operating characteristic (ROC) areas and logit rank slopes were used to evaluate sets of measures. RESULTS: In weighted logistic regression models, six and five measures were significantly associated with difficulty and inability in walking a quarter of a mile, respectively. These mainly included measures of lower extremity and lung function. A relatively minimal loss of sensitivity and specificity occurred from using more economical models, employing a subset of the identified measures. CONCLUSIONS: Subsets of measures associated with reported mobility disability could provide objective indices of mobility-related limitation for comparing populations or long-term population health monitoring.

Aged↗