A comparison of approaches for association studies of polymorphisms and colorectal cancer risk.

AIM: Meta-analyses have been used to evaluate associations between polymorphisms and colorectal cancer risk, but the quality of individual studies used to inform them may vary substantially. Our aim was to apply well-established quality-control criteria to individual association studies and then compare the results of meta-analyses that included or excluded studies that did not meet these criteria. METHOD: We used meta-analyses of studies reporting a relationship between polymorphisms and colorectal cancer published between 1996 and 2008. Polymorphism-cancer associations were derived in separate meta-analyses including only those meeting the quality-control criteria. RESULTS: Relative ORs varied substantially between the open and restricted group meta-analyses for all variants except MTHFR 677 CT. However, the associations were modest and the direction of relative risk did not change after applying criteria. Publication bias was detected for all associations, except the restricted set of studies for GSTP1 GG. CONCLUSION: We observed variation in calculated relative risk and changes in tests for publication bias that were dependent on the inclusion criteria used for association studies of polymorphisms and colorectal cancer. Standardizing study inclusion criteria may reduce the variation in findings for meta-analyses of gene-association studies of common diseases such as colorectal cancer.

Patterns of blood product use among patients with myelodysplastic syndrome.

BACKGROUND AND OBJECTIVES: Most patients with myelodysplastic syndrome (MDS) require blood product support to manage the severe anaemias, which frequently accompany MDS. Our objective was to show the feasibility of linking the Surveillance, Epidemiology and End Results (SEER) database with records from Puget Sound Blood Center (PSBC) to characterize blood product use over time in successive cohorts of patients with MDS. MATERIALS AND METHODS: We identified patients with MDS in the SEER registry. The cohort was then linked to PSBC records to discern blood product use. RESULTS: Included in the analysis were 783 patients with MDS entered in the SEER database from 2001 to 2007 for whom data were also available in the PSBC database. Among patients with MDS who received transfusions, 97% received packed red blood cells; 52% received platelets. The proportion of patients with MDS receiving blood products declined from 2001 to 2007. CONCLUSION: These data show a recent decline in blood product use for patients with MDS. Future studies are needed to further evaluate the reasons for this finding, specifically exploring the impact of newer medications on blood product use in patients with MDS.

Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice.

Glyburide's pharmacokinetics (PK) and pharmacodynamics have not been studied in women with gestational diabetes mellitus (GDM). The objective of this study was to assess steady-state PK of glyburide, as well as insulin sensitivity, beta-cell responsivity, and overall disposition indices after a mixed-meal tolerance test (MMTT) in women with GDM (n = 40), nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 26), and healthy pregnant women (n = 40, MMTT only). At equivalent doses, glyburide plasma concentrations were approximately 50% lower in pregnant women than in nonpregnant subjects. The average umbilical cord/maternal plasma glyburide concentration ratio at the time of delivery was 0.7 +/- 0.4. Insulin sensitivity was approximately fivefold lower in women with GDM as compared with healthy pregnant women. Despite comparable beta-cell responsivity indices, the average beta-cell function corrected for insulin resistance was more than 3.5-fold lower in women with glyburide-treated GDM than in healthy pregnant women. Women with GDM in whom glyburide treatment has failed may benefit from alternative medication or dosage escalation; however, fetal safety should be kept in mind.

Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis.

The small intestine and liver express high levels of cytochrome P450 3A (CYP3A), an enzyme subfamily that contributes significantly to drug metabolism. In patients with cirrhosis, reduced metabolism of drugs is typically attributed to decreased liver function, but it is unclear whether drug metabolism in the intestine is also compromised. In this study, we compared CYP3A protein expression and in vitro midazolam hydroxylation in duodenal mucosal biopsies from subjects with normal liver function (controls; n = 20) and subjects with various levels of severity of cirrhosis (n = 23). In samples from subjects with cirrhosis, duodenal CYP3A expression and total midazolam hydroxylation were lower by 47 and 34%, respectively, as compared with samples from controls. Greater decreases in CYP3A expression were seen in subjects with more severe cirrhosis. Therefore, patients with advanced cirrhosis may have greater drug exposure following oral dosing as a result of both impaired liver function and decreased intestinal CYP3A expression and activity.

Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals.

BACKGROUND AND PURPOSE: Most analyses of intravenous tissue plasminogen activator (IV tPA) use for acute stroke in routine practice have been limited by sample size and generally restricted to patients treated in large academic medical facilities. In the present study, we sought to estimate among community hospitals the use of IV tPA and to identify factors associated with the use of IV tPA and inpatient mortality. METHODS: We evaluated a retrospective cohort of 23 058 patients with ischemic stroke from 137 community hospitals. RESULTS: Three hundred sixty-two (1.6%) patients were treated with IV tPA, and 9.9% of those patients died during the hospitalization period. In 35.0% of the hospitals, no patients were treated with IV tPA, whereas 14.6% of hospitals treated approximately 3.0% with IV tPA. After control for multiple factors, younger patients, more severely ill patients (OR 2.02, 95% CI 1.36 to 3.01), and patients treated in rural hospitals (OR 1.80, 95% CI 0.99 to 3.26) were more likely to receive IV tPA, whereas black patients were less likely (OR 0.54, 95% CI 0.31 to 0.95). There also was a trend showing that women were less likely to receive IV tPA (OR 0.84, 95% CI 0.69 to 1.03). Factors associated with an increased odds of inpatient mortality included receipt of IV tPA among men (OR 2.81, 95% CI 1.72 to 4.58) and increased age. Black patients were 27% less likely to die during hospitalization (95% CI 0.60 to 0.90). CONCLUSIONS: In this large, retrospective evaluation of community hospital practice, the use IV tPA and inpatient mortality rates among IV tPA-treated patients were consistent with those of other studies. The likelihood of receiving IV tPA varies by race, age, disease severity, and possibly gender. These factors may influence mortality rates.

Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

Inpatient costs, length of stay, and mortality for cerebrovascular events in community hospitals.

BACKGROUND: Accurate estimates of inpatient cost, length of stay (LOS), and mortality are necessary for the development of economic models to estimate the cost-effectiveness of stroke-related treatments. Estimates based on data from academic institutions may not be generalizable to community hospitals. In this study, the authors estimated inpatient costs, LOS, and in-hospital mortality for patients with subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), ischemic cerebral infarction (ICI), and TIA who were treated in community hospitals. METHODS: The authors selected patients using International Classification of Diseases-9-Clinical Modification primary diagnosis codes from the HBSI EXPLORE database. They analyzed patient-level data and inpatient costs, derived from detailed utilization data, for all patients admitted to 137 community hospitals in 1998. Multivariate statistical techniques were used to examine patient-, hospital-, and outcome-related factors associated with inpatient costs. RESULTS: Patients with SAH incurred the highest average cost ($23,777, n = 1,124), followed by patients with ICH ($10,241, n = 3,139), ICI ($5,837, n = 18,740), and TIA ($3,350, n = 7,861). Patient subgroups ranked in the same order for average LOS at 11.5 days for SAH, 7.5 days for ICH, 5.9 days for ICI, and 3.4 days for TIA. Almost one third of patients with SAH (29.0%) and ICH (33.1%) died during hospitalization, whereas 7.0% with ICI and 0.2% with TIA died. For each event, as patient age increased, average costs consistently decreased. Also, average costs were higher among patients treated in community teaching hospitals compared to community nonteaching hospitals for each cerebrovascular event (10 to 29%). CONCLUSIONS: Inpatient costs, LOS, and mortality for patients with cerebrovascular disease are dependent on patient and hospital characteristics.

Medication adherence in elderly patients receiving home health services following hospital discharge.

OBJECTIVE: To assess prevalence and risk factors for medication under- and overadherence in a two-week period following hospital discharge in adults > or = 65 years. DESIGN: Prospective, cohort study. SETTING: Three home healthcare agencies in Madison, Wisconsin, and surrounding vicinity. PARTICIPANTS: One hundred forty-seven older participants taking three or more medications who were hospitalized for medical illness, received home nursing after discharge, and completed the two-week interview. MEASUREMENTS: The main outcome measures were having at least one medication with less than 70% adherence (underadherence) and having at least one medication with more than 120% adherence (overadherence) based on pill counts. RESULTS: Forty-five (30.6%) participants were underadherent and 27 (18.4%) participants were overadherent with at least one medication> In a multivariate model, underadherence was predicted by poor cognition (OR 2.5; 95% CI 1.02 to 6.10) and higher medication use (OR 1.16; 95% CI 1.03 to 1.31, for each 1-unit increase in number of medications). Both poor cognition and low education were significantly associated with overadherence in univariate analysis; however, neither variable was significant once included in the multivariate model. CONCLUSIONS: Under- and overadherence to medications is common after hospital discharge. Poor cognition and a greater number of medications were associated with underadherence. Poor and lower education were markers for overadherence; however, further study is needed to determined whether these are independent predictors. Patients who have impaired cognition or are taking a greater number of medications after hospitalization may benefit from targeted interventions to monitor and improve medication compliance.

Some contributions of signal detection theory to the analysis of stimulus control in animals.

This paper reviews some applications of Signal Detection Theory (SDT) to the quantitative analysis of non-human animal discrimination. The basic detection model is briefly outlined and the separation of sensitivity and bias is illustrated. Several other applications and ideas are reviewed, including the rating method, some implications of signal and criterion variance, and the measurement of 'guesses' not encompassed by standard SDT. The conceptual framework and analytic tools of SDT help to clarify processes underlying stimulus control and provide direction to more complete process models.

Tramadol and seizures: a surveillance study in a managed care population.

STUDY OBJECTIVE: To investigate the occurrence of tramadol-associated seizures. DESIGN: Retrospective cohort and case-control studies. SETTING: UnitedHealth Group-affiliated independent practice model health plans, from different regions of the United States, contracting with large networks of physicians. INTERVENTION: Analysis of administrative data from a large U.S. managed care population. PATIENTS: A cohort of 9218 adult tramadol users and 37,232 concurrent nonusers. MEASUREMENTS AND MAIN RESULTS: Fewer than 1% of users (80) had a presumed incident seizure claim after the first tramadol prescription. Risk of seizure claim was increased 2- to 6-fold among users adjusted for selected comorbidities and concomitant drugs. Risk was highest among those aged 25-54 years, those with more than four tramadol prescriptions, and those with history of alcohol abuse, stroke, or head injury. A case-control study among users was conducted to validate incident seizure outcomes from medical records. Only eight cases were confirmed, and all had cofactors associated with increased seizure risk. CONCLUSION: In a general population, risk of seizure may be associated with long-term therapy with tramadol or the presence of cofactors, or confined to a small sensitive population subset.

Effects of priming, discriminability, and reinforcement on reaction-time components of pigeon visual search.

Pigeons searched computer screens for 1 of 4 letter targets among 55 alphanumeric distractors. In Experiment 1, valid-cue trials used distinctive patterns to signal the subsequent appearance of specific targets, whereas ambiguous-cue trials used a signal common to all targets. Search reaction times (RTs) after valid cues were shorter than after the ambiguous cue; increased target discriminability also reduced RT. In Experiment 2, when reinforcement for 2 targets shifted from 10% to 20%, RTs to those targets dropped, whereas RTs to the other 2 targets rose. RT distributions suggested that precues and discriminability both affect the momentary probability of finding a target, as embodied in the decay constant of an underlying exponentially distributed RT component. Reinforcement changes appeared to affect different components of the response process, embodied in changes in the mean of an underlying lognormal distribution.

Patient-level estimates of the cost of complications in diabetes in a managed-care population.

OBJECTIVE: To develop incidence-based estimates of the cost of several diabetes-related complications. DESIGN AND SETTING: This was a retrospective cohort study in a large health maintenance organisation. A total of 8905 patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus and 36,520 age- and gender-matched controls without diabetes were observed from 1992 to 1995. Incidence rates of 6 major diabetes-related complications were computed for both populations. Annual health expenditures in the first and second year following diagnosis were computed for each complication. For comparison, annual costs were derived for individuals without diabetes or the complication of interest. MAIN OUTCOME MEASURES AND RESULTS: Over 3 years of observation, incidence rates for the groups with and without diabetes were as follows: myocardial infarction 9.0 versus 3.2%; stroke 8.7 versus 3.8%; hypertension 26.2 versus 16.9%; end-stage renal disease 5.9 versus 1.4%; foot ulcer 7.9 versus 1.1%; and eye disease 44.3 versus 2.8%. Expressed as a multiple of the average annual cost of care for those without diabetes [$US3400/year (1995 dollars) for those over 65 years of age] and the related complication of interest, excess expenditures for those with diabetes were as follows for the first year following diagnosis: no complications 1.59; myocardial infarction 4.1; stroke 3.5; hypertension 2.56; end-stage renal disease 4.32; foot ulcer 4.0; and eye disease 2.46. For younger cohorts (less prevalent in the sample), incremental costs for each complication were generally greater than in the older group. CONCLUSIONS: The high incidences and costs may support the value of aggressive early intervention for patients with diabetes. These data will be useful for pharmacoeconomic modelling of the cost effectiveness of new and existing therapies for this condition.

Adverse drug events in elderly patients receiving home health services following hospital discharge.

OBJECTIVE: To assess incidence, healthcare consequences, and identify risk factors for adverse drug events (ADEs) in elderly patients receiving home health services during the month following hospital discharge. METHOD: This was a prospective cohort study of three home health agencies in Madison, Wisconsin, and its surrounding area. The sample consisted of 256 participants aged > or =65 years who were hospitalized for medical illness, received home nursing after discharge, and completed the one-month interview. The main outcome measure was self-reported ADEs (possible, probable, or definite) during the month following hospital discharge. RESULTS: Incidence of ADEs was 20%. Fifty-two participants (20.3%) reported 64 ADEs: 23 possible, 37 probable, and four definite. The most common ADEs involved the gastrointestinal tract (31.3%) and the central nervous system (31.3%). Of 53 ADEs reported to providers, 59% of the drugs were discontinued or altered. One ADE resulted in hospitalization. In logistic regression, female gender (OR = 2.26; 95% CI 1.06 to 4.77) and the interaction between number of new medications and cognition were significantly associated with ADEs. The risk of an event increased with the number of new medications at discharge; however, risk was elevated primarily for participants with lower cognition. CONCLUSIONS: ADEs were common during the month following hospital discharge, were more frequent in women, and often resulted in medication changes. Individuals at particular risk were those with lower cognition who were discharged with several new medications.

The medical cost of undiagnosed sleep apnea.

Obstructive sleep apnea is an under-diagnosed, but common disorder with serious adverse consequences. Cost data from the year prior to the diagnosis of sleep-disordered breathing in a consecutive series of 238 cases were used to estimate the potential medical cost of undiagnosed sleep apnea and to determine the relationship between the severity of sleep-disordered breathing and the magnitude of medical costs. Among cases, mean annual medical cost prior to diagnosis was $2720 versus $1384 for age and gender matched controls (p<0.01). Regression analysis showed that the reciprocal of the apnea hypopnea index among cases was significantly related to log-transformed annual medical costs after adjusting for age, gender, and body mass index (p<0.05). We conclude that patients with undiagnosed sleep apnea had considerably higher medical costs than age and sex matched individuals and that the severity of sleep-disordered breathing was associated with the magnitude of medical costs. Using available data on the prevalence of undiagnosed moderate to severe sleep apnea in middle-aged adults, we estimate that untreated sleep apnea may cause $3.4 billion in additional medical costs in the U.S. Whether medical cost savings occur with treatment of sleep apnea remains to be determined.

Modeling risk using generalized linear models.

Traditionally, linear regression has been the technique of choice for predicting medical risk. This paper presents a new approach to modeling the second part of two-part models utilizing extensions of the generalized linear model. The primary method of estimation for this model is maximum likelihood. This method as well as the generalizations quasi-likelihood and extended quasi-likelihood are discussed. An example using medical expense data from Washington State employees is used to illustrate the methods. The model includes demographic variables as well as an Ambulatory. Care Group variable to account for prior health status.

Incidence, outcomes, and cost of foot ulcers in patients with diabetes.

OBJECTIVE: To determine the incidence of foot ulcers in a large cohort of patients with diabetes, the risk of developing serious complications after diagnosis, and the attributable cost of care compared with that in patients without foot ulcers. RESEARCH DESIGN AND METHODS: Retrospective cohort study of patients with diabetes in a large staff-model health maintenance organization from 1993 to 1995. Patients with diabetes were identified by algorithm using administrative, laboratory, and pharmacy records. The data were used to calculate incidence of foot ulcers, risk of osteomyelitis, amputation, and death after diagnosis of foot ulcer, and attributable costs in foot ulcer patients compared with patients without foot ulcers. RESULTS: Among 8,905 patients identified with type 1 or type 2 diabetes, 514 developed a foot ulcer over 3 years of observation (cumulative incidence 5.8%). On or after the time of diagnosis, 77 (15%) patients developed osteomyelitis and 80 (15.6%) required amputation. Survival at 3 years was 72% for the foot ulcer patients versus 87% for a group of age- and sex-matched diabetic patients without foot ulcers (P < 0.001). The attributable cost for a 40- to 65-year-old male with a new foot ulcer was $27,987 for the 2 years after diagnosis. CONCLUSIONS: The incidence of foot ulcers in this cohort of patients with diabetes was nearly 2.0% per year. For those who developed ulcers, morbidity, mortality, and excess care costs were substantial compared with those for patients without foot ulcers. The results appear to support the value of foot-ulcer prevention programs for patients with diabetes.

Context reinforcement degrades discriminative control: a memory approach.

This study measured effects of context reinforcement on a visual discrimination. Five pigeons responded to 1 key in the presence of 6 shorter wavelengths and to another key for 6 longer wavelengths. Psychometric functions provided measures of discriminative sensitivity (d') and overall stimulus control. Sensitivity and control were slightly but significantly better when 20% of correct choices yielded reinforcement than when 5% did. Reinforcement of pecks to the sample stimulus reduced control substantially and sensitivity slightly; noncontingent reinforcement during intertrial intervals also reduced control, whether such reinforcement was signaled or not. Accuracy was excellent during an extinction session, but it fell substantially when reinforcement for sample pecks was added during choice extinction. Simulations based on a memory model of the discrimination process reproduced most of the experimental findings.

Reaction time drifts identify objects of attention in pigeon visual search.

Three pigeons searched for a unique target form among 31 identical distractors, and search reaction time (RT) was measured. Within experiments, target and distractor on each trial were drawn from the same small set of forms that differed from each other by simple features. Correlations across sessions among RTs to the various form pairs were analyzed. Experiment 1 indicated drifts of attention between the top of the forms, where a gap might appear, and the bottom, where a line might appear, and also suggested drifts of attention to the line as a target feature. Experiment 2 indicated similar drifts between the top and bottom of the forms and between small differences and large differences in target features. Attention to intraform location appeared relatively independent of attention to target features. The method provides a new way to identify functionally separable aspects of stimulus processing and to describe their temporal properties.

Effects of stimulus frequency and reinforcement variables on reaction time.

Pigeons pecked at one of two black forms, "+" or "O," either of which could appear alone on a white computer monitor screen. In baseline series of sessions, each form appeared equally often, and two pecks at it produced food reinforcement on 10% of trials. Test series varied the relative probability or duration of reinforcement or frequency of appearance of the targets. Peck reaction times, measured from target onset to the first peck, were found to vary as a function of reinforcement probability but not as a function of relative target frequency or of reinforcement duration. Reaction times to the two targets remained approximately equal as long as the probability of reinforcement, per trial, was equal for the targets, even if the relative frequency of the targets differed by as much as 19 to 1. The results address issues raised in visual search experiments and indicate that attentional priming is unimportant when targets are easy to detect. The results also suggest that equalizing reinforcement probability per trial for all targets removes differential reinforcement as an important variable. That reaction time was sensitive to the probability but not the duration of reinforcement raises interesting questions about the processes reflected in reaction time compared with rate as a response measure.

Contrast as seen in visual search reaction times.

Three pigeons searched arrays of alphabetic letters displayed on computer monitors. On each trial, either an A or an E appeared, and the reaction time and accuracy with which the bird pecked at this target were measured. In each block of trials, each target (A or E) was displayed alone, or together with a number of distractor letters (2 or 18) that varied in their similarity to the target. During a baseline series of sessions, responses to the A and to the E each yielded food reinforcement on 10% of the trials. In the next series of sessions, reinforcement continued at 10% for A, but rose to 30% for E. In a final series, these reinforcement conditions were reversed. As expected, reaction times increased with target-distractor similarity and (for similar distractors) with the number of distractors. Increased reinforcement of E had no effect on reaction times to E, but produced a very consistent increase in reaction times to A; the average increase was constant across the various display conditions. Reversal of the differential reinforcement conditions reversed this contrast effect. Analysis of the reaction time distributions indicated that increased reinforcement to E decreased the momentary probability of response to A by a constant amount, regardless of display conditions. These results are discussed in relation to theories of contrast, memory, and of the search image.