Biomedical subjects

L M McShane

Publications and source records attributed to L M McShane.

At least 19 recordsLinked to original sources

PubMed2006

Reporting recommendations for tumor marker prognostic studies (remark).

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often, initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute - European Organisation for Research and Treatment of Cancer (NCI - EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Biomarkers, Tumor↗

PubMed2005

REporting recommendations for tumour MARKer prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Biomarkers, Tumor↗

PubMed2002

Identifying pre-post chemotherapy differences in gene expression in breast tumours: a statistical method appropriate for this aim.

Although widely used for the analysis of gene expression microarray data, cluster analysis may not be the most appropriate statistical technique for some study aims. We demonstrate this by considering a previous analysis of microarray data obtained on breast tumour specimens, many of which were paired specimens from the same patient before and after chemotherapy. Reanalysing the data using statistical methods that appropriately utilise the paired differences for identification of differentially expressed genes, we find 17 genes that we can confidently identify as more expressed after chemotherapy than before. These findings were not reported by the original investigators who analysed the data using cluster analysis techniques.

Antineoplastic Agents↗

PubMed2001

Covariate measurement error adjustment for matched case-control studies.

We propose a conditional scores procedure for obtaining bias-corrected estimates of log odds ratios from matched case-control data in which one or more covariates are subject to measurement error. The approach involves conditioning on sufficient statistics for the unobservable true covariates that are treated as fixed unknown parameters. For the case of Gaussian nondifferential measurement error, we derive a set of unbiased score equations that can then be solved to estimate the log odds ratio parameters of interest. The procedure successfully removes the bias in naive estimates, and standard error estimates are obtained by resampling methods. We present an example of the procedure applied to data from a matched case-control study of prostate cancer and serum hormone levels, and we compare its performance to that of regression calibration procedures.

Bias↗

PubMed2001

Latent class modeling approaches for assessing diagnostic error without a gold standard: with applications to p53 immunohistochemical assays in bladder tumors.

Improved characterization of tumors for purposes of guiding treatment decisions for cancer patients will require that accurate and reproducible assays be developed for a variety of tumor markers. No gold standards exist for most tumor marker assays. Therefore, estimates of assay sensitivity and specificity cannot be obtained unless a latent class model-based approach is used. Our goal in this article is to estimate sensitivity and specificity for p53 immunohistochemical assays of bladder tumors using data from a reproducibility study conducted by the National Cancer Institute Bladder Tumor Marker Network. We review latent class modeling approaches proposed by previous authors, and we find that many of these approaches impose assumptions about specimen heterogeneity that are not consistent with the biology of bladder tumors. We present flexible mixture model alternatives that are biologically plausible for our example, and we use them to estimate sensitivity and specificity for our p53 assay example. These mixture models are shown to offer an improvement over other methods in a variety of settings, but we caution that, in general, care must be taken in applying latent class models.

Diagnostic Errors↗

PubMed2000

Measuring cell proliferation in the rectal mucosa. comparing bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA) assays.

Cell proliferation in the human colorectum can be measured using bromodeoxyuridine (BrdU) or proliferating cell nuclear antigen (PCNA) assays. Using data from the National Cancer Institute's Polyp Prevention Trial, these two assays are compared using correlation coefficients and variance components analysis. Adjusting for fixed as well as for the random effects of between-biopsy and scoring variation, the estimated correlation is 0.46 for the log labeling index and 0.45 for log proliferative height. This is an estimate of the highest correlation that can be achieved by taking multiple biopsies scored by multiple scorers. For single biopsies, the estimated correlation is 0.16 and 0.10, respectively. There are significant differences between the variance components for the two assays. For example, for log labeling index, PCNA has a lower variation between biopsies than BrdU, but higher variation between scorings. When used in a clinical or epidemiological setting, it is important to take multiple biopsies at multiple time points.

Adenoma↗

PubMed2000

Statistical issues in tumor marker studies.

CONTEXT: Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. OBJECTIVE: To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. RESULTS: Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. CONCLUSION: Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources.

Biomarkers, Tumor↗

PubMed2000

Reproducibility of p53 immunohistochemistry in bladder tumors. National Cancer Institute, Bladder Tumor Marker Network.

The National Cancer Institute Bladder Tumor Marker Network conducted a study to evaluate the reproducibility of immunohistochemistry for measuring p53 expression in bladder tumors. Fifty paraffin blocks (10 from each of the five network institutions) were chosen at random from among high-grade invasive primary bladder tumors. Two sections from each block were sent to each laboratory for staining and scoring, and then all sections were randomly redistributed among the laboratories for a second scoring. Intra- and interlaboratory reproducibility was assessed with regard to both staining and scoring. For overall assessments of p53 positivity, the results demonstrated that intralaboratory reproducibility was quite good. Concordance across the five participating laboratories was high for specimens exhibiting no or minimal nuclear immunostaining of tumor cells or high percentages of tumor cells with nuclear immunoreactivities. However, there was a reduced level of concordance on specimens with percentages of stained tumor cells in an intermediate range. The discordancies were due mainly to staining differences in one of the five laboratories and scoring differences in another laboratory. These results indicate that some caution must be used in comparing results across studies from different groups. Standardization of staining protocols and selection of a uniform threshold for binary interpretation of results may improve assay reproducibility between laboratories.

Analysis of Variance↗

PubMed1999

Cytokine and immunoglobulin concentrations in cervical secretions: reproducibility of the Weck-cel collection instrument and correlates of immune measures.

Elucidation of local immune response at the cervix is important for understanding and evaluating STD vaccine approaches currently being proposed. However, no well-validated method exists for the collection of cervical secretions for evaluation of cervical immune response. The purpose of this study was to determine the reproducibility of the Weck-cel sponge used to collect cervical secretions for immunological assessment. Additionally, it was possible to examine correlates of immunity as part of our investigation. Two cervical secretion specimens were collected sequentially from each of 120 women using Weck-cel sponges. Cervical secretions were collected prior to Pap smear sampling to avoid blood contamination. At the laboratory, the duplicate specimens were weighed and tested in replicate wells to determine the concentration of two cytokines (IL-10 and IL-12) and two immunoglobulin isotypes (IgG and IgA). IL-12, total IgG, and total IgA showed a strong correlation between samples from the same woman ranging from 0.78 to 0.84. Kappa coefficients obtained after categorizing assay results ranged from 0.62 to 0.67. Variance components analysis suggested that 69% to 85% of the variance observed was accounted for by between-women variance, with the remaining variability attributed to variation between samples collected from the same woman. IL-10 results were less reproducible than those obtained from the other assays examined, suggesting problems with the assay used to measure this cytokine rather than with the Weck-cel sampling instrument. Various factors were found to significantly correlate with cytokine and immunoglobulin measures at the cervix. Age and reproductive status were associated with all four immune measures; women over 50 years of age and those who were postmenopausal had increased concentrations of IL-10, IL-12, IgG, and IgA. Hemoglobin concentrations were positively correlated with IgG and IL-10 concentrations, but not with IgA or IL-12 concentrations, suggesting local production of IgA and IL-12. The concentration of all immune measures decreased with increasing volume of collection. No significant association was observed between time from collection to freezing of specimens and concentrations of cytokines or immunoglobulins. Overall, our data suggest that measurement of immunological parameters in cervical secretions collected using Weck-cel sponges are reproducible. In addition, various correlates of cytokine and immunoglobulin concentrations were identified.

Adult↗

PubMed1998

An evaluation of rectal mucosal proliferation measure variability sources in the polyp prevention trial: can we detect informative differences among individuals' proliferation measures amid the noise?

We assessed components of total variability of bromodeoxyuridine (BrdUrd) and proliferating cell nuclear antigen (PCNA) assays of rectal mucosal proliferation in a subset of 390 participants from the U. S. National Cancer Institute's multicenter Polyp Prevention Trial. Biopsies were blindly double-scored by two technicians. For those participants for whom at least one evaluable biopsy was obtained, a mean of 2.0 and 2.6 biopsies, and 6.2 and 8.7 crypts/biopsy were evaluated, respectively, with the BrdUrd and PCNA assays. Factors such as clinical center, scorer, and month of biopsy collection significantly affected the observed values of the labeling index (LI) and proliferative height (PH). Therefore, it is essential to control or adjust for these variables in proliferation studies. Sources of random variation for LI and PH measures remaining after the aforementioned factors include between-participant variation and several sources of within-participant variation, including variation over time, between biopsies, and between multiple measurements on the same biopsy. Both LI and PH measurements exhibited substantial variability over time, between biopsies, and from reading-to-reading of the same biopsy. When other sources of variability have been accounted for, the PCNA LI seems to have little between-participant variation. This brings into question its utility as a marker in colorectal cancer studies. The PCNA PH showed significant between-participant variability and may hold some promise as a useful marker in colorectal cancer studies. Results for BrdUrd were less conclusive. The BrdUrd LI showed marginally significant between-participant variation, whereas the corresponding variation for PH was nonsignificant.

Adult↗

PubMed1998

Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland.

Several lines of evidence suggest that sex hormones may be involved in the etiology of prostate cancer. We conducted a prospective nested case-control study to evaluate the relationships of serum androgens and estrogens to prostate cancer using serum collected at baseline for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The 29,133 male smokers who participated in the trial were 50-69 years old at baseline. During 5-8 years of follow-up, 246 men were diagnosed with prostate cancer, and 116 of these were randomly selected for inclusion in the current study. For each case, two controls matched on age, date of blood collection, intervention group, and study center were selected. Hormones were measured in serum by RIA using standard procedures. None of the individual androgens or estrogens was significantly related to prostate cancer. These findings were unaltered by simultaneous evaluation of serum androgen and estrogen concentrations in multivariate models. These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers. Within-person variation in concentrations of some hormones may have contributed to the lack of significant associations.

Aged↗

PubMed1997

A comparison of spatial prediction techniques for an exploratory analysis of human cortical motor representations.

We compare the use of two-dimensional Laplacian smoothing splines and median polish kriging for an exploratory analysis of spatial data sets. Splines were developed originally for modelling a process with determinstic mean structure, while median polish kriging was developed for predicting a spatial random process. We review the fundamentals of both methods, including smoothing parameter selection for splines and variogram estimation and solving the kriging equations for median polish kriging. We demonstrate application of the methods on maps of muscle representations on the human motor cortex (cortical maps). After applying both methods to 20 cortical maps (left and right hemispheres on each of 10 subjects), we compare the fitted surfaces on the basis of predictive ability, aesthetic appeal, and ease of computation.

Analysis of Variance↗

PubMed1997

Timing of onset of afferent responses and of use of kinesthetic information for control of movement in normal and cerebellar-impaired subjects.

A coordinated triggering task requiring use of kinesthetic information was employed to assess the timing of use of kinesthetic information in normal subjects and patients with cerebellar dysfunction. Passive movements of varying velocity were imposed in the flexor direction about the metacarpophalangeal joint of the right index finger. Subjects attempted to depress a switch with their left thumb when the index finger moved past a specified angle that was learned during a training session. The velocities ranged from 10 degrees/s to 88 degrees/s in 2 degrees/s increments. After 200 trials, subjects were then instructed instead to react as quickly as possible (reaction-time task) to the onset of movement for an additional 200 trials. For the same movements, the timing of onset of responses of muscle spindle afferents and cutaneous mechanoreceptors was determined by recording the responses of these afferents using microneurography. For slow velocities, patients were able to perform similarly to normals but at faster velocities patients triggered too late compared with normals. Patients required more time to use kinesthetic information than did normal subjects. An estimate of kinesthetic processing was not longer in patients. The chief explanation for the prolonged time required to use kinesthetic information in patients was that their reaction times were prolonged by 93 ms. In addition, the movement time was also prolonged, but this accounted for only 23 ms. Impaired motor performance in tasks requiring the use of kinesthetic information in cerebellar patients can be explained largely by their prolonged reaction times. Muscle spindle afferents responded on average much sooner than cutaneous mechanoreceptors. Because of the limited time available to perform the kinesthetic triggering task, the role for cutaneous mechanoreceptors to provide signals for on-line coordination of movement appears limited compared with muscle spindle afferents.

Action Potentials↗

PubMed1997

A latent process regression model for spatially correlated count data.

This paper proposes a regression model for spatially correlated count data that generalizes the work of Zeger (1988, Biometrika 75, 621-629) developed in a time-series setting. In this approach, spatial correlation is introduced through a latent process, and the marginal mean function may contain spatial trends and covariates. Generalized estimating equations are used to estimate and perform marginal inference on the spatial trend and covariate effects. The feasibility of this approach is demonstrated using an example of the distribution of neuronal cell counts in a laboratory culture dish.

Animals↗

PubMed1996

Reliability and validity of serum sex hormone measurements.

The laboratory reliability and validity of sex hormone measurements were examined at multiple levels, including lower levels characteristic of children and postmenopausal women. Serum was drawn from four adult male and four adult female healthy volunteers. From each individual's serum pool, a medium- and a low-dilution pool were created. Biochemical analyses for total and non-sex hormone-binding globulin (SHBG)-bound estradiol, estrone, estrone sulfate, progesterone, and SHBG were performed on female samples. Male samples were analyzed for total and non-SHBG-bound testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone sulfate. Two aliquots from each pool were assayed twice in each of two labs. All assays except SHBG in one lab used RIA procedures. Reliability was assessed by variance components analyses and estimated coefficients of variation (CVs). Validity was assessed by comparing observed measurements versus expected values based on known dilution ratios. For the testosterone and dihydrotestosterone assays, CVs were usually less than 10%. For estradiol and progesterone, CVs were usually less than 15%. Assays with larger estimated CVs included androstenedione, dehydroepiandrosterone sulfate, estrone, and estrone sulfate. Absolute levels differed markedly between labs for most assays. Observed measurements generally agreed with values expected from the dilution ratios. A notable exception was the estrone assay at the lowest dilution level, where observed measurements were 2-4 times those expected. A similar but less pronounced overestimation bias for the low levels of estradiol was also suggested. This intra- and interlaboratory variability and apparent low dilution overestimation should be accounted for in studies relating hormones to cancer risk, especially those involving children and postmenopausal women.

Adolescent↗

PubMed1996

Surrogate end points in cancer research: a critique.

Studies using surrogate end points of malignant disease may be smaller, shorter, and less expensive than studies with incident cancer end points. Researchers have proposed a broad range of histological, cellular, and molecular markers as surrogate end points for cancer (SECs). We define a valid SEC as follows: the effect of an intervention on (or the association of a risk factor with) the SEC is concordant with its effect on (or association with) incident cancer. Adenomatous polyps and persistent human papillomavirus infections are examples of reasonably valid SECs (for colorectal and cervical cancer, respectively) because these markers are necessary precursors of most of these malignancies. Inferences from other potential SECs, however, are problematic if there exist major alternative causal pathways to malignancy bypassing the SEC. Furthermore, in such circumstances, an SEC that is valid for one intervention or exposure may not be valid for another. Even for those end points without such major alternative pathways, an intervention could differentially affect two intermediate markers on the same pathway, thus disturbing the concordance between its effect on a given SEC and its effect on cancer. Thus, an understanding of the causal structure underlying the relations of interventions/exposures, potential SECs, and cancer is critical in evaluating SECs. Three questions are pertinent to elucidating this structure: (a) What is the relation of the SEC to cancer? (b) What is the relation of the intervention/exposure to the SEC? and (c) To what extent doses the SEC mediate the relation between the intervention/exposure and cancer? Ecological, metabolic, observational epidemiological, and intervention studies may provide data relevant to one or more of these questions. Data on SEC variability are critical in evaluating whether marker findings have been attenuated by random sources of intra-individual variation. We emphasize the importance of conducting studies, especially SEC-cancer and intervention/exposure-SEC-cancer mediation studies, to evaluate problematic SECs such as epithelial cell hyperproliferation. For some time to come, hard and policy-relevant evidence on cancer etiology and prevention will emerge only from studies with cancer end points or, at a somewhat lower level of certainty, SECs that are (for the most part) obligatory steps on the causal pathway to malignant disease.

Biomarkers, Tumor↗

PubMed1995

Silent brain infarcts and transient ischemic attacks. A three-year study of first-ever ischemic stroke patients: the Klosterneuburg Stroke Data Bank.

BACKGROUND AND PURPOSE: We undertook to study the clinical relevance of silent strokes and history of transient ischemic attacks (TIAs) and their individual and combined effects on outcome variables of neurological and epidemiological interest in first-ever stroke patients. METHODS: We performed univariate and multivariate analyses of data prospectively collected in the Klosterneuburg Stroke Data Bank, a hospital-based registry in Austria that includes a 3-year follow-up program. RESULTS: Of 728 patients (mean age, 68 +/- 10 years) with a first-ever ischemic stroke, 110 (15%) had had a previous TIA, and 66/618 (11%) patients did not have a history of TIA but showed evidence of silent brain infarct on CT. Outcome variables of neurological interest were not significantly different between groups, including time between stroke and study entry, activities of daily living status at first presentation, median time of hospitalization, 30-day mortality, or 3-year mortality. Univariate analyses of epidemiologically important risk factors showed either history of TIA or evidence of silent infarct to be more frequently associated with hypertension (P = .007). Cox models of survival showed that neither history of TIA nor evidence of silent infarct were significantly associated with an increase in 3-year mortality. CONCLUSIONS: Over a period of 3 years, neither history of TIA nor evidence of silent infarct diagnosed at the time of the presenting major stroke in first-ever ischemic stroke patients exert an important influence on neurological or epidemiological outcome variables.

Adult↗

PubMed1995

A generalized estimating equations approach for spatially correlated binary data: applications to the analysis of neuroimaging data.

This paper proposes a generalized estimating equations approach for the analysis of spatially correlated binary data when there are large numbers of spatially correlated observations on a moderate number of subjects. This approach is useful when the scientific focus is on modeling the marginal mean structure. Proper modeling of the spatial correlation structure is shown to provide large efficiency gains along with precise standard error estimates for inference on mean structure parameters. Generalized estimating equations for estimating the parameters of both the mean and spatial correlation structure are proposed. The use of semivariogram models for parameterizing the correlation structure is discussed, and estimation of the sample semivariogram is proposed as a technique for choosing parametric models and starting values for generalized estimating equations estimation. The methodology is illustrated with neuroimaging data collected as part of the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank. A simulation study demonstrates the importance of accurate modeling of the spatial correlation structure in data with large numbers of spatially correlated observations such as those found in neuroimaging studies.

Brain↗