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PubMed1991

Nonparametric tests of association between survival time and continuously measured covariates: the logit-rank and associated procedures.

O'Brien's logit-rank procedure (1978, Biometrics 34, 243-250) is shown to arise as a score test based on the partial likelihood for a proportional hazards model provided the covariate structure is suitably defined. Within this framework the asymptotic properties claimed by O'Brien can be readily deduced and can be seen to be valid under a more general model of censoring than that considered in his paper. More important, perhaps, it is now possible to make a more natural and interpretable generalization to the multiple regression problem than that suggested by O'Brien as a means of accounting for the effects of nuisance covariates. This can be achieved either by modelling or stratification. The proportional hazards framework is also helpful in that it enables us to recognize the logit-rank procedure as being one member of a class of contending procedures. One consequence of this is that the relative efficiencies of any two procedures can be readily evaluated using the results of Lagakos (1988, Biometrika 75, 156-160). Our own evaluations suggest that, for non-time-dependent covariates, a simplification of the logit-rank procedure, leading to considerable reduction in computational complexity, is to be preferred to the procedure originally outlined by O'Brien.

Biometry↗
PubMed2026

Premenarche risk factors for future dysmenorrhoea: a prospective cohort study.

BACKGROUND: Dysmenorrhoea, or pain during menstruation, is common in adolescence and is often dismissed or left untreated. Dysmenorrhoea can interfere with daily functioning and can lead to other chronic pain conditions; however, little is known about the risk factors for dysmenorrhoea. We aimed to characterise premenarche risk factors for the presence and severity of future dysmenorrhoea. METHODS: In this prospective cohort study, we obtained data for female adolescents from the population-based Adolescent Brain Cognitive Development Study (USA) who were premenarchal at baseline (age 9-10 years) and had both reached menarche and completed the Menstrual Cycle Survey at 3-year follow-up (age 12-13 years). Parents or guardians provided sociodemographic information and completed the Child Behavior Checklist, the Sleep Disturbance Scale for Children, and the Pubertal Development Scale, which captured data on non-painful somatic symptoms, attention problems, anxiety, depression, sleep disturbances, and pubertal development at baseline. Our primary objective was to analyse associations between dysmenorrhoea at 3-year follow-up (status and severity) with select symptom domains (sleep problems, attention problems, somatic symptoms, anxious or depressive symptoms, and baseline pain status) at baseline. We also investigated associations between dysmenorrhoea and participant characteristics (pubertal status, race or ethnicity, and income-to-needs ratio) that underlie social determinants of health. Differences by race were tested using Fisher exact tests. Differences by ethnicity and baseline pain status were tested using &#x3c7;2 tests. Differences in continuous variables were assessed using ANOVA. Wilcoxon-Rank Sum tests were used in analyses of sleep problems, attention problems, and somatic symptoms, and ANOVA was used for pubertal status and income-to-needs ratio. Multinomial logistic regression was used to test associations with dysmenorrhoea severity, and linear regression was used to test associations with dysmenorrhoea status and menstrual pain interference. FINDINGS: 2254 female adolescents were included in this study. 1299 (57&#xb7;6%) participants developed dysmenorrhoea at age 12-13 years, and 247 (19&#xb7;0% of those with dysmenorrhoea) reported severe dysmenorrhoea. Non-painful somatic symptoms were prospectively associated with future dysmenorrhoea (odds ratio [OR] 1&#xb7;17 [95% CI 1&#xb7;04-1&#xb7;32]; p=0&#xb7;0070), whereas anxiety or depression, sleep disturbances, and attention problems were not. Sleep disturbances were prospectively associated with menstrual pain interference (&#x3b2; coefficient 0&#xb7;16 [95% CI 0&#xb7;01-0&#xb7;31]). Advanced pubertal status at ages 9-10 years was prospectively associated with risk of dysmenorrhoea 3 years later (OR 1&#xb7;79 [95% CI 1&#xb7;47-2&#xb7;17]; p<0&#xb7;0001), as was lower income-to-needs ratio (0&#xb7;96 [0&#xb7;93-1&#xb7;00]; p=0&#xb7;031). Black (1&#xb7;38 [1&#xb7;05-1&#xb7;83]; p=0&#xb7;024) and Hispanic (1&#xb7;34 [1&#xb7;03-1&#xb7;68]; p=0&#xb7;010) young females were at a significantly greater risk of experiencing dysmenorrhoea than were White and non-Hispanic young females, respectively. INTERPRETATION: Sociodemographic characteristics and clinical symptoms present before menarche might help to identify at-risk individuals for dysmenorrhoea before pain becomes a lifelong issue. FUNDING: The National Institute of Nursing Research, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Eunice Kennedy Shriver National Institute for Child Health and Human Development.

Humans↗
PubMed1996

General score tests for associations of genetic markers with disease using cases and their parents.

Association studies of genetic markers with disease play a critical role in the dissection of genetically complex traits because they are relatively easy to conduct and are useful for fine-scale mapping of genetic traits. The advantage of family-based controls has recently received much attention because spurious associations caused by population structure can be controlled for, and marker genotype information on diseased cases and their parents can be used to test the compound hypothesis of both linkage and linkage disequilibrium. However, debate still exists regarding the statistical methods of analysis. Herein are presented statistical methods to test for linkage (in the presence of linkage disequilibrium) between multiallelic genetic markers and disease when diseased subjects (cases) and their parents are sampled. Theoretical considerations for the development of general statistical tests are presented as well as asymptotic formulas to compute their power when planning a study. Furthermore, simulation results for nine specific statistics are used to contrast the power of these methods under different genetic mechanisms leading to disease (dominant vs. recessive, one vs. two high-risk alleles). These results demonstrate substantial gains in power for specific statistical tests designed to detect specified genetic mechanisms. However, without a priori knowledge of the likely genetic mechanism, it is desirable to rely on a fairly robust statistical method, robust so that power is not drastically lost when either dominant or recessive mechanisms are acting, and when either one or more than one marker alleles are associated with disease. Based on both theoretical and simulation results, a general score statistic, which generalizes the transmission/disequilibrium test, tends to offer sufficient power for a variety of genetic mechanisms, so that it is worth considering for broad use in studies which use genetic marker information from both diseased cases and their parents.

Adult↗
PubMed2006

ST segment elevation in lead aVR during exercise testing is associated with LAD stenosis.

PURPOSE: To evaluate, in patients with chest pain, the diagnostic value of ST elevation (STE) in lead aVR during stress testing prior to (99m) Tc-sestamibi scanning correlating ischaemic territory with angiographic findings. METHODS: Consecutive patients attending for (99m) Tc-sestamibi myocardial perfusion imaging (MPI) completed a treadmill protocol. Peak exercise ECGs were coded. STE >or=0.05 mV in lead aVR was considered significant. Gated perfusion images and findings at angiography were assessed. RESULTS: STE in lead aVR occurred in 25% (138/557) of the patients. More patients with STE in aVR had a reversible defect on imaging compared with those who had no STE in aVR (41%, 56/138 vs 27%, 114/419, p=0.003). Defects indicating a left anterior descending artery (LAD) culprit lesion were more common in the STE in aVR group (20%, 27/138 vs 9%, 39/419, p=0.001). There was a trend towards coronary artery stenosis (>70%) in a double vessel distribution involving the LAD in those patients who had STE in aVR compared with those who did not (22%, 8/37 vs 5%, 4/77, p=0.06). Logistic regression analysis demonstrated that STE in aVR (OR 1.36, p=0.233) is not an independent predictor of inducible abnormality when adjusted for STD >0.1 mV (OR 1.69, p=0.026). However, using anterior wall defect as an end-point, STE in aVR (OR 2.77, p=0.008) was a predictor even after adjustment for STD (OR 1.43, p=0.281). CONCLUSION: STE in lead aVR during exercise does not diagnose more inducible abnormalities than STD alone. However, unlike STD, which is not predictive of a territory of ischaemia, STE in aVR may indicate an anterior wall defect.

Aged↗
PubMed2002

Alcohol use and risky sexual behavior among college students and youth: evaluating the evidence.

OBJECTIVE: To evaluate the empirical associations between alcohol use and risky sex at two levels of analysis. Global associations test whether individuals who engage in one behavior are more likely to engage in the other, whereas event-specific associations test whether the likelihood of engaging in one behavior on a given occasion varies as a function of engaging in the other on that same occasion. METHOD: Studies examining the association between drinking and risky sex in samples of college students and youth were reviewed. Those published in the past 10 years and using event-level methodology or random sampling were emphasized. RESULTS: Findings were generally consistent across levels of analysis, but differed across types of risky behaviors. Drinking was strongly related to the decision to have sex and to indiscriminate forms of risky sex (e.g., having multiple or casual sex partners), but was inconsistently related to protective behaviors (e.g., condom use). Moreover, the links among alcohol use, the decision to have sex and indiscriminate behaviors were found in both between-persons and within-persons analyses, suggesting that these relationships cannot be adequately explained by stable individual differences between people who do and do not drink. Analysis of event characteristics showed that drinking was more strongly associated with decreased protective behaviors among younger individuals, on first intercourse experiences and for events that occurred on average longer ago. CONCLUSIONS: Future efforts aimed at reducing alcohol use in potentially sexual situations may decrease some forms of risky sex, but are less likely to affect protective behaviors directly.

Adolescent↗
PubMed2004

Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: Transmission of the brain-derived neurotrophic factor (BDNF) Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was examined. METHOD: The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one cardinal mania criterion (i.e., euphoria and/or grandiosity) to ensure differentiation from attention deficit hyperactivity disorder. Probands (mean age=10.7 years, SD=2.7) were obtained by consecutive new case ascertainment from designated pediatric and psychiatric venues. Parents and probands were interviewed separately by research nurses who were blind to the probands' diagnoses. Genotyping was done with TaqMan Assay-on-Demand. Analysis was done with the Family Based Association Test program. RESULTS: There were 53 complete, independent trios. The BDNF Val66 allele was preferentially transmitted (Family Based Association Test: chi(2)=6.0, df=1, p=0.014). CONCLUSIONS: This finding in child bipolar disorder is consistent with data for adults with bipolar disorder that show preferential transmission of the Val66 allele.

Adolescent↗
PubMed2005

Use of the dog as non-rodent test species in the safety testing schedule associated with the registration of crop and plant protection products (pesticides): present status.

The results from a survey of the expert information that is publicly accessible on the use of the dog as test species during the regulatory evaluation of agricultural chemicals and pesticides are reported. Methods that are being used or considered in order to reduce the number of dogs used for this purpose are described. Regulatory evaluation aims at establishing threshold values for safe human exposure; it is based on no-observed-adverse-effect levels (NOELs) determined in animal studies. Current regulations require testing in two species, a rodent species (usually rat or mouse), and a non-rodent species (usually the dog). Subchronic (90-day) and chronic (12-month) repeated-dose feeding studies must be routinely conducted in dogs. This report first focuses on the results from a retrospective study analysing data on 216 pesticides kept on record by the Bundesinstitut für Risikobewertung, BfR (German Federal Institute for Risk Assessment), the competent regulatory authority in Germany. The study was sponsored and coordinated by SET, the German Foundation for the Promotion of Research on Replacement and Complementary Methods to Reduce Animal Testing (Stiftung zur Förderung der Erforschung von Ersatz-und Ergänzungsmethoden zur Einschränkung von Tierversuchen, Mainz) and conducted by the BfR. Since the data submitted for registration of a product is the property of the manufacturer, the study could only proceed with the collaboration of the German Association of Manufacturers of Agricultural Chemicals (Industrieverband Agrar, IVA). To ensure confidentiality, designated codes were used instead of the compounds' proper names when the study was published. The results support two major conclusions. The use of the dog for the testing of pesticides is indeed necessary because the dog has proved to be the most sensitive species for about 15% of the compounds examined. However, chronic studies are only of limited value since they only provide essential information that cannot be obtained in sub-chronic studies in about 5% of cases. These conclusions are supported by several retrospective analyses using data on pharmaceutical drugs carried out in the context of the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). Over 90% of drugs elicited no toxic symptoms in 12-month studies in dogs in addition to those that had been recorded previously in studies conducted for 90 or 180 days in dogs and rats. Another approach comparing the results from pre-clinical animal studies with clinical studies noted that animal studies predicted about 70% of the effects observed in volunteers, and in about 94% of cases the effects occurred in animal studies lasting not more than one month. Furthermore, the report summarises the current methods under consideration that could refine or reduce the use of dogs in toxicity testing: industrial data sharing and harmonisation of guidelines, in vitro methods, human studies, computational prediction models, and integrated testing approaches. The integrated Agricultural Chemicals Safety Assessment (ACSA) testing scheme, which is currently being developed in an international project initiated by the International Life Sciences Institute (ILSI, USA), is of particular relevance, since an ambitious attempt is being made to design a new comprehensive test framework incorporating modern scientific approaches and covering most aspects of current regulatory testing requirements. The ACSA project has access to the pesticide database of the US EPA's Office of Pesticide Programs (OPP). Preliminary results have confirmed the two major conclusions from the joint SET/BfR study conducted in Germany. Taking these results into account, it is recommended that the regulatory requirement for 12-month studies to be routinely carried out in dogs should be abandoned. While 90-day studies should be conducted in both rats and dogs, chronic studies should only take place in rats. If the dog is more sensitive than the rat in the 90-day study, an additional safety factor to the NOEL value obtained in the chronic rat study should be applied in order to set the threshold for safe human exposure, instead of conducting a 12-month study in dogs. This safety factor may be calculated from chronic NOEL data available in several pesticide databases. Chronic tests using dogs would then only be required if the test compound belongs to a new class of chemicals that has never been tested before. Thus, the report concludes that, according to current scientific knowledge, the routine 12-month studies in dogs are no longer required for agricultural chemicals and pesticides, and international regulations should be changed accordingly. Active international support of such measures is welcomed, from both an economical and an animal welfare perspective.

Animal Testing Alternatives↗
PubMed2001

Colorectal cancer-screening tests and associated health behaviors.

BACKGROUND: Studies have shown that screening reduces colorectal cancer mortality. We analyzed national survey data to determine rates of use of fecal occult blood testing (FOBT) and sigmoidoscopy, and to determine if these rates differ by demographic factors and other health behaviors. METHODS: A total of 52,754 respondents aged >or=50 years were questioned in the 1997 Behavioral Risk Factor Surveillance System (BRFSS) survey (a random-digit-dialing telephone survey of the non-institutionalized U.S. population) about their use of FOBT and sigmoidoscopy. RESULTS: The age-adjusted proportion of respondents who reported having had a colorectal cancer screening test during the recommended time interval (past year for FOBT and past 5 years for sigmoidoscopy) was 19.8% for FOBT, 30.5% for sigmoidoscopy, and 41.1% for either FOBT or sigmoidoscopy. Rates of use of colorectal cancer screening tests were higher for those who had other screening tests (mammography, Papanicolaou smear, and cholesterol check). There were also differences in rates of use of colorectal cancer screening tests according to other health behaviors (smoking, seat belt use, fruit and vegetable intake, and physical activity) and several demographic factors. However, none of the subgroups that we examined reported a rate of FOBT use above 29% within the past year or a rate of sigmoidoscopy use above 41% within the past 5 years. CONCLUSIONS: While rates of use of FOBT and sigmoidoscopy were higher among people who practiced other healthy behaviors, rates of use were still quite low in all subgroups. There is a need for increased awareness of the importance of colorectal cancer screening.

Aged↗
PubMed2005

Association between lipid testing and statin therapy in acute myocardial infarction patients.

BACKGROUND: Clinical guidelines recommend lipid testing in all hospitalized acute myocardial infarction (AMI) patients. Inhospital lipid testing has also been proposed as a quality indicator for AMI care, but little is known about its use or importance. We sought to examine rates of inhospital lipid testing and its association with statin therapy at hospital discharge. METHODS: We performed an analysis using medical chart abstraction data that included demographic and comprehensive clinical information for patients hospitalized in Ontario, Canada, with an AMI from 1999 to 2001. RESULTS: Among 11,468 patients, inhospital lipid testing was performed in 6,019 (52.5%) patients and in 4,169 (36.4%) patients within 24 hours of admission. Patients who had lipid testing were significantly more likely to be discharged on statin therapy compared with patients not tested (41.4% vs 23.0%, P < .001). In addition, inhospital lipid testing was strongly associated (odds ratio 3.61, 95% CI 3.15-4.14) with statin therapy prescription at hospital discharge after adjusting for other clinical, physician, and hospital factors. CONCLUSIONS: Despite endorsements from practice guidelines, less than half of all admitted AMI patients received lipid testing within 24 hours of hospital admission. Because inhospital lipid testing was strongly associated with the initiation of statin therapy at discharge, many opportunities to initiate statin therapy were lost. Efforts to increase the use of lipid testing in hospitalized AMI patients may translate into higher rates of lipid-lowering therapy and improved patient outcomes.

Aged↗
PubMed2004

The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women.

Abnormalities in insulin regulation are central to the pathogenesis of type 2 diabetes. We assessed variation in the insulin gene variable number tandem repeat (INS VNTR) minisatellite (using the -23Hph1 A/T single nucleotide polymorphism) as a risk factor for 92 cases of incident type 2 diabetes in 883 unrelated Framingham Heart Study (FHS) subjects and in a separate sample of 698 members of 282 FHS nuclear families with 62 diabetes cases. In the unrelated sample, the -23Hph1 TT genotype frequency was 8.0% and was associated with a diabetes hazard ratio of 1.89 [95% confidence interval (CI), 1.01-3.52; P = 0.045] compared with the AA genotype using diabetes age of onset as the time failure variable in a proportional hazards model adjusted for age, offspring sex, body mass index, parental diabetes, and sex by parental diabetes interactions. In sex-stratified analyses, TT increased risk for diabetes in women (hazard ratio, 4.25; 95% CI, 1.76-10.3), but not men (hazard ratio, 1.01; 95% CI, 0.39-2.60). Using a family-based association test to assess transmission disequilibrium in the sample of related subjects, the age- and sex-adjusted z-score for diabetes associated with the T allele was 2.07 (P = 0.04), and a family-based association test using age of onset in a proportional hazards model was also statistically significant (P = 0.03), indicating that increased risk of diabetes was not attributable to population admixture. These data support the hypothesis that the INS VNTR is a genetic risk factor for type 2 diabetes, with the TT genotype accounting for about 6.6% of cases in the FHS population.

Adult↗
PubMed1996

Psychometric test results associated with high achievement in basic science components of a medical curriculum.

PURPOSE: To analyze the correlation between scores obtained on the 25 scales and vectors of the California Psychological Inventory (CPI) and academic test results obtained in various subjects by the same students in the first three years of the six-year medical curriculum at Monash University. METHOD: The study participants were 133 students who commenced their medical education in 1990 or 1991 and completed their third year in 1993. The student took the CPI in their first year. The academic test results were classified according to assessment type and content. Pearson product-moment correlation coefficients were then calculated between the CPI scores and the test results. RESULTS: With respect to assessment type, the results for multiple-choice question test (MCQs), practicals, calculations, and to a lesser extent, essays were negatively correlated with some CPI scores that might be notionally desirable in a caring profession. Essay and oral examination results were positively correlated with scales such as Socialization, Self-control, and Work Orientation. Results of oral examinations, unlike those of other types assessments, were positively correlated with the CPI scales of Intellectual Efficiency and Management Potential. Three of the assessment types--MCQs, practicals, and calculations--were highly significantly negatively associated with the Empathy scale. With respect to assessment content, results for cell and tissue studies were negatively correlated with several CPI scales, including Empathy. By complete contrast, the scores from clinical and communication skills assessments were positively correlated with many notionally desirable CPI scales, including Empathy, Responsibility, and Tolerance. CONCLUSION: The results indicate that students with high achievement in many components of the curriculum tend to have personality profiles that seem inappropriate to their chosen careers as physicians. Medical schools espousing humanistic qualities in their educational objectives may be offering a contradictory message to their students by rewarding those with inappropriate personal qualities.

Attitude↗
PubMed1995

Monte Carlo tests for associations between disease and alleles at highly polymorphic loci.

In an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi-squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association.

Alleles↗