Biomedical subjects
L Ryan
Publications and source records attributed to L Ryan.
Relation of female infertility to consumption of caffeinated beverages.
Several studies have reported an association between caffeine intake and delay to conception. To study this relation further, the authors examined caffeine use in 1,050 women with primary infertility and 3,833 women who had recently given birth during the period 1981-1983 in the United States and Canada. The cases were separated by the cause of their infertility: ovulatory factor, tubal disease, cervical factor, endometriosis, or idiopathic infertility. The relative risks of each type of infertility associated with caffeine were calculated using separate logistic regression models and controlling for relevant confounding factors, such as age, center, cigarette smoking, lifetime number of sexual partners, alcohol consumption, contraception, body mass index, and exercise. A significant increase in the risk of infertility due to tubal disease or endometriosis was observed for the upper levels of caffeine intake, indicating a threshold effect. For tubal infertility, a relative risk of 1.5 (95% confidence interval (CI) 1.1-2.0) was found in women who consumed more than 7 g of caffeine per month as compared with those who consumed 3 g or less per month. For endometriosis, the relative risk was 1.9 (95% CI 1.2-2.9) in women who consumed 5.1-7 g/month and 1.6 (95% CI 1.1-2.4) in those with an intake of more than 7 g/month. These data suggest that caffeine deserves further study with regard to its effects on the female reproductive system.
Prognostic factors in metastatic melanoma.
BACKGROUND: Each year, 6000 people die in the United States from metastatic melanoma. Further study of factors affecting the prognosis of patients with this disease is needed. METHODS: The authors analyzed response and survival data from 635 patients who had entered three Eastern Cooperative Oncology Group trials for metastatic melanoma. RESULTS: Factors associated with poorer survival after study entry included poor performance status and the presence of symptoms, such as reduced appetite, fever, or nausea/vomiting. Male patients had poor survival, as did patients entering the study less than 1 year after a documented recurrence to study entry. As expected, characteristics of the initial primary disease (treatment and symptoms) had little association with survival after entering the advanced disease protocol. Two summary measures of the extent of metastatic involvement had a strong influence on survival. These were the number of nonbone metastases and the clinician's assessment as to the most significant metastatic site. Patients with the liver as their clinically most significant metastatic site had a poorer prognosis than those otherwise classified, including those with central nervous system metastases. The prognosis also worsened with an increasing number of sites of nonbone metastases, including skin and soft tissue. Tumor response occurred in only 11% of the patients. Patients with poor performance status and those with lung involvement had a significantly lower response rate than did others. Although the frequency of response was low, patients with objective responses survived significantly longer than did the nonresponders (based on an analysis appropriately adjusted for the time of response using a time-dependent proportional-hazards model). CONCLUSIONS: These results provide useful guidelines for the design and analysis of clinical trials in metastatic melanoma.
The involvement of CD14 in stimulation of cytokine production by uronic acid polymers.
In this study the molecular mechanisms behind the stimulatory activities of the uronic acid polymers poly mannuronic acid (poly M), high M alginate and oxidized cellulose (C60XY) were investigated and compared with lipopolysaccharide (LPS). The cytokine-inducing abilities of the uronic acid polymers and LPS were examined on CD14-positive human monocytes and CD14-negative U373 astrocytoma cells. It was found that LPS induced monocytes and U373 cells to produce tumor necrosis factor (TNF) and interleukin(IL)-6, respectively, by different mechanisms. The poly uronic acids induced monocytes to produce TNF, but with 100-1000 times less potency compared to LPS. On U373 cells, LPS at concentrations > or = 32 ng/ml resulted in a dose-related IL-6 production, whereas the poly uronic acids had negligible effects even at 1 mg/ml. The binding data demonstrate that only the CD14-positive monocytes in the peripheral blood mononuclear cells population bound poly M. Furthermore, poly M was found to bind to CD14 in the presence of serum. Antibodies against CD14 also inhibited the TNF-inducing activity of the three uronic acid polymers tested. In conclusion, these results demonstrate that uronic acid polymers induce TNF production through mechanisms which involve CD14.
Rate of speech effects in aphasia: voice onset time.
This study investigated the ability to produce appropriate voice onset time (VOT) contrasts under conditions of rate modulation in groups of nonfluent aphasic subjects, fluent aphasic subjects, and nonneurological controls. Acoustic analyses of the consonants [b d g p t k] produced in the context of the vowels [i e a o u] at two different rates of speech revealed that normal subjects' VOTs were significantly shorter at the fast rate of speech relative to the slow/normal rate, as expected. In addition, the rate change had a significantly greater effect on voiceless stops as compared to voiced and on velar consonants as compared to labials and alveolars. The nonfluent aphasic patients exhibited a similar pattern except that no differences in magnitude of rate-related changes were found across place of articulation. Further, similar to previous studies, the nonfluent aphasic patients produced voice and voiceless consonants with somewhat overlapping VOT distributions, indicating an impairment in temporal integration in these subjects. Finally, the fluent aphasic patients demonstrated a surprisingly aberrant pattern of results, with VOTs under th fast condition shorter than under the slow, but no differences in magnitude of change across place of articulation or voicing categories. The results are discussed in relation to the nature of speech production deficits in both nonfluent and fluent aphasic patients. Implications for remediation are considered.
Models of cognitive deficit and statistical hypotheses: multiple sclerosis, an example.
The purpose of the current study was to describe four models of cognitive deficit and to outline the statistical hypotheses underlying each model. The four models of cognitive deficit were (a) specific deficit; (b) subgroup deficit; (c) a syndrome dissociation model; and (d) a global function dissociation model. Neuropsychological data are analyzed to examine each of these four models in a sample of mild Multiple Sclerosis (MS) patients. The results suggest that for these subjects and tests, the specific deficit model best fits the data. The results are reviewed initially in the context of MS. There follows a consideration of statistical caveats and finally, general applications of the proposed procedures.
Implications of statistical tests of variance and means.
The primary purpose of this paper is to illustrate that tests for the homogeneity of variance in the statistical analysis of clinical neuropsychological data may provide unique information. Specifically, tests of variance homogeneity are more sensitive to outliers than the more commonly used tests of group means. Moreover, when both a test of means and of variance are done and the results compared, the nature of the deficit within the sample can be interpreted with greater confidence.
Self-reported use of pharmaceuticals and primary ovulatory infertility.
Over 1.5 billion prescriptions were filled by pharmacies in 1990, but little information exists on the effect that pharmaceutical agents have on female reproductive capacity. As part of a case-control study of risk factors for primary ovulatory infertility, we examined self-reported use of several prescription and nonprescription medications in 597 women with ovulatory infertility and 3,833 controls admitted for delivery at seven hospitals. Only women reporting use of a drug for at least 6 months, beginning before the onset of infertility in cases and before conception in controls, were considered exposed. An elevated risk of ovulatory infertility was found for women who ever used thyroid preparations [relative risk (RR) = 2.3, 95% confidence interval (CI) = 1.5-3.5] or antidepressants (RR = 2.9, 95% CI = 0.9-8.3), although the latter estimate was based on only five cases who reported having taken antidepressants. Current users of tranquilizers and ever-users for more than 2 years were also at greater risk of infertility than never-users (RR = 3.2, 95% CI = 1.1-8.5 and RR = 2.9, 95% CI = 0.8-11, respectively). Women who used asthma medication before age 21 had more than a twofold increase in risk of ovulatory infertility (RR = 2.5, 95% CI = 1.0-5.9).
Similar mechanisms of action of defined polysaccharides and lipopolysaccharides: characterization of binding and tumor necrosis factor alpha induction.
Little has been reported about the effects of different polysaccharides on cytokine production from human monocytes. In this study, we show that several well-defined polysaccharides, including polymers with different sizes of beta 1-4-linked D-mannuronic acid (poly-M, high-M alginate, and M-blocks) and cellulose oxidized in the C-6 position, induced human monocytes to produce tumor necrosis factor alpha (TNF-alpha). Poly-M was the most efficient polysaccharide tested and, on a weight basis, was approximately as efficient as lipopolysaccharide (LPS) from Escherichia coli. TNF-alpha production was shown to depend strongly on the molecular weights of poly-M and high-M alginate, with maximal TNF-alpha production occurring at molecular weights above 50,000 and 200,000, respectively. G-blocks, alpha 1-4-linked L-guluronic acid polymers that did not induce cytokine production from monocytes, reduced the cytokine production induced by the beta 1-4-linked polyuronic acids and LPS. Furthermore, both G-blocks and LPS were found to inhibit the binding of poly-M to monocytes, as measured by flow cytometry. In addition, we found that the binding of LPS to monocytes was inhibited by G-blocks, M-blocks, and poly-M. Our results indicate that beta 1-4-linked polyuronic acids and LPS may stimulate monocytes to produce TNF-alpha by similar mechanisms and may bind to a common receptor.
Using historical controls in the analysis of developmental toxicity data.
Historical control data can often aid in the interpretation of the results from laboratory dose-response experiments. For example, formal statistical methods for using historical data are well established for carcinogenicity studies. In that case, a score test derived from a beta-binomial model yields a simple modification of the standard Cochran-Armitage test for trend. However, this test cannot be used for developmental toxicity studies since it does not allow for the additional correlation structure induced by the presence of litter effects. In this paper, quasi-likelihood methods are used to incorporate historical control information into a trend test for the types of correlated binary outcomes that typically arise in developmental toxicity studies. The proposed test is asymptotically equivalent to the beta-binomial score test in the special case when all the litter sizes are equal to 1. Malformation data from a series of developmental toxicity studies illustrate the results.
Global tests for multiple binary outcomes.
The applied statistician often encounters the need to compare two or more groups with respect to more than one outcome or response. Several options are generally available, including reducing the dimension of the problem by averaging or summarizing the outcomes, using Bonferroni or other adjustments for multiple comparisons, or applying a global test based on a suitable multivariate model. For normally distributed data, it is well established that global tests tend to be significantly more sensitive than other procedures. While global tests have also been proposed for multiple binary outcomes, their properties have not been well studied nor have they been widely discussed in the context of clustered data. In this paper, we derive a class of quasi-likelihood score tests for multiple binary outcomes, and show that special cases of this class correspond to other tests that have been proposed. We discuss extensions to allow for clustered data, and compare the results to the simple approach of collapsing the data to a single binary outcome, indicating the presence or absence of at least one response. The asymptotic relative efficiencies of the tests are shown to depend not only on the correlation between the outcomes, but also on the response probabilities. Although global tests based on a multivariate model are generally recommended, our findings suggest that a test based on the collapsed data can maintain surprisingly high efficiency, especially when the outcomes of interest are rare. Data from several developmental toxicity studies illustrate our results.
Efficacy of ifosfamide in combination with doxorubicin for the treatment of metastatic soft-tissue sarcoma. The Eastern Cooperative Oncology Group.
On the basis of ifosfamide's demonstrated single-agent activity in adult soft-tissue sarcoma, the Eastern Cooperative Oncology Group (ECOG) tested whether ifosfamide would add to the efficacy of doxorubicin in a three-regimen, controlled phase III trial. Doxorubicin, ECOG's standard to which newer chemotherapeutic treatments are compared, was given at a dose of 80 mg/m2 every 3 weeks and was designated the control regimen. Ifosfamide was given at a dose of 3,750 mg/m2 on days 1 and 2 every 3 weeks in combination with 30 mg/m2 doxorubicin given each day for 2 days; additionally, mesna was given to counter the genitourinary toxicity associated with ifosfamide. A second experimental regimen consisted of doxorubicin (40 mg/m2), mitomycin (8 mg/m2), and cisplatin (60 mg/m2), all given intravenously on day 1, with repeated cycles being scheduled for day 21. Of the 279 adults with soft-tissue sarcoma who were entered in the study, 260 were analyzed. The overall response rate was 20% for doxorubicin, 34% for ifosfamide/doxorubicin, and 31% for doxorubicin/mitomycin/cisplatin, with the difference between the first two regimens being significant (P = 0.04). The median survival was 8.8, 11.5, and 9 months, respectively, for the three regimens. Myelosuppression, the predominant toxicity, occurred in 60%, 88%, and 58% of patients, respectively.
Statistical properties of the NOAEL.
The use of the no observed adverse effect level (NOAEL) in setting allowable exposure levels for noncancer endpoints is a source of controversy. Based on computer simulations and empirical studies, several authors have criticized the use of the NOAEL in terms of its sensitivity to sample size and its high sampling variability from experiment to experiment. The purpose of this paper is to derive the statistical distribution of the NOAEL. Using Weibull models, we investigate the impact of the shape of the underlying dose-response curve on the distribution of the NOAEL. The results confirm previous criticisms of the NOAEL and show that average risk levels associated with the NOAEL may be substantial. These results provide additional motivation for developing alternative approaches to risk assessment.
Phase II trials of interferons-alpha and -beta in advanced sarcomas.
Interferons (IFNs)-alpha and -beta were administered to patients with metastatic sarcomas in two different Eastern Cooperative Oncology Group studies. In one study, patients received IFN-alpha 2b, 20 million units/m2 i.v. 5 days/week x 4, then 10 million units s.c.t.i.w. In the second study, patients received IFN-beta ser 180 million units t.i.w. Of 87 patients evaluable for response, there were three responses in 64 patients (5%) treated with IFN-alpha-2b and no responses in 23 patients treated with IFN-beta ser. Severe or life-threatening fatigue with decline in performance status complicated treatment of 37% of patients receiving IFN-alpha 2b and 17% of patients receiving IFN-beta ser. Further investigation of IFNs in sarcomas should depend on evidence from preclinical studies demonstrating synergistic effects of IFNs combined with a cytoreductive modality which has proven activity in these malignancies.
The use of generalized estimating equations for risk assessment in developmental toxicity.
This paper reviews and compares several approaches to fitting dose-response models to developmental toxicity data. The main issue of interest is how to appropriately account for litter effects. Among the approaches reviewed are Beta Binomial models, models that attempt to characterize the litter effect through the use of covariates, and models that avoid the complication of correlated offspring by modeling "affected litter" rather than fetus-specific outcomes. Finally, we discuss our recommended approach, which is to use Generalized Estimating Equations, or quasi-likelihood. We give a number of reasons for preferring the latter and illustrate its application with an example.
Expression of the epidermal growth factor receptor gene in human brain metastases.
Biopsy specimens of human brain metastases were examined for amplification and expression of the proto-oncogene c-erbB1 (located on chromosome 7) encoding the epidermal growth factor receptor (EGFR). Moreover, the tumour DNA was also examined for amplification of other cancer-related genes on this chromosome: the proto-oncogene c-met, the gene for platelet-derived growth factor A-chain, and the gene for plasminogen activator inhibitory type 1. All 18 brain metastases demonstrated positive binding of biotinylated EGF on cryosections. Three out of 18 metastases had amplification of the EGFR gene; the other chromosome-7 genes tested were not amplified. Thus, an increased EGFR gene expression seems to be a general finding in a wide range of carcinomas metastatic to the brain, whereas we found only occasional selective EGFR gene amplifications in single cases.
Noninvasive diagnosis of carotid artery disease: the Oak Ridge experience in stroke prevention.
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Quantitative risk assessment for developmental toxicity.
Pharmaceutical companies and governmental regulatory agencies are becoming increasingly aware of the need for improved statistical methods for developmental toxicity experiments. Although a number of statisticians have become interested in this area, activity has centered mostly on the development of methods to analyze binary outcomes, such as malformations among live pups, while accounting appropriately for the correlation induced by the litter effect. In contrast, the topic of quantitative risk assessment has received relatively little attention. This paper addresses the specific question of how to assess risk appropriately when exposure causes a variety of adverse effects, including resorption and fetal death, in addition to malformations. It will be seen that risk assessments based on a single developmental outcome, such as malformation, may be conservative. A method is proposed for estimating an exposure level at which the overall risk of any adverse effect is acceptably low. The method is based on a continuation ratio formulation of a multinomial distribution, with an additional scale parameter to account for overdispersion. Comparisons are made with binary models on prenatal death and malformation, as well as a binary model that makes no distinction between death and malformation, but simply classifies each fetus as normal or abnormal. Data from several developmental toxicity studies illustrate the results and findings.