Data Management for Applications of Patient Reported Outcomes.

CONTEXT: Patient reported outcomes (PROs) are one means of systematically gathering meaningful subjective information for patient care, population health, and patient centered outcomes research. However, optimal data management for effective PRO applications is unclear. CASE DESCRIPTION: Delivery systems associated with the Health Care Systems Research Network (HCSRN) have implemented PRO data collection as part of the Medicare annual Health Risk Assessment (HRA). A questionnaire assessed data content, collection, storage, and extractability in HCSRN delivery systems. FINDINGS: Responses were received from 15 (83.3 percent) of 18 sites. The proportion of Medicare beneficiaries completing an HRA ranged from less than 10 to 42 percent. Most sites collected core HRA elements and 10 collected information on additional domains such as social support. Measures for core domains varied across sites. Data were collected at and prior to visits. Modes included paper, clinician entry, patient portals, and interactive voice response. Data were stored in the electronic health record (EHR) in scanned documents, free text, and discrete fields, and in summary databases. MAJOR THEMES: PRO implementation requires effectively collecting, storing, extracting, and applying patient-reported data. Standardizing PRO measures and storing data in extractable formats can facilitate multi-site uses for PRO data, while access to individual PROs in the EHR may be sufficient for use at the point of care. CONCLUSION: Collecting comparable PRO data elements, storing data in extractable fields, and collecting data from a higher proportion of eligible respondents represents an optimal approach to support multi-site applications of PRO information.

Incident atrial fibrillation and the risk of fracture in the cardiovascular health study.

In this prospective cohort of 4462 older adults, incident atrial fibrillation (AF) was not statistically significantly associated with subsequent risk of incident fracture. INTRODUCTION: AF is associated with stroke, heart failure, dementia, and death, but its association with fracture is unknown. Therefore, we examined the association of incident AF with the risk of subsequent fracture in the Cardiovascular Health Study (CHS) cohort. METHODS: Of the CHS participants aged ≥65 years, 4462 were followed between 1991 and 2009, mean follow-up 8.8 years. Incident AF was identified by annual study electrocardiogram (ECG), hospital discharge diagnosis codes, or Medicare claims. Fractures of the hip, distal forearm, humerus, or pelvis were identified using hospital discharge diagnosis codes or Medicare claims. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between incident AF (time-varying) and the risk of subsequent fracture. We also evaluated whether AF was associated with risk of sustaining a fall. RESULTS: Crude incident fracture rate was 22.9 per 1000 person-years in participants with AF and 17.7 per 1000 person-years in participants without AF. Individuals with incident AF were not at significantly higher risk of hip fracture (adjusted HR = 1.09, 95 % CI 0.83-1.42) or fracture at any selected site (adjusted HR = 0.97, 95 % CI 0.77-1.22) or risk of sustaining a fall (adjusted HR = 1.00, 95 % CI = 0.87-1.16) compared with those without AF. CONCLUSION: In this cohort of older, community-dwelling adults, incident AF was not shown to be associated with falls or hip or other fractures.

Case-control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke.

We conducted a population-based case-control study to assess the myocardial infarction (MI) and stroke risks associated with sulphonylureas and insulin when used in combination with metformin. Cases had type 2 diabetes and used metformin + insulin or metformin + sulphonylureas at the time of a first MI or first stroke between 1995 and 2010; controls used the same treatment combinations and were randomly sampled from the same population. MI and stroke diagnoses and potential confounders were validated by medical record reviews. Compared with metformin + sulphonylurea, metformin + insulin was associated with similar risks of MI or stroke [odds ratio 0.98 (95% confidence interval 0.63-1.52)]. Meta-analysis with another observational study improved the precision of the risk estimate [relative risk 0.92 (95% confidence interval 0.69-1.24)]. Current evidence suggests that there may not be large differences in cardiovascular risk associated with the use of insulin or sulphonylureas when used in combination with metformin.

Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent Alzheimer dementia (AD). METHODS: We analyzed the association of prior NSAID exposure with incident dementia and AD in the Adult Changes in Thought population-based cohort aged > or = 65 years (median 74.8) at enrollment. Participants were members of Group Health, which provided computerized pharmacy dispensing records from 1977 onward. We studied 2,736 dementia-free enrollees with extensive prior pharmacy data, following them biennially for up to 12 years to identify dementia and AD. Cox proportional hazards regression assessed association of dementia or AD with NSAID use graded in standard daily doses (SDD) dispensed over 2 years (e.g., heavy use = 500 + SDD), with some analyses also adding consecutive biennial self-reports of NSAID use. RESULTS: Pharmacy records identified 351 participants (12.8%) with history of heavy NSAID use at enrollment. Another 107 became heavy users during follow-up. Some 476 individuals developed incident dementia, 356 with AD (median onset ages 83.5 and 83.8 years). Contrary to the hypothesis that NSAIDs protect against AD, pharmacy-defined heavy NSAID users showed increased incidence of dementia and AD, with adjusted hazard ratios of 1.66 (95% confidence interval, 1.24-2.24) and 1.57 (95% confidence interval, 1.10-2.23). Addition of self-reported exposure data did not alter these results. CONCLUSIONS: These findings differ from those of other studies with younger cohorts. The results observed elsewhere may reflect delayed onset of Alzheimer dementia (AD) in nonsteroidal anti-inflammatory drug (NSAID) users. Conceivably, such delay could result in increased AD incidence in late old age. The relation of NSAID use and AD pathogenesis needs further investigation.

Blood pressure control and risk of incident atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia that affects more than 2 million people in the United States. We sought to determine whether the risk of incident AF among patients treated for hypertension differs by the degree of blood pressure control. METHODS: A population-based, case-control study of 433 patients with verified incident AF and 899 controls was conducted to investigate the relationship between average achieved systolic (SBP) and diastolic (DBP) blood pressure and risk of AF. All patients were members of an integrated health-care delivery system and were pharmacologically treated for hypertension. Medical records were reviewed to confirm the diagnosis of new onset AF and to collect information on medical conditions, health behaviors, and measured blood pressures. Average achieved SBP and DBP were calculated from the three most recent outpatient blood pressure measurements. RESULTS: Compared with the reference level of 120-129 mm Hg, for categories of average achieved SBP of <120, 130-139, 140-149, 150-159, 160-169, and > or =170 mm Hg, the odds ratios (ORs; 95% confidence interval (CI)) for incident AF were 1.99 (1.10, 3.62), 1.19 (0.78, 1.81), 1.40 (0.93, 2.09), 2.02 (1.30, 3.15), 2.27 (1.31, 3.93), and 1.84 (0.89, 3.80), respectively. Based on the population attributable fraction, we estimated that, among patients with treated hypertension, 17.2% (95% CI 4.3%, 28.3%) of incident AF was attributable to an average achieved SBP > or =140 mm Hg. CONCLUSION: Among patients treated for hypertension, uncontrolled elevated SBP and SBP <120 mm Hg were associated with an increased risk of incident AF.

Diabetes and the risk of prostate cancer: the role of diabetes treatment and complications.

Epidemiologic evidence suggests diabetic men have a slightly lower prostate cancer risk than non-diabetic men. We examined this association in a prospective cohort study of 35 239 men, 50-76 years old, in Washington State who completed a baseline questionnaire between 2000 and 2002. Incident prostate cancers as of 31 December 2004 were identified through the SEER registry. Diabetic men had a slightly lower risk of prostate cancer than non-diabetic men (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.64-1.07). Insulin users overall and insulin users with diabetic complications had decreased risks, compared to non-diabetic men (HR 0.49, 95% CI 0.26-0.92) and (HR 0.36, 95% CI 0.15-0.87), respectively. Oral medication use for diabetes was not associated with prostate cancer. Insulin is likely a marker of severity of diabetes. Future studies of this association should consider diabetes type, treatment, severity, complications and biomarkers.

Maternal and neonatal outcomes after induction of labor without an identified indication.

OBJECTIVE: This study was undertaken to examine associations between induction of labor and maternal and neonatal outcomes among women without an identified indication for induction. STUDY DESIGN: This was a population-based cohort study of 2886 women with induced labor and 9648 women with spontaneous labor who were delivered at 37 to 41 weeks' gestation, all without identified medical and obstetric indications for induction. RESULTS: Among nulliparous women 19% of women with induced labor versus 10% of those with spontaneous labor underwent cesarean delivery (adjusted relative risk, 1.77; 95% confidence interval, 1.50-2.08). No association was seen in multiparous women (relative risk, 1.07; 95% confidence interval, 0. 81-1.39). Among all women induction was associated with modest increases in instrumental delivery (19% vs 15%; relative risk, 1.20; 95% confidence interval, 1.09-1.32) and shoulder dystocia (3.0% vs 1. 7%; relative risk, 1.32; 95% confidence interval, 1.02-1.69). CONCLUSION: Among women who lacked an identified indication for induction of labor, induction was associated with increased likelihood of cesarean delivery for nulliparous but not multiparous women and with modest increases in the risk of instrumental delivery and shoulder dystocia for all women.

Accounting for time-dependent covariates whose levels are influenced by exposure status.

When measuring the association between an exposure and disease, one must decide whether to account for confounding or modifying variables whose levels are altered by the presence of the exposure. For example, to assess the impact of cessation of unopposed estrogen therapy on the occurrence of endometrial cancer, a researcher needs to consider the duration of the estrogen therapy, a strong risk factor for endometrial cancer, as a potential confounder or effect modifier. Duration of estrogen therapy, however, is itself influenced by the decision to stop the therapy (the "exposure" of interest). In such a case, two distinct approaches may be taken, depending upon the question being considered. One may wish to assess the degree to which the exposure predicts disease incidence, over and above the additional variable, at some later point in time. In this case, it is appropriate to consider the value of the other variable (for example, duration) at that later time. On the other hand, one may also wish to measure the rate of disease beginning at the time of cessation of the exposure, relative to the corresponding rate in persons with continuing exposure Here, the most appropriate analysis considers the level of the confounding variable (for example, duration) measured only until the time of exposure of interest occurs (for example, cessation of unopposed estrogen therapy). Examples are given to illustrate that the specific question being addressed dictates the handling of covariates of this type.

Methods for rapid detection of a recurrent nonsense mutation and documentation of phenotypic features in neurofibromatosis type 1 patients.

We have developed a rapid screening method to detect a recurrent mutation in the neurofibromatosis type 1 gene. Using gene amplification and hybridization with allele-specific oligonucleotides, we screened 97 unrelated affected individuals for the recurrent C-->T substitution in codon 1947. The mutation was detected in 1 patient and found to cosegregate with the disease phenotype in the patient's family. Although the estimated prevalence of this mutation is low, rapid screening of different patient cohorts would identify multiple individuals carrying the same mutation. Such data would provide the first opportunity for examining correlations between phenotypic characteristics and molecular genotype and would allow clinicians to offer early diagnosis and prenatal screening to affected families. A format for the comparison of phenotypic features in other settings is presented.

Perinatal transmission of HIV type 1: associations with maternal anti-HIV serological reactivity. Mothers and Infants Cohort Study and the HIV-1 Perinatal Serology Working Group.

As a hypothesis-generating study of large regions of the human immunodeficiency virus type 1 (HIV-1) envelope, we collaborated with several laboratories to test sera from subgroups of 65 HIV-1-positive pregnant women, 18 (28%) of whom transmitted the virus to their infants. Assays included neutralizing antibodies to HIVLAI and reactivity to 102 HIV-1 Env peptides with sequences based on strains LAI, MN, SC, RF, and WMJ-2 as well as several clinical isolates, spanning about 65% of gp120 and about 80% of gp41. Results for the V3 loop and for neutralizing activity were conflicting and for the most part did not reach statistical significance. Transmission risk appeared lower with reactivity to a few gp41 epitopes (amino acids 571-585, 736-750, and perhaps 650-663), whereas risk appeared higher with reactivity to two gp120 epitopes (amino acids 466-480 and 475-486) and one gp41 epitope (amino acids 547-576). However, these associations could have occurred simply by chance because such a large number of peptides was tested. With independently synthesized peptides, results between laboratories often were inconsistent. However, reproducibility was good (rank correlation coefficient > or = 0.78) when the same protocols and peptides were used. Although this study could not identify a humoral immune response to linear Env peptides that consistently and broadly protected against perinatal transmission of HIV-1, there were regions of gp120 and gp41 that should be evaluated in larger cohorts and with techniques to investigate potential conformational epitopes and neutralization to autologous or clinical isolates of HIV-1 from the community.

Patterns and predictors of high-risk sexual behavior in female partners of HIV-infected men with hemophilia.

OBJECTIVE: To characterize and quantify high-risk heterosexual activity in HIV-discordant couples. DESIGN: Analysis of cross-sectional and longitudinal questionnaire data from 217 HIV-negative female sexual partners of HIV-infected hemophilic men. METHODS: Comparison of prevalence rates of anal sex, oral sex, vaginal intercourse with or without condoms, and use of other contraceptives between 1985 and 1991. Logistic regression analysis of demographic, sexual and clinical variables to predict unprotected vaginal sex. Actuarial estimates of semi-annual relapse rates to unsafe sex. RESULTS: The proportion of women at low risk increased from 7 to 69% between 1985 and 1991, mainly because more women were using condoms during all acts of vaginal intercourse. Other contraceptive practices did not change during this time. The proportion engaging in oral or anal sex decreased (from 26 to 13% and 13 to 4%, respectively). Unprotected vaginal sex was more common among women who enrolled earlier, had less education, engaged in oral or anal sex, and among those whose partners had not had AIDS. Unprotected vaginal sex before enrollment was the strongest predictor of this high-risk activity during follow-up. Two-year rates of relapse to high-risk behavior were significantly higher among women who enrolled at high risk compared with those who enrolled at low risk (39 versus 8%, P = 0.005). CONCLUSIONS: Although high-risk sexual behavior became much less prevalent in this population between 1985 and 1991, many continued to have unprotected vaginal sex occasionally. Counseling efforts should target couples who have been the most sexually active or have less education, and should emphasize not only initial risk reduction but also maintenance of low-risk behavior.

PIP: This study sought to characterize and quantify the high-risk heterosexual activity in HIV-discordant couples. An analysis of cross-sectional and longitudinal questionnaire data from 217 HIV-negative female sexual partners of HIV-infected hemophiliac men were included in this study. There was a comparison of prevalence rates of anal sex, oral sex, vaginal intercourse with or without condoms, and use of other contraceptives between 1985-91. Logistic regression analysis of demographic, sexual, and clinical variables was used to predict unprotected vaginal sex. Actuarial estimates of semiannual relapse rates to unsafe sex were used. The proportion of women at low risk increases from 7 to 69% between 1985-91, mainly because more women were using condoms during all acts of vaginal intercourse. Other contraceptive practices did not change during this time. The proportion who engaged in oral or anal sex decreased from 26 to 13% and from 13% to 4%, respectively. Unprotected vaginal sex was more common among women who enrolled earlier, had less education, engaged in oral or anal sex, and among those whose partners had not had AIDS. Unprotected vaginal sex before enrollment was the strongest predictor of this high-risk activity during followup. 2-year rates of relapse to high-risk behavior were significantly higher among women who enrolled at high risk compared with those who enrolled at low risk (39 vs 8%, p=0.005). Although high risk sexual behavior become much less prevalent in this population between 1985-91, many continued to have unprotected vaginal sex occasionally. Counseling efforts should target couples who have been the most sexually active or have less education, and should emphasize not only initial risk reduction but also maintenance of low-risk behavior.