Jaclyn L. F. Bosco

A most stubborn bias: No adjustment method fully resolves confounding by indication in observational studies

OBJECTIVE To evaluate the effectiveness of methods that control for confounding by indication, we compared breast cancer recurrence rates among women receiving adjuvant chemotherapy with those who did not. STUDY DESIGN AND SETTING In a medical record review-based study of breast cancer treatment in older women (n=1798) diagnosed between 1990 and 1994, our crude analysis suggested that adjuvant chemotherapy was positively associated with recurrence (hazard ratio [HR]=2.6; 95% confidence interval [CI]=1.9, 3.5). We expected a protective effect, so postulated that the crude association was confounded by indications for chemotherapy. We attempted to adjust for this confounding by restriction, multivariable regression, propensity scores (PSs), and instrumental variable (IV) methods. RESULTS After restricting to women at high risk for recurrence (n=946), chemotherapy was not associated with recurrence (HR=1.1; 95% CI=0.7, 1.6) using multivariable regression. PS adjustment yielded similar results (HR=1.3; 95% CI=0.8, 2.0). The IV-like method yielded a protective estimate (HR=0.9; 95% CI=0.2, 4.3); however, imbalances of measured factors across levels of the IV suggested residual confounding. CONCLUSION Conventional methods do not control for unmeasured factors, which often remain important when addressing confounding by indication. PS and IV analysis methods can be useful under specific situations, but neither method adequately controlled confounding by indication in this study.

Metformin and Incident Breast Cancer among Diabetic Women: A Population-Based Case–Control Study in Denmark

Background: Preliminary evidence suggests that metformin may decrease breast cancer risk by decreasing insulin levels and reducing cell proliferation. We evaluated the effect of metformin medication on the risk of incident breast cancer among peri- and postmenopausal women. Methods: We used Danish medical registries to conduct a nested case–control study among type 2 diabetic women 50 years or older who resided in northern Denmark from 1989 to 2008 (n = 4,323). We identified 393 diabetic cases and used risk-set sampling to select 10 diabetic controls per case (n = 3,930) matched on county of residence. Odds ratios (OR) and 95% CIs were estimated by conditional logistic regression associating metformin use with breast cancer occurrence. Results: Ninety-six cases (24%) and 1,154 controls (29%) used metformin for at least 1-year duration. Cases were slightly older on average than controls, but they were similar in distribution for parity, use of hormone replacement therapy, and history of diabetes complications. Metformin users were less likely with a diagnosis of breast cancer (OR = 0.77; 95% CI = 0.61–0.99) than nonmetformin users. Adjustment for diabetes complications, clinically diagnosed obesity, and important predictors of breast cancer did not substantially alter the association (OR = 0.81; 95% CI = 0.63–0.96). Conclusion: Our results suggest that metformin may protect against breast cancer in type 2 diabetic peri- or postmenopausal women. Impact: This study supports the growing evidence of a role for metformin in breast cancer chemoprevention. Cancer Epidemiol Biomarkers Prev; 20(1); 101–11. ©2011 AACR.

Use of Antiepileptic Medications in Pregnancy in Relation to Risks of Birth Defects

PURPOSE To evaluate use of specific antiepileptic drugs (AEDs) in pregnancy in relation to specific birth defects. METHODS Using data from the National Birth Defects Prevention Study, we assessed use of AEDs and the risk of neural tube defects (NTDs), oral clefts (OCs), heart defects (HDs), hypospadias, and other major birth defects, taking specific agent, timing, and indication into consideration. RESULTS Drug-specific increased risks were observed for valproic acid in relation to NTDs [adjusted odds ratio (aOR), 9.7;, 95% confidence interval (CI), 3.4-27.5], OCs (aOR, 4.4; 95% CI, 1.6-12.2), HDs (aOR, 2.0; 95% CI, 0.78-5.3), and hypospadias (aOR. 2.4; 95% CI, 0.62-9.0), and for carbamazapine in relation to NTDs (aOR, 5.0; 95% CI, 1.9-12.7). Epilepsy history without AED use did not seem to increase risk. CONCLUSIONS Valproic acid, which current guidelines suggest should be avoided in pregnancy, was most notable in terms of strength and breadth of its associations. Carbamazapine was associated with NTDs, even after controlling for folic acid use. Sample sizes were still too small to adequately assess risks of less commonly used AEDs, but our findings support further study to identify lower risk options for pregnant women.

The Personal Patient Profile-Prostate decision support for men with localized prostate cancer: A multi-center randomized trial ☆

OBJECTIVE The purpose of this trial was to compare usual patient education plus the Internet-based Personal Patient Profile-Prostate, vs. usual education alone, on conflict associated with decision making, plus explore time-to-treatment, and treatment choice. METHODS A randomized, multi-center clinical trial was conducted with measures at baseline, 1-, and 6 months. Men with newly diagnosed localized prostate cancer (CaP) who sought consultation at urology, radiation oncology, or multi-disciplinary clinics in 4 geographically-distinct American cities were recruited. Intervention group participants used the Personal Patient Profile-Prostate, a decision support system comprised of customized text and video coaching regarding potential outcomes, influential factors, and communication with care providers. The primary outcome, patient-reported decisional conflict, was evaluated over time using generalized estimating equations to fit generalized linear models. Additional outcomes, time-to-treatment, treatment choice, and program acceptability/usefulness, were explored. RESULTS A total of 494 eligible men were randomized (266 intervention; 228 control). The intervention reduced adjusted decisional conflict over time compared with the control group, for the uncertainty score (estimate -3.61; (confidence interval, -7.01, 0.22), and values clarity (estimate -3.57; confidence interval (-5.85,-1.30). Borderline effect was seen for the total decisional conflict score (estimate -1.75; confidence interval (-3.61,0.11). Time-to-treatment was comparable between groups, while undecided men in the intervention group chose brachytherapy more often than in the control group. Acceptability and usefulness were highly rated. CONCLUSION The Personal Patient Profile-Prostate is the first intervention to significantly reduce decisional conflict in a multi-center trial of American men with newly diagnosed localized CaP. Our findings support efficacy of P3P for addressing decision uncertainty and facilitating patient selection of a CaP treatment that is consistent with the patient values and preferences.

Maternal Vasoactive Exposures, Amniotic Bands, and Terminal Transverse Limb Defects

BACKGROUND Limb reduction deficiencies that are accompanied by amniotic bands (AB-Ls) and terminal transverse limb deficiencies (TLDs) have each been attributed to vascular disruption; for the former, however, it is not clear if amniotic bands are the primary cause of or are secondary to vascular disruption. If amniotic bands are secondary to vascular disruption, then a shared pathogenesis for each case group might be exhibited by similar risk factors. METHODS We evaluated maternal age, education, race/ethnicity, parity, pregnancy wantedness, and vasoactive exposures among 139 AB-L and 373 TLD cases, using interview data collected from mothers in 10 states by the National Birth Defects Prevention Study. Vasoactive exposures included maternal cigarette smoking and use of decongestants, nonsteroid anti-inflammatory drugs, and antihypertensive drugs in the periconceptional period. RESULTS Increased risk estimates were observed for Black mothers (OR 2.5; 95% CI: 1.5-4.1) and nulliparous mothers (2.1; 1.4-3.0) in relation to AB-L, while neither was associated with TLD. Hispanic women (1.4; 1.0-1.9) and those not wanting the pregnancy (1.5; 1.1-2.1) had increased risks of TLD, but not AB-L. Maternal cigarette smoking and aspirin use each increased the risk of AB-L, but not TLD; while decongestants and possibly antihypertensive medications increased the risk of TLD, but not AB-L. CONCLUSIONS The lack of consistent findings for the two case groups suggests that AB-L and TLD may be distinct entities. The inconsistencies also suggest that these vasoactive exposures may not be markers for vascular disruption or that vascular disruption may not play a major role in the pathogenesis of these two types of limb deficiencies.

Referral, Receipt, and Completion of Chemotherapy in Patients With Early-Stage Breast Cancer Older Than 65 Years and at High Risk of Breast Cancer Recurrence

PURPOSE Some women with early-stage breast cancer are at higher risk of recurrence and can benefit from chemotherapy. We describe patterns of referral, receipt, and completion of chemotherapy among older women at high risk of recurrence. PATIENTS AND METHODS A total of 2,124 women age 65 years or older who were diagnosed with early-stage breast cancer between 1990 and 1994 and 1996 to 1999 were included; 1,090 of these were at high risk of recurrence. We reviewed medical records to categorize chemotherapy outcomes as follows: did not discuss or were not referred to a medical oncologist (n = 133); discussed and/or referred to a medical oncologist but received no chemotherapy (n = 742); received an incomplete chemotherapy course (n = 29), or received a completed chemotherapy course (n = 186). RESULTS Overall, 19.7% of high-risk women received any chemotherapy, and 86.5% of these women completed their chemotherapy courses. Just greater than 10% of high-risk women did not have a discussion about chemotherapy as part of breast cancer treatment documented in the medical record; these women also received fewer diagnostic assessments of their initial tumors. CONCLUSION Individuals who receive chemotherapy for early-stage breast cancer are a select subgroup of patients at high risk of recurrence. This study identifies characteristics of women who were referred for and who received chemotherapy, and this study plays an important role in understanding generalizability of studies that examine chemotherapy treatment effectiveness. Outcomes after breast cancer could continue to be improved with increased receipt of chemotherapy among older women at high risk of breast cancer recurrence.

Age, Comorbidity, and Breast Cancer Severity: Impact on Receipt of Definitive Local Therapy and Rate of Recurrence among Older Women with Early Stage Breast Cancer

BACKGROUND The definitive local therapy options for early-stage breast cancer are mastectomy and breast-conserving surgery followed by radiation therapy. Older women and those with comorbidities frequently receive breast-conserving surgery alone. The interaction of age and comorbidity with breast cancer severity and their impact on receipt of definitive therapy have not been well-studied. STUDY DESIGN In a cohort of 1,837 women aged 65 years and older receiving treatment for early-stage breast cancer in 6 integrated health care delivery systems in 1990-1994 and followed for 10 years, we examined predictors of receiving nondefinitive local therapy and assessed the impact on breast cancer recurrence within levels of severity, defined as level of risk for recurrence. RESULTS Age and comorbidity were associated with receipt of nondefinitive therapy. Compared with those at low risk, women at the highest risk were less likely to receive nondefinitive therapy (odds ratio = 0.32; 95% CI, 0.22-0.47), and women at moderate risk were about half as likely (odds ratio = 0.54; 95% CI, 0.35-0.84). Nondefinitive local therapy was associated with higher rates of recurrence among women at moderate (hazard ratio = 5.1; 95% CI, 1.9-13.5) and low risk (hazard ratio = 3.2; 95% CI, 1.1-8.9). The association among women at high risk was weak (hazard ratio = 1.3; 95% CI, 0.75-2.1). CONCLUSIONS Among these older women with early-stage breast cancer, decisions about therapy partially balanced breast cancer severity against age and comorbidity. However, even among women at low risk, omitting definitive local therapy was associated with increased recurrence.

Personal preferences and discordant prostate cancer treatment choice in an intervention trial of men newly diagnosed with localized prostate cancer.

BackgroundMen diagnosed with localized prostate cancer (LPC) can choose from multiple treatment regimens and are faced with a decision in which medical factors and personal preferences are important. The Personal Patient Profile-Prostate (P3P) is a computerized decision aid for men with LPC that focuses on personal preferences. We determined whether the P3P intervention improved the concordance of treatment choice with self-reported influential side-effects compared with a control group.MethodsEnglish/Spanish-speaking men diagnosed with LPC (2007–2009) from four US cities were enrolled into a randomized trial and followed through 6-months via mailed or online questionnaire. Men were randomized to receive the P3P intervention or standard education plus links to reputable websites. We classified choice as concordant if men were concerned with (a) sexual function and chose external beam radiotherapy or brachytherapy, (b) bowel function and chose prostatectomy, (c) sex, bowel, and/or bladder function and chose active surveillance, or (d) not concerned with any side effect and chose any treatment. Using logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between the P3P intervention and concordance.ResultsOf 448 men, most were <65 years, non-Hispanic white, had multiple physician consultations prior to enrollment, and chose a treatment discordant with concerns about potential side effects. There was no significant difference in concordance between the intervention (45%) and control (50%) group (OR = 0.82; 95%CI = 0.56, 1.2).ConclusionsThe P3P intervention did not improve concordance between potential side effects and treatment choice. Information and/or physician consultation immediately after diagnosis was likely to influence decisions despite concerns about side effects. The intervention may be more effective before the first treatment options consultation.Trial registrationNCT00692653 http://clinicaltrials.gov/ct2/show/NCT00692653

Patient self-appraisal of change and minimal clinically important difference on the European organization for the research and treatment of cancer quality of life questionnaire core 30 before and during cancer therapy

BackgroundClinical interpretation of health related quality of life (HRQOL) scores is challenging. The purpose of this analysis was to interpret score changes and identify minimal clinically important differences (MCID) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) before (T1) and during (T2) cancer treatment.MethodsPatients (N = 627) in stem cell transplant (SCT) and medical (MED) or radiation (RAD) oncology at two comprehensive cancer centers, enrolled in the Electronic Self-Report Assessment-Cancer study and completed the QLQ-C30 at T1 and T2. Perceived changes in five QOL domains, physical (PF), emotional (EF), social (SF), cognitive functioning (CF) and global quality of life (QOL), were reported using the Subject Significance Questionnaire (SSQ) at T2. Anchored on SSQ ratings indicating “improvement”, “the same”, or “deterioration”, means and effect sizes were calculated for QLQ-C30 score changes. MCID was calculated as the mean difference in QLQ-C30 score changes reflecting one category change on SSQ rating, using a two-piece linear regression model.ResultsA majority of SCT patients (54%) perceived deteriorating global HRQOL versus improvement (17%), while approximately equal proportions of MED/RAD patients perceived improvement (25%) and deterioration (26%). Global QOL decreased 14.2 (SCT) and 2.0 (MED/RAD) units, respectively, among patients reporting “the same” in the SSQ. The MCID ranged 5.7-11.4 (SCT) and 7.2-11.8 (MED/RAD) units among patients reporting deteriorated HRQOL; ranged 2.7-3.4 units among MED/RAD patients reporting improvement. Excepting for the global QOL (MCID =6.9), no meaningful MCID was identified among SCT patients reporting improvement.ConclusionsCancer treatment has greater impact on HRQOL among SCT patients than MED/RAD patients. The MCID for QLQ-C30 score change differed across domains, and differed for perceived improvement and deterioration, suggesting different standards for self-evaluating changes in HRQOL during cancer treatment. Specifically, clinical attention can be focused on patients who report at least a 6 point decrease, and for patients who report at least a 3 point increase on QLQ-C30 domains.Trial registrationThe trial was registered with ClinicalTrials.gov: NCT00852852

Reproducibility of reported nutrient intake and supplement use during a past pregnancy: a report from the Children's Oncology Group

Maternal diet and nutrition have been thought to play a role in many childhood conditions. Studies using food frequency questionnaires (FFQ) have reported associations with maternal diet, but these findings are difficult to interpret because the reliability and validity of the FFQs for diet during a past pregnancy are not known. We determined the reproducibility of reported diet and supplement use during a past pregnancy in a subset of mothers interviewed for a case-control study of maternal diet in relation to the risk of childhood brain tumours. Cases were Childrens Oncology Group patients, diagnosed at age <6 with medulloblastoma or primitive neuroectodermal tumour from 1991 to 1997. Area code, race/ethnicity, and birth date matched controls were selected by random-digit-dialling. Case and control mothers completed a modified Willett FFQ a mean of 5 years after the index childs birth. A mean of 3.6 months later, a subset of mothers consisting of 52 case and 51 control mothers repeated the interview; these comprise the reproducibility study population. The mean intra-class correlation was 0.59 (range 0.41, 0.69) for energy-adjusted nutrients from dietary sources only; it was 0.41 (range 0.06, 0.70) when supplements were included. Agreement for reporting multivitamin use during pregnancy by time period and pattern was good to very good (kappa = 0.66-0.85). Overall, the reproducibility of nutrient estimates and supplement use in pregnancy was good and similar to that reported for adult diet.