PubMed Health⌕ Search

Biomedical subjects

Timothy L Lash

Publications and source records attributed to Timothy L Lash.

At least 19 recordsLinked to original sources

Heuristic thinking and inference from observational epidemiology.

Epidemiologic research is an exercise in measurement. Observational epidemiologic results usually include a point estimate, a measure of random error such as a frequentist confidence interval, and a qualitative discussion of study limitations. Without randomization of study subjects to exposure groups, inference from study results requires an educated guess about the strength of the systematic errors compared with the strength of the exposure effects. Although quantitative methods to make these educated guesses exist, the conventional approach is qualitative, which reduces the educated guessing to a problem of reasoning under uncertainty. In circumstances such as these, humans predictably reason poorly. Heuristics and resulting biases that simplify the judgmental tasks tend to underestimate the systematic error, underestimate the uncertainty, and focus the inference on the study's specific evidence while excluding countervailing external information. Common warnings to interpret results with trepidation are an ineffective solution. The methods that quantify systematic error and uncertainty challenge the analyst to specify the alternative explanations for associations that are otherwise too readily judged causal.

Bias↗

Effect of undertreatment on the disparity in age-related breast cancer-specific survival among older women.

OBJECTIVES: Assess the relationship between age and breast cancer-specific survival among older women and determine whether the observed age-related disparities in survival is explained by differences in breast cancer treatments received. METHODS: Women > or =65 years old at diagnosis with stage I-IIIA breast cancer diagnosed between 1997 and 1998 were recruited from four regions of the United States and followed prospectively for 5 years after diagnosis. Data was obtained from tumor registries, medical records, and telephone interviews. The primary endpoint was breast cancer-specific survival. Our independent variables were age operationalized as < or =75 years vs. >75 years, and receipt of recommended guideline therapy, adapted from the National Institutes of Health guideline consensus conference. RESULTS: Of 689 women, 36% were >75 years. Women >75 years were less likely to have received the following; axillary lymph node dissection (84% vs. 93%, P = 0.0003), radiotherapy (40% vs. 54%, P = 0.0003), definitive primary therapy (71% vs. 84%, P < 0.0001), chemotherapy (9% vs. 28%, P < 0.0001), and guideline therapy (31% vs. 54%, P < 0.0001). The 5-year breast cancer-specific survival was 95% (95% confidence interval [CI], 90%, 97%) for those < or =75 years who received guideline therapy, 94% (95% CI, 90%, 97%) for those < or =75 years who did not receive guideline therapy, 96% (95% CI, 88%, 99%) for those >75 years who received guideline therapy and 83% (95% CI, 74%, 89%) for those >75 years who did not receive guideline therapy, (P = 0.002) by the log-rank test. CONCLUSION: Receipt of guideline therapy may reduce the age-related disparity in breast cancer survival among older women.

Age Distribution↗

Breast cancer treatment of older women in integrated health care settings.

PURPOSE: A substantial literature describes age-dependent variations in breast cancer treatment, showing that older women are less likely to receive standard treatment than younger women. We sought to identify patient and tumor characteristics associated with the nonreceipt of standard primary tumor and systemic adjuvant therapies. PATIENTS AND METHODS: We studied 1,859 women age 65 years or older with stage I and II breast cancer diagnosed between 1990 and 1994 who were cared for in six geographically dispersed community-based health care systems. We collected demographic, tumor, treatment, and comorbidity data from electronic data sources, including cancer registry, administrative, and clinical databases, and from subjects' medical records. RESULTS: Women 75 years of age or older and women with higher comorbidity indices were more likely to receive nonstandard primary tumor therapy, to not receive axillary lymph node dissection, and to not receive radiation therapy after breast-conserving surgery (BCS). Asian women were less likely to receive BCS, and African American women were less likely to be prescribed tamoxifen. Although nonreceipt of most therapies was associated with a lower baseline risk of recurrence, an important minority of high-risk women (16% to 30%) did not receive guideline therapies. CONCLUSION: Age is an independent risk factor for nonreceipt of effective cancer therapies, even when comorbidity and risk of recurrence are taken into account. Information regarding treatment effectiveness in this age group and tools that allow physicians and patients to estimate the benefits versus the risks of therapies, taking into account age and comorbidity burden, are critically needed.

Black or African American↗

Prognosis of ovarian cancer subsequent to venous thromboembolism: a nationwide Danish cohort study.

BACKGROUND: Venous thromboembolism (VTE) is associated with ovarian cancer and may impact the prognosis of ovarian cancer. Our aims were to examine the extent of disease at the time of the diagnosis of ovarian cancer and to estimate the impact of VTE on survival of ovarian cancer. METHODS: We identified 12,835 ovarian cancer patients diagnosed from 1980 to 2003 in the Danish Cancer Registry and obtained information on previous primary VTE diagnosis from the Danish National Hospital Discharge Registry. Ovarian cancer patients with previous VTE related to other cancers, surgery, or pregnancy were excluded. The vital status was determined by linking data to the Civil Registration System. RESULTS: We identified 50 ovarian cancer patients diagnosed less than 4 months after the VTE and 78 ovarian cancer patients diagnosed more than 4 months after the VTE diagnosis. Advanced stages tended to be more common among patients with VTE. One-year survivals were 44% and 54% among the two VTE groups, compared with 63% among patients without VTE. Adjusted (for age, calendar time, comorbidity, and FIGO-stage) mortality ratios were 1.7 (95% CI = 1.2-2.5) and 1.2 (95% CI = 0.8-1.7), respectively. CONCLUSION: Ovarian cancer diagnosed less than four months before VTE is associated with an advanced stage and a poorer prognosis.

Aged↗

Increased CUG triplet repeat-binding protein-1 predisposes to impaired adipogenesis with aging.

Preadipocyte differentiation capacity declines between middle and old age. Expression of the adipogenic transcription factors, CCAAT/enhancer-binding protein (C/EBP) alpha and peroxisome proliferator-activated receptor gamma (PPARgamma), is lower in differentiating preadipocytes from old than young animals, although no age-related changes occur in C/EBPbeta mRNA, which is upstream of C/EBPalpha and PPARgamma. C/EBPbeta-liver-enriched inhibitory protein (C/EBPbeta-LIP), a truncated C/EBPbeta isoform that is a dominant inhibitor of differentiation, increases with aging in rat fat tissue and preadipocytes. CUG triplet repeat-binding protein-1 (CUGBP1) binds to C/EBPbeta mRNA, increasing C/EBPbeta-LIP translation. Abundance and nucleotide binding activity of CUGBP1 increased with aging in preadipocytes. CUGBP1 overexpression in preadipocytes from young animals increased C/EBPbeta-LIP and impaired adipogenesis. Decreasing CUGBP1 in preadipocytes from old rats by RNA interference reduced C/EBPbeta-LIP abundance and promoted adipogenesis. Tumor necrosis factor-alpha, levels of which are elevated in fat tissue with aging, increased CUGBP1 protein, CUGBP1 binding activity, and C/EBPbeta-LIP in preadipocytes from young rats. Thus, CUGBP1 contributes to regulation of adipogenesis in primary preadipocytes and is responsive to tumor necrosis factor-alpha. With aging, preadipocyte CUGBP1 abundance and activity increases, resulting in enhanced translation of the C/EBPbeta-LIP isoform, thereby blocking effects of adipogenic transcription factors, predisposing preadipocytes from old animals to resist adipogenesis. Altered translational processing, possibly related to changes in cytokine milieu and activation of stress responses, may contribute to changes in progenitor differentiation and tissue function with aging.

Adipocytes↗

Adherence to tamoxifen over the five-year course.

PURPOSE: To estimate the proportion of older women who fail to complete 5 years of tamoxifen therapy and to identify predictors of non-adherence. PATIENTS AND METHODS: We followed 462 women 65-years-old or older with stage I-IIIA breast cancer diagnosed in four US regions between 1996 and 1999 and who initiated tamoxifen therapy. We interviewed patients annually to assess tamoxifen adherence and collected information about predictors of adherence by medical record review, patient interview, and physician questionnaire. RESULTS: Thirty-one percent of patients who started tamoxifen failed to complete the recommended 5-year course. Patients who had initial severe side effects [hazard ratio (HR) per side effect=1.2, 95% confidence interval (CI) 0.97, 1.5] or developed them (HR per new side effect=1.3, 95% CI 1.0, 1.6) were more likely to discontinue. Patients with more prescription medications at baseline were less likely to discontinue (HR per baseline prescription equaled 0.90, 95% CI 0.81, 0.99), whereas patients who added a prescription were more likely to discontinue (HR per new prescription equaled 1.2, 95% CI 1.0, 1.4). Patients with positive views of tamoxifen at baseline (HR for a 10-point higher score=0.93, 95% CI 0.83, 1.0) and an improving view over follow-up (HR for a 10-point positive change=0.93, 95% CI 0.87, 1.0) were less likely to discontinue. CONCLUSION: Five years of tamoxifen confers a significant benefit beyond 1-2 years of tamoxifen, so physicians should ask patients about side effects, other prescriptions, and beliefs about tamoxifen and should educate them about the benefits of completing adjuvant therapy.

Aged↗

Departure from multiplicative interaction for catechol-O-methyltransferase genotype and active/passive exposure to tobacco smoke among women with breast cancer.

BACKGROUND: Women with homozygous polymorphic alleles of catechol-O-methyltransferase (COMT-LL) metabolize 2-hydroxylated estradiol, a suspected anticarcinogenic metabolite of estrogen, at a four-fold lower rate than women with no polymorphic alleles (COMT-HH) or heterozygous women (COMT-HL). We hypothesized that COMT-LL women exposed actively or passively to tobacco smoke would have higher exposure to 2-hydroxylated estradiol than never-active/never passive exposed women, and should therefore have a lower risk of breast cancer than women exposed to tobacco smoke or with higher COMT activity. METHODS: We used a case-only design to evaluate departure from multiplicative interaction between COMT genotype and smoking status. We identified 502 cases of invasive incident breast cancer and characterized COMT genotype. Information on tobacco use and other potential breast cancer risk factors were obtained by structured interviews. RESULTS: We observed moderate departure from multiplicative interaction for COMT-HL genotype and history of ever-active smoking (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 0.7, 3.8) and more pronounced departure for women who smoked 40 or more years (aOR = 2.3, 95% CI: 0.8, 7.0). We observed considerable departure from multiplicative interaction for COMT-HL genotype and history of ever-passive smoking (aOR = 2.0, 95% CI: 0.8, 5.2) or for having lived with a smoker after age 20 (aOR = 2.8, 95% CI: 0.8, 10). CONCLUSION: With greater control over potential misclassification errors and a large case-only population, we found evidence to support an interaction between COMT genotype and tobacco smoke exposure in breast cancer etiology.

Journal Article↗

Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies.

Observational analogs of randomized clinical trials (RCTs) are well accepted in the study of disease risk factors, diagnosis, and prognosis. There is controversy about observational studies when the focus is on the intended benefit due to lack of blinding and poor control for unmeasured confounding. Well-designed randomized clinical trials are costly both in time and money. Therefore, existing databases are used increasingly and are often the only feasible source with which to examine delayed health effects. We reviewed the reasons for possible discrepancies between RCTs and observational studies. There can be different patient populations, differences in therapeutic regimen, control of confounding, follow-up, measuring outcome, and differences arising from the intention-to-treat analysis. Observational studies cannot replace trials, nor do trials make observational studies unnecessary. Both designs are susceptible to particular bias, so neither provides perfect information.

Observation↗

Risk of decline in upper-body function and symptoms among older breast cancer patients.

BACKGROUND: Decline in upper-body function and development of upper-body symptoms are adverse effects of breast cancer therapy and may affect functional independence, particularly among older survivors. The long-term risks and predictors are poorly understood. OBJECTIVE: To characterize the risk of decline in upper-body function and development of symptoms over 4 years of follow-up. DESIGN: We used a prospective cohort design. PARTICIPANTS: Six hundred and forty-four early stage breast cancer patients 65 years old or older at surgery enrolled in Rhode Island, North Carolina, Minnesota, and Los Angeles between 1996 and 1999. MEASUREMENTS: Upper-body function and symptoms were self-reported at baseline, 6, 15 months, and annually thereafter to 51 months after surgery. RESULTS: One half of the participants had a decline in upper-body function and one-quarter developed upper-body symptoms. Breast cancer patients were 5-fold more likely to have a decline in upper-body function over 4 years of follow-up than a similar cohort without breast cancer. Better baseline mental health protected against a decline in upper-body function (odds ratio [OR]=0.93, 95% confidence interval [CI] 0.88 to 0.97 for 8-point higher mental health index). Baseline obesity (OR for body mass index [BMI] > or =30 kg/m2 vs <30 kg/m2=2.5, CI=1.6 to 4.0) and axillary node dissection (OR for axillary dissection vs not=3.9, CI=1.1 to 14) predicted the development of upper-body symptoms. CONCLUSIONS: Primary care physicians should address upper-body function and symptoms with older breast cancer patients, and inform them that these complications of breast cancer treatment are common.

Activities of Daily Living↗

A method to automate probabilistic sensitivity analyses of misclassified binary variables.

BACKGROUND: Misclassification bias is present in most studies, yet uncertainty about its magnitude or direction is rarely quantified. METHODS: The authors present a method for probabilistic sensitivity analysis to quantify likely effects of misclassification of a dichotomous outcome, exposure or covariate. This method involves reconstructing the data that would have been observed had the misclassified variable been correctly classified, given the sensitivity and specificity of classification. The accompanying SAS macro implements the method and allows users to specify ranges of sensitivity and specificity of misclassification parameters to yield simulation intervals that incorporate both systematic and random error. RESULTS: The authors illustrate the method and the accompanying SAS macro code by applying it to a study of the relation between occupational resin exposure and lung-cancer deaths. The authors compare the results using this method with the conventional result, which accounts for random error only, and with the original sensitivity analysis results. CONCLUSION: By accounting for plausible degrees of misclassification, investigators can present study results in a way that incorporates uncertainty about the bias due to misclassification, and so avoid misleadingly precise-looking results.

Bias↗

Predictors and outcomes of surgeons' referral of older breast cancer patients to medical oncologists.

BACKGROUND: Older women are less likely than younger women to receive definitive care for a new diagnosis of breast cancer, but the reasons are not well understood. Although coordination of referral among specialists is an important component of quality of care, it has not been studied as a factor that contributes to observed age-related variations in breast cancer care. METHODS: Treatment recommendations by 191 surgeons of 559 patients aged > or = 65 years with Stage I to IIIa breast cancer provided patient-specific assessments of comorbidity and medical oncologist referral. Demographic, tumor, and treatment characteristics from medical records and telephone interviews were evaluated by statistical regression methods to identify factors associated with referral to a medical oncologist and to evaluate whether a referral resulted in discussion and prescription of tamoxifen. RESULTS: Estrogen receptor protein negativity and higher tumor stage increased the likelihood of referral (odds ratio [OR] = 5.6, 95% confidence interval [CI] = 1.9-16.7, and OR = 4.2, 95% CI = 1.7-10.3, respectively), whereas a moderate to severely ill health status decreased the likelihood of referral (OR = 0.4, 95% CI = 0.2-0.9). Those referred were twice as likely to report having a discussion about tamoxifen (OR = 2.0, 95% CI = 1.06-3.7) and to have been prescribed tamoxifen (OR = 2.1, 95% CI = 0.99-4.3). CONCLUSIONS: Referral to medical oncologists is associated with receipt of adjuvant tamoxifen therapy. The current study findings suggest that more consistent referral of older women to medical oncologists may enhance quality of discussion and participation in decisions concerning treatment options.

Age Factors↗

A case-only analysis of the interaction between N-acetyltransferase 2 haplotypes and tobacco smoke in breast cancer etiology.

INTRODUCTION: N-acetyltransferase 2 is a polymorphic enzyme in humans. Women who possess homozygous polymorphic alleles have a slower rate of metabolic activation of aryl aromatic amines, one of the constituents of tobacco smoke that has been identified as carcinogenic. We hypothesized that women with breast cancer who were slow acetylators would be at increased risk of breast cancer associated with active and passive exposure to tobacco smoke. METHODS: We used a case-only study design to evaluate departure from multiplicativity between acetylation status and smoking status. We extracted DNA from buccal cell samples collected from 502 women with incident primary breast cancer and assigned acetylation status by genotyping ten single-nucleotide polymorphisms. Information on tobacco use and breast cancer risk factors was obtained by structured interviews. RESULTS: We observed no substantial departure from multiplicativity between acetylation status and history of ever having been an active smoking (adjusted odds ratio estimate of departure from multiplicativity = 0.9, 95% confidence interval 0.5 to 1.7) or ever having had passive residential exposure to tobacco smoke (adjusted odds ratio = 0.7, 95% confidence interval 0.4 to 1.5). The estimates for departure from multiplicativity between acetylation status and various measures of intensity, duration, and timing of active and passive tobacco exposure lacked consistency and were generally not supportive of the idea of a gene-environment interaction. CONCLUSION: In this, the largest case-only study to evaluate the interaction between acetylation status and active or passive exposure to tobacco smoke, we found little evidence to support the idea of a departure from multiplicativity.

Acetylation↗

Tamoxifen-treated breast carcinoma patients and the risk of acute myocardial infarction and newly-diagnosed angina.

BACKGROUND: It is known that tamoxifen therapy favorably affects blood cholesterol levels and other cardiovascular disease risk factors; however, to our knowledge, few studies to date have reported a lower risk of heart disease for breast carcinoma patients who are treated with tamoxifen. METHODS: A nested, matched, case-control study design was used with data from the General Practice Research Database to examine whether patients with breast carcinoma who had been treated with tamoxifen were at reduced risk of having a first acute myocardial infarction (MI) or of developing angina compared with unexposed women. All women between age 30 years and age 85 years who had been diagnosed with breast carcinoma and treated with tamoxifen, or who had been diagnosed with carcinoma of the bladder or colorectum, or nonmelanoma skin cancer between January 1991 and December 1999 were identified. From this population, all women were identified who had newly diagnosed acute MI or angina that occurred at least 1 year after their cancer diagnosis. Four female control participants were matched to each case based on age (+/- 1 year), date of MI or angina diagnosis (corresponding date for matched controls), and date of cancer diagnosis (+/- 6 months). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using conditional logistic regression, controlling for the matching factors, and adjusting for important risk factors, including body mass index, use of hormone replacement therapy, smoking status, and treated hypertension. RESULTS: Current users of tamoxifen had a reduced rate ratio of acute MI or angina (adjusted OR, 0.4; 95% CI, 0.2-0.7) compared with nonusers. The effect persisted with increasing cumulative dose and length of use. CONCLUSIONS: The treatment of breast carcinoma with tamoxifen was found to reduce a woman's risk of acute MI or angina during the 5 years of recommended therapy.

Adult↗

Breast cancer survival of American Indian/Alaska Native women, 1973-1996.

OBJECTIVE: To assess breast cancer mortality rates among American Indian/Alaska Native women compared with non-Hispanic White women in the five years after diagnosis. METHODS: Surveillance, Epidemiology, and End Results data from 1973-1996 were used to compare survival in the two races, controlling for age, marital status, stage, and therapy. RESULTS: The adjusted relative hazard of death was 58% higher for American Indian/Alaska Native women than for non-Hispanic White women (HR = 1.58, 95% Cl 1.26-2.00). The survival disparity persisted even when limited to women who received definitive therapy, i.e. mastectomy with axillary node dissection or breast-conserving surgery with axillary node dissection and radiation treatment (HR = 1.88, 95% Cl 1.40-2.52). CONCLUSIONS: American Indian/Alaska Native women were at greater risk for breast cancer mortality than non-Hispanic White women, even when restricted to women who received definitive breast cancer therapy.

Adult↗

Reduced rates of cancer-related worries and mortality associated with guideline surveillance after breast cancer therapy.

OBJECTIVE: Guidelines have been developed for appropriate post-therapy surveillance for breast cancer recurrence. Two objectives of post-therapy surveillance are to support and counsel patients and to detect potentially curable local recurrences and new cancers in the opposite breast. The objective of this investigation was to assess the impact of guideline surveillance (history, physical examination, and annual mammography) on cancer-related worries and all-cause mortality. STUDY DESIGN AND SETTING: We collected data on a cohort of 303 Massachusetts women with stages I or II breast cancer diagnosed between 1992 and 1994. Cases were women with increasing cancer-related worries or decedents. We used risk-set sampling to match five controls to each case on follow-up time. Cases and members of their matched risk set were characterized with respect to receipt of guideline surveillance and covariates preceding the date of their outcomes. RESULTS: The adjusted odds ratio associating guideline surveillance in the preceding year with an increase in cancer-related worries equaled 0.37 (95% CI = 0.14-0.99). The adjusted odds ratio associating continuous guideline surveillance with all-cause mortality equaled 0.66 (95% CI = 0.51-0.86). CONCLUSION: The results are consistent with the stated objectives of surveillance follow-up of breast cancer patients after the completion of their primary therapy.

Aftercare↗

A sensitivity analysis of a randomized controlled trial of zinc in treatment of falciparum malaria in children.

BACKGROUND: The randomized trial has long been recognized as a means to assess the efficacy of new interventions, because the investigator can reduce or eliminate many sources of error. As such, clinical trials often do not include quantitative assessments of the extent that systematic error could affect their results. We examined the impact of different sources of bias on a randomized controlled trial of the efficacy of zinc as an adjuvant to malaria therapy in reducing time to total parasite clearance. METHODS: Using data from a previously published study, we identified two sources of bias and used the sensitivity analysis technique developed by Lash and Fink to assess the impact of each source of bias on the outcome. RESULTS: After correcting for each source of bias and reincorporating random error into our results, the point estimate of effect comparing those who received placebo to those who received zinc changed slightly (SMR changed from 0.92 to 0.90) but the 95% interval increased 22% (changing from 0.73-1.16 in the conventional analysis to 0.65-1.26 in the sensitivity analysis). CONCLUSIONS: The findings of this sensitivity analysis serve as a reminder that the frequentist confidence interval underestimates the total error, even in a randomized controlled trial. Authors of randomized controlled trial investigations ought to conduct a complete assessment of the impact of potential sources of bias in their studies. CONSORT guidelines for reporting trial results should be updated to encourage authors to assess the impact of non-random errors on their studies.

Antimalarials↗

Physicians' assessments of adjuvant tamoxifen's effectiveness in older patients with primary breast cancer.

OBJECTIVES: To examine physicians' assessments of tamoxifen effectiveness in breast cancer patients, identify predictors of these assessments, and estimate the relationship between these assessments and receipt of tamoxifen prescription. DESIGN: A cohort of breast cancer patients aged 65 and older at diagnosis and their physicians were surveyed using mailed questionnaires and telephone interviews. SETTING: Community and academic hospitals in Rhode Island; North Carolina; Minnesota; and Los Angeles, California between 1996 and 1998. PARTICIPANTS: Physicians completed treatment recommendation forms for 496 of 865 Stage Ic to IIIa breast cancer patients. MEASUREMENTS: Visual scales measured physicians' assessments of the risk that individual patients would have a breast cancer recurrence or die of breast cancer with, and without, tamoxifen therapy. RESULTS: The mean risk ratio+/-standard deviation comparing risk of recurrence without tamoxifen with the risk with tamoxifen was 1.8+/-1.0 and for breast cancer mortality was 1.8+/-1.2. Only estrogen-receptor status and enrollment site emerged as significant predictors of recurrence and mortality risk ratios in regression models. Patients for whom the physician estimated that the recurrence or mortality risk doubled without tamoxifen were more likely to receive a tamoxifen prescription than patients for whom the physician estimated that tamoxifen would have no effect (odds ratio (OR)=1.4, 95% confidence interval (CI)=0.98-2.1 for recurrence risk, OR=1.8; 95% CI=1.2-2.6 for mortality risk). CONCLUSION: Estrogen receptor status most strongly influenced physicians' assessments of tamoxifen's effectiveness in individual patients; this effectiveness was not found to be associated with advancing patient age. Estrogen receptor status and enrollment site were related to receipt of tamoxifen prescription, but advancing age was not after accounting for physician's individualized assessment of tamoxifen's effectiveness. These findings suggest that an evidence-based approach for hormonal therapy has been widely adopted for care of older patients with breast cancer.

Aged↗