Flagging unusual clusters based on linear mixed models using weighted and self-calibrated predictors.

Statistical models incorporating cluster-specific intercepts are commonly used in hierarchical settings, for example, observations clustered within patients or patients clustered within hospitals. Predicted values of these intercepts are often used to identify or "flag" extreme or outlying clusters, such as poorly performing hospitals or patients with rapid declines in their health. We consider a variety of flagging rules, assessing different predictors, and using different accuracy measures. Using theoretical calculations and comprehensive numerical evaluation, we show that previously proposed rules based on the 2 most commonly used predictors, the usual best linear unbiased predictor and fixed effects predictor, perform extremely poorly: the incorrect flagging rates are either unacceptably high (approaching 0.5 in the limit) or overly conservative (eg, much <0.05 for reasonable parameter values, leading to very low correct flagging rates). We develop novel methods for flagging extreme clusters that can control the incorrect flagging rates, including very simple-to-use versions that we call "self-calibrated." The new methods have substantially higher correct flagging rates than previously proposed methods for flagging extreme values, while controlling the incorrect flagging rates. We illustrate their application using data on length of stay in pediatric hospitals for children admitted for asthma diagnoses.

Community-level social vulnerability and individual socioeconomic status on liver transplant referral outcome.

BACKGROUND: Recent endeavors emphasize the importance of understanding early barriers to liver transplantation (LT) by consistently collecting data on patient demographics, socioeconomic factors, and geographic social deprivation indices. METHODS: In this retrospective single-center cohort study of 1657 adults referred for LT evaluation, we assessed the association between community-level vulnerability and individual socioeconomic status measures on the rate of waitlisting and transplantation. Patients' addresses were linked to Social Vulnerability Index (SVI) at the census tract-level to characterize community-level vulnerability. Descriptive statistics were used to describe patient characteristics. Multivariable cause-specific HRs were used to assess the association between community-level vulnerability, individual measures of the socioeconomic status, and LT evaluation outcomes (waitlist and transplantation). RESULTS: Among the 1657 patients referred for LT during the study period, 54% were waitlisted and 26% underwent LT. A 0.1 increase in overall SVI correlated with an 8% lower rate of waitlisting (HR 0.92, 95% CI 0.87-0.96, p < 0.001), with socioeconomic status, household characteristics, housing type and transportation, and racial and ethnic minority status domains contributing significantly to this association. Patients residing in more vulnerable communities experienced a 6% lower rate of transplantation (HR 0.94, 95% CI 0.91- 0.98, p = 0.007), with socioeconomic status and household characteristic domain of SVI significantly contributing to this association. At the individual level, both government insurance and employment status were associated with lower rates of waitlisting and transplantation. There was no association with mortality prior to waitlisting or mortality while on the waitlist. CONCLUSION: Our findings indicate that both individual and community measures of the socioeconomic status (overall SVI) are associated with LT evaluation outcomes. Furthermore, we identified individual measures of neighborhood deprivation associated with both waitlisting and transplantation.

Post-diagnostic health behaviour scores and risk of prostate cancer progression and mortality.

BACKGROUND: Individual behaviours are associated with prostate cancer (PC) progression. Behavioural scores, comprised of multiple risk factors, allow assessment of the combined impact of multiple behaviours. METHODS: We examined the association between six a priori scores and risk of PC progression and mortality among 2156 men with PC in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort: two scores developed based on the PC survivorship literature ('2021 Score [+ Diet]'); a score developed based on pre-diagnostic PC literature ('2015 Score'); and three scores based on US recommendations for cancer prevention ('WCRF/AICR Score') and survival ('ACS Score [+ Alcohol]'). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for progression and PC mortality via parametric survival models (interval censoring) and Cox models, respectively. RESULTS: Over a median (IQR) of 6.4 (1.3, 13.7) years, we observed 192 progression and 73 PC mortality events. Higher (i.e., healthier) 2021 Score + Diet and WCRF/AICR Scores were inversely associated with risk of PC progression (2021 + Diet: HRcontinuous = 0.76, 95% CI: 0.63-0.90. WCRF/AICR: HRcontinuous = 0.83, 95% CI: 0.67-1.02) and mortality (2021 + Diet: HRcontinuous = 0.65, 95% CI: 0.45-0.93. WCRF/AICR: HRcontinuous = 0.71; 95% CI: 0.57-0.89). The ACS Score + Alcohol was only associated with progression (HRcontinuous = 0.89, 95% CI: 0.81-0.98) while the 2021 Score was only associated with PC mortality (HRcontinuous = 0.62, 95% CI: 0.45-0.85). The 2015 was not associated with PC progression or mortality. CONCLUSION: Findings strengthen the evidence that behavioural modifications following a prostate cancer diagnosis may improve clinical outcomes.

Mammography prevalence in Mexico from 2001-2018: Results from the Mexican Health and Aging study.

After introducing guidelines for breast cancer screening in 2003, Mexico began to prioritize the implementation of mammography screening nationally. Since then, there have been no studies assessing changes in mammography in Mexico using the two-year prevalence interval that corresponds to national guidelines for screening frequency. The present study analyzes the Mexican Health and Aging Study (MHAS), a national population-based panel study of adults aged 50 and older, to evaluate changes in 2-year mammography prevalence among women aged 50 to 69 across five survey waves from 2001 to 2018 (n = 11,773). We calculated unadjusted and adjusted mammography prevalence by survey year and health insurance type. Overall prevalence increased substantially from 2003 to 2012 and leveled off in the period from 2012 to 2018 (2001: 20.2 % [95 % CI 18.3, 22.1]; 2003: 22.7 % [20.4, 25.0]; 2012: 56.5 % [53.2, 59.7]; 2015: 62.0 % [58.8, 65.2]; 2018: 59.4 % [56.7,62.1]; unadjusted prevalence). Prevalence was higher among respondents with social security insurance, who are more likely to work in the formal economy, than among respondents without social security, who are more likely to work in the informal economy or be unemployed. The overall prevalence estimates observed were higher than previously published estimates of mammography prevalence in Mexico. More research is needed to confirm findings regarding two-year mammography prevalence in Mexico and to better understand the causes of observed disparities.

Trends in FDA Adverse Events Reporting for Inferior Vena Cava Filters and Estimated Insertions in the US, 2016 to 2020.

This quality improvement study identifies adverse events for inferior vena cava filters and reports changes in adverse event reporting and estimated insertions between 2016 and 2020 in the US.

Diagnostic methods for uncovering outcome dependent visit processes.

With the advent of electronic health records, information collected in the course of regular health care is increasingly being used for clinical research. The hope is that the wealth of clinical data and the realistic setting (compared with information derived from highly controlled experiments like randomized trials) will aid in the investigation of determinants of disease and understanding of which treatments are effective in regular practice and for which patients. The availability of information in such databases is often driven by how a patient feels and may therefore be associated with the health outcomes being considered. We call this an outcome dependent visit process and recent work has shown that ignoring the outcome dependence can produce significant bias in the regression coefficients when fitting longitudinal data models. It is therefore important to have tools to recognize datasets exhibiting outcome dependence. We develop a score statistic to motivate the form of diagnostic test statistics, suggest a variety of approaches for diagnosing such situations, and evaluate their performance. Simple diagnostic tests achieve high power for diagnosing outcome dependent visit processes. This occurs when generalized estimating equations methods begin to be exhibit bias in estimating regression coefficients and before likelihood based methods are substantially biased.

Regional variations in longitudinal pulmonary function: A comparison of Hispanic and non-Hispanic subjects with cystic fibrosis in the United States.

BACKGROUND: Hispanic subjects with cystic fibrosis (CF) have increased morbidity and mortality than non-Hispanic white subjects. The ethnic disparity in mortality varies by region. Factors influencing pulmonary function vary by both ethnicity and region. OBJECTIVE: To determine if the ethnic difference in pulmonary function varies by region. METHODS: This retrospective cohort study compared differences in longitudinal pulmonary function (percent-predicted forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1 ], forced expiratory flow at 25% to 75% [FEF25-75 ], FEV1 /FVC, and FEV1 decline) between Hispanic and non-Hispanic white subjects with CF by Census region of the United States (West, South, Midwest, and Northeast). Subjects were of ages 6 to 25 years and in the CF Foundation Patient Registry from 2008 to 2013. We used linear mixed effects models with subject-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. RESULTS: Of 14 932 subjects, 1433 (9.6%) were Hispanic and 13 499 (90.4%) were non-Hispanic white. Hispanic subjects' FEV1 was 9.0% (8.3%-9.8%) lower than non-Hispanic white subjects in the West, while Hispanic subjects' FEV1 was only 4.0% (3.0%-5.0%) lower in the Midwest, 4.4% (3.1%-5.7%) lower in the Northeast, and 4.4% (3.2%-5.5%) lower in the South. Similarly, FVC and FEF25-75 were lower among Hispanic subjects compared to non-Hispanic white subjects in all US regions, with the biggest differences in the West. Only in the West was FEV1 /FVC significantly lower in Hispanic subjects (-0.019; -0.022 to -0.015). FEV1 decline was not significantly different between ethnicities in any region. CONCLUSIONS: In CF, Hispanic subjects have lower pulmonary function than non-Hispanic white subjects in all geographic regions with the largest difference in occurring in the West.

Analysis of longitudinal data from outcome-dependent visit processes: Failure of proposed methods in realistic settings and potential improvements.

The timing and frequency of the measurement of longitudinal outcomes in databases may be associated with the value of the outcome. Such visit processes are termed outcome dependent, and previous work showed that conducting standard analyses that ignore outcome-dependent visit times can produce highly biased estimates of the associations of covariates with outcomes. The literature contains several classes of approaches to analyze longitudinal data subject to outcome-dependent visit times, and all of these are based on simplifying assumptions about the visit process. Based on extensive discussions with subject matter investigators, we identified common characteristics of outcome-dependent visit processes that allowed us to evaluate the performance of existing methods in settings with more realistic visit processes than have been previously investigated. This paper uses the analysis of data from a study of kidney function, theory, and simulation studies to examine a range of settings that vary from those where all visits have a low degree of missingness and outcome dependence (which we call "regular" visits) to those where all visits have a high degree of missingness and outcome dependence (which we call "irregular" visits). Our results show that while all the approaches we studied can yield biased estimates of some covariate effects, other covariate effects can be estimated with little bias. In particular, mixed effects models fit by maximum likelihood yielded little bias in estimates of the effects of covariates not associated with the random effects and small bias in estimates of the effects of covariates associated with the random effects. Other approaches produced estimates with greater bias. Our results also show that the presence of some regular visits in the data set protects mixed model analyses from bias but not other methods.

Pulmonary function disparities exist and persist in Hispanic patients with cystic fibrosis: A longitudinal analysis.

BACKGROUND: Hispanic patients with cystic fibrosis (CF) have decreased life expectancy compared to non-Hispanic white patients. Pulmonary function is a main predictor of life expectancy in CF. Ethnic differences in pulmonary function in CF have been understudied. The objective was to compare longitudinal pulmonary function between Hispanic and non-Hispanic white patients with CF. METHODS: This cohort study of 15 018 6-25 years old patients in the CF Foundation Patient Registry from 2008 to 2013 compared FEV1 percent predicted and longitudinal change in FEV1 percent predicted in Hispanic to non-Hispanic white patients. We used linear mixed effects models with patient-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. We did sub-analyses by CFTR class, F508del copies, and PERT use. RESULTS: Hispanic patients had lower FEV1 percent predicted (79.9%) compared with non-Hispanic white patients (85.6%); (-5.8%, 95%CI -6.7% to -4.8%, P < 0.001), however, there was no difference in FEV1 decline over time. Patients on PERT had a larger difference between Hispanic and non-Hispanic white patients in FEV1 percent predicted than patients not on PERT (-6.0% vs -4.1%, P = 0.02). The ethnic difference in FEV1 percent predicted was not statistically significant between CFTR classes (Class I-III: -6.1%, Class IV-V: -5.9%, Unclassified: -5.7%, P > 0.05) or between F508del copies (None: -7.6%, Heterozygotes: -5.6%, Homozygotes: -5.3%, P > 0.05). CONCLUSIONS: Disparities in pulmonary function exist in Hispanic patients with CF early in life and then persist without improving or worsening over time. It is valuable to investigate the factors contributing to pulmonary function in Hispanic patients with CF.

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.

BACKGROUND: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals. METHODS AND FINDINGS: We included cognitively unimpaired individuals aged 60-75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer's Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60-64, 65-69, 70-75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60-64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65-69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70-75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80-85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%-38.45% at age 60-64 y, 30.76%-40.26% at 65-69 y, and 33.3%-35.17% at 70-75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables. CONCLUSIONS: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies-with implications for informed consent and design for clinical trials targeting high-risk individuals.

Influence of neighbourhood socioeconomic position on the transition to type II diabetes in older Mexican Americans: the Sacramento Area Longitudinal Study on Aging.

OBJECTIVE: To examine the influence of neighbourhood socioeconomic position (NSEP) on development of diabetes over time. DESIGN: A longitudinal cohort study. SETTING: The data reported were from the Sacramento Area Latino Study on Aging, a longitudinal study of the health of 1789 older Latinos. PARTICIPANTS: Community-dwelling older Mexican Americans residing in the Sacramento Metropolitan Statistical Area. MAIN OUTCOME: Multistate Markov regression were used to model transitions through four possible states over time: 1=normal; 2=pre-diabetic; 3=diabetic; and 4=death without diabetes. RESULTS: At baseline, nearly 50% were non-diabetic, 17.5% were pre-diabetic and nearly 33% were diabetic. At the end of follow-up, there were a total of 824 people with type 2 diabetes. In a fully adjusted MSM regression model, among non-diabetics, higher NSEP was not associated with a transition to pre-diabetes. Among non-diabetics, higher NSEP was associated with an increased risk of diabetes (HR=1.66, 95% CI 1.14 to 2.42) and decreased risk of death without diabetes (HR: 0.56, 95% CI 0.33 to 0.96). Among pre-diabetics, higher NSEP was significantly associated with a transition to non-diabetic status (HR: 1.22, 95% CI 0.99 to 1.50). Adjusting for BMI, age, education, physical activity, smoking, alcohol consumption, medical insurance and nativity did not affect this relationship. CONCLUSIONS: Our findings show that high NSEP poses higher risk of progression from normal to diabetes compared with a lower risk of death without diabetes. This work presents a possibility that these associations are modified by nativity or culture.

Biased and unbiased estimation in longitudinal studies with informative visit processes.

The availability of data in longitudinal studies is often driven by features of the characteristics being studied. For example, clinical databases are increasingly being used for research to address longitudinal questions. Because visit times in such data are often driven by patient characteristics that may be related to the outcome being studied, the danger is that this will result in biased estimation compared to designed, prospective studies. We study longitudinal data that follow a generalized linear mixed model and use a log link to relate an informative visit process to random effects in the mixed model. This device allows us to elucidate which parameters are biased under the informative visit process and to what degree. We show that the informative visit process can badly bias estimators of parameters of covariates associated with the random effects, while allowing consistent estimation of other parameters.

Racial and Ethnic Differences in Advance Directive Possession: Role of Demographic Factors, Religious Affiliation, and Personal Health Values in a National Survey of Older Adults.

BACKGROUND: Black and Hispanic older Americans are less likely than white older Americans to possess advance directives. Understanding the reasons for this racial and ethnic difference is necessary to identify targets for future interventions to improve advance care planning in these populations. METHODS: The aim of the study was to evaluate whether racial and ethnic differences in advance directive possession are explained by other demographic factors, religious characteristics, and personal health values. A general population survey was conducted in a nationally representative sample using a web-enabled survey panel of American adults aged 50 and older (n = 2154). RESULTS: In a sample of older Americans, white participants are significantly more likely to possess advance directives (44.0%) than black older Americans (24.0%, p < 0.001) and Hispanic older Americans (29.0%, p = 0.006). Gender, age, retired or disabled employment status, educational attainment, religious affiliation, Internet access, preferences for physician-centered decision making, and desiring longevity regardless of functional status were independent predictors of advance directive possession. In fully adjusted multivariable models with all predictors included, black older Americans remained significantly less likely than white older Americans to have an advance directive (odds ratio [OR] = 0.42, 95% confidence interval [CI] = 0.24-0.75), whereas the effect of Hispanic ethnicity was no longer statistically significant (OR = 0.65, 95% CI = 0.39-1.1). CONCLUSION: In a nationally representative sample, black race is an independent predictor for advance directive possession. This association remains even after adjustment for other demographic variables, religious characteristics, and personal health values. These findings support targeted efforts to mitigate racial disparities in access to advance care planning.

Gender Differences in the Combined Effects of Cardiovascular Disease and Osteoarthritis on Progression to Functional Impairment in Older Mexican Americans.

BACKGROUND: Comorbidity (COM) is an important issue in aging. Cardiovascular disease (CVD) and osteoarthritis separately and together may modify the trajectories of functional decline. This analysis examines whether specific and unrelated COMs influence functional change differently and vary by gender. METHODS: A cohort study of 1,789 (aged 60 years and older) Mexican Americans was followed annually for up to 10 years. We created four groups of COM (CVD alone, lower body osteoarthritis alone [OA], neither, or both). We employed mixed effects Poisson models with Instrumental Activities of Daily Living (IADL) as the outcome. We tested whether the association between COM and decline in functional status differed by gender. RESULTS: IADL impairments in those with CVD, OA, or both were significantly higher at baseline and increased more rapidly over time compared to those with neither condition. Compared to women with no COM, the number of IADL impairments in women with CVD alone were 1.36 times greater, with OA were 1.35 times greater, and both conditions were 1.26 times greater. Compared to men with no COM, IADL impairments in men with CVD alone were 1.15 times greater, OA alone were 1.12 times greater, and both were 1.26 times greater. CONCLUSIONS: Over time, the influence of COM on functional decline differs by specific combinations of COM and by gender. Aggregate COM scales obscure the biological and temporal heterogeneity in the effects of COM. Time-dependent-specific COMs better assess the development of impairment. Women experience a higher burden of functional impairment due to COM than men.

Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study.

INTRODUCTION: The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS. METHODS: We conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates. RESULTS: Plasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman's rho = 0.37, p < 0.01). Overall mortality was 16%. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury. CONCLUSION: Elevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.

Mental Health Diagnoses 3 Years After Receiving or Being Denied an Abortion in the United States.

OBJECTIVES: We set out to assess the occurrence of new depression and anxiety diagnoses in women 3 years after they sought an abortion. METHODS: We conducted semiannual telephone interviews of 956 women who sought abortions from 30 US facilities. Adjusted multivariable discrete-time logistic survival models examined whether the study group (women who obtained abortions just under a facility's gestational age limit, who were denied abortions and carried to term, who were denied abortions and did not carry to term, and who received first-trimester abortions) predicted depression or anxiety onset during seven 6-month time intervals. RESULTS: The 3-year cumulative probability of professionally diagnosed depression was 9% to 14%; for anxiety it was 10% to 15%, with no study group differences. Women in the first-trimester group and women denied abortions who did not give birth had greater odds of new self-diagnosed anxiety than did women who obtained abortions just under facility gestational limits. CONCLUSIONS: Among women seeking abortions near facility gestational limits, those who obtained abortions were at no greater mental health risk than were women who carried an unwanted pregnancy to term.

Trajectories of fear of recurrence in women with breast cancer.

PURPOSE: Although fear of recurrence (FCR) is common among cancer survivors, it remains unclear what factors predict initial levels (e.g., prior to surgery) or changes in FCR in the post-treatment period. Among women treated for breast cancer, this study evaluated the effects of demographic, clinical, symptom, and psychosocial adjustment characteristics on the initial (preoperative) levels of FCR and trajectories of FCR over 6 months following surgery. METHODS: Prior to and for 6 months following breast cancer surgery, 396 women were assessed for demographic and clinical (disease and treatment) characteristics, symptoms, psychological adjustment characteristics, and quality of life (QOL). FCR was assessed using a four-item subscale from the QOL instrument. Hierarchical linear modeling was used to examine changes in FCR scores and to identify predictors of inter-individual differences in preoperative FCR levels and trajectories over 6 months. RESULTS: From before surgery to 6 months post-operatively, women with breast cancer showed a high degree of inter-individual variability in FCR. Preoperatively, women who lived with someone, experienced greater changes in spiritual life, had higher state anxiety, had more difficulty coping, or experienced more distress due to diagnosis or distress to family members reported higher FCR scores. Patients who reported better overall physical health and higher FCR scores at enrollment demonstrated a steeper decrease in FCR scores over time. CONCLUSIONS: These findings highlight inter-individual heterogeneity in initial levels and changes in FCR over time among women undergoing breast cancer surgery. Further work is needed to identify and provide interventions for women experiencing FCR during and after breast cancer treatment.

Persistent arm pain is distinct from persistent breast pain following breast cancer surgery.

UNLABELLED: Persistent pain following breast cancer surgery is well documented. However, it is not well characterized in terms of the anatomic site affected (ie, breast, arm). In 2 separate growth mixture modeling analyses, we identified subgroups of women (N = 398) with distinct breast pain and arm pain trajectories. The fact that these latent classes differed by anatomic site, types of tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. The purposes of this companion study were to identify demographic and clinical characteristics that differed between the 2 arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection sites, pain qualities, pain interference, and hand and arm function, as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the moderate arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and axillary lymph node dissection site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility. PERSPECTIVE: For persistent breast and arm pain, changes in sensation following breast cancer surgery were notable. Persistent arm pain was associated with sustained interference with daily functioning and upper body mobility impairments. Long-term management of persistent pain following breast cancer surgery is warranted to improve the quality of survivorship for these women.

Likelihood-based analysis of longitudinal data from outcome-related sampling designs.

Investigators commonly gather longitudinal data to assess changes in responses over time and to relate these changes to within-subject changes in predictors. With rare or expensive outcomes such as uncommon diseases and costly radiologic measurements, outcome-dependent, and more generally outcome-related, sampling plans can improve estimation efficiency and reduce cost. Longitudinal follow up of subjects gathered in an initial outcome-related sample can then be used to study the trajectories of responses over time and to assess the association of changes in predictors within subjects with change in response. In this article, we develop two likelihood-based approaches for fitting generalized linear mixed models (GLMMs) to longitudinal data from a wide variety of outcome-related sampling designs. The first is an extension of the semi-parametric maximum likelihood approach developed in Neuhaus, Scott and Wild (2002, Biometrika 89, 23-37) and Neuhaus, Scott and Wild (2006, Biometrics 62, 488-494) and applies quite generally. The second approach is an adaptation of standard conditional likelihood methods and is limited to random intercept models with a canonical link. Data from a study of attention deficit hyperactivity disorder in children motivates the work and illustrates the findings.

COVARIATE DECOMPOSITION METHODS FOR LONGITUDINAL MISSING-AT-RANDOM DATA AND PREDICTORS ASSOCIATED WITH SUBJECT-SPECIFIC EFFECTS.

Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within-subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject-specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are `missing at random' (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between- and within-cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy-to-use approach to simultaneously protect against bias from both cluster-level confounding and MAR missingness in assessments of change.