Regression-based Change Scores Research Articles

Cognitive function in patients with HR+ advanced breast cancer treated with endocrine therapy with or without CDK4/6 inhibitors in the SONIA trial.

1016 Background: Given the important role of estrogen in normal neuronal function, endocrine treatment for breast cancer may adversely affect cognition, including memory, planning and attention. Previous studies showed mixed results but were often underpowered. It is unknown whether CDK4/6 inhibitors have cognitive side effects. SONIA-EfFECT is a side-study of the SONIA trial that investigates cognitive functioning in HR+ advanced breast cancer patients treated with endocrine therapy with or without CDK4/6 inhibitors. Methods: Patients randomized in the SONIA trial to receive first-line treatment with aromatase inhibitors with (Arm A) or without (Arm B) CDK4/6 inhibition were approached to participate in the SONIA-EfFECT side-study. Patients were asked to identify a female relative or friend without cancer to serve as a cancer-free control. Both patients and controls were asked to complete the Amsterdam Cognition Scan, an online neuropsychological test battery, at baseline and after 9 months. Patients who switched to second-line treatment within nine months were not retested. To prevent confounding effects of imbalance in age, education, and computer use between patient groups and controls, propensity score matching was performed. Baseline cognitive function was assessed by converting raw test scores to standardized Z-scores adjusted for computer use, based on baseline performance in the matched control group. To investigate the effect of endocrine therapy ±CDK4/6 inhibitors over time, standardized regression-based change scores were computed based on baseline and follow-up performance in the matched control group. One-way analyses of variance were conducted to compare baseline performance and cognitive change between the two arms and the matched control group. Results: 260 patients (130 Arm A/130 Arm B) and 196 controls completed baseline assessments. A matched sample of 130 controls was selected. 199 patients (108 Arm A/91 Arm B) and 119 matched controls had complete follow-up assessments. Patients in both study arms performed significantly worse than the controls on the domains of verbal memory, working memory, processing speed, executive function, and motor function. In both patient arms and the controls, standardized regression-based change scores showed limited decline in cognitive function over the 9-month interval. Moreover, minimal differences in cognitive change were observed between the patients treated with and without CDK4/6 inhibitors, and between patients and the controls. Conclusions: HR+ advanced breast cancer patients show worse cognitive function on all cognitive domains compared to a control group without cancer. Nine months of treatment with endocrine therapy with or without CDK4/6 inhibitors does not further worsen cognitive function in this study. Clinical trial information: NCT03425838 .

Quantifying Individual Personality Change More Accurately by Regression-Based Change Scores

We investigated three different approaches for quantifying individual change and reporting it back to persons: (a) the common change score, which is obtained by first computing scale scores from two consecutive measurements and then subtract these scores from one another, (b) the ad-hoc approach, which is similar to the former approach but uses regression scores instead of scale scores, and (c) Kelley’s approach, which computes the change score directly from a regression. Specifically, we compared these approaches with one another with regard to the mean squared error (MSE), a measure of the accuracy of an estimator. Our findings indicated that the ad-hoc approach and Kelley’s approach provide change scores that can be more accurate in terms of the MSE than the common change score and that Kelley’s approach can be more accurate than the ad-hoc approach under certain conditions. Moreover, we present an example and provide a step by step guide to implement the approaches.

Characterization and Prediction of Short-term Outcomes in Memory After Temporal Lobe Resection in Children With Epilepsy.

The aim of this study was to characterize short-term outcomes in episodic memory, as assessed by the Children's Memory Scale (CMS), after temporal lobe resection in children with epilepsy using empirical methods for assessing cognitive change (i.e., reliable change indices [RCI] and standardized regression-based change scores [SRB]) and develop and internally validate clinically applicable models to predict postoperative memory decline. This retrospective cohort study included children aged 6-16 years who underwent resective epilepsy surgery that included the temporal lobe (temporal only: "temporal" and multilobar: "temporal plus") and who completed preoperative and postoperative neuropsychological assessments including the CMS. Change scores on the CMS delayed memory subtests (Faces, Stories, and Word Pairs) were classified as decline, no change, or improvement using epilepsy-specific RCI and SRB. Logistic regression models for predicting postoperative memory decline were developed and internally validated with bootstrapping. Of the 126 children included, most of them demonstrated either no significant change (54%-69%) or improvement (8%-14%) in memory performance using RCI on individual measures at a median of 7 months after surgery. A subset of children (23%-33%) showed postoperative declines. Change distributions obtained using RCI and SRB were not statistically significantly different from each other. Preoperative memory test score, surgery side, surgery extent, and preoperative full-scale IQ were predictors of memory decline. Prediction models for memory decline included subsets of these variables with bias-corrected concordance statistics ranging from 0.70 to 0.75. The models were well calibrated although slightly overestimated the probability of verbal memory decline in high-risk patients. This study used empiric methodology to characterize memory outcome in children after temporal lobe resection. Provided online calculator and nomograms may be used by clinicians to estimate the risk of postoperative memory decline for individual patients before surgery.

Longitudinal neurobehavioral profiles in children and young adults with PTEN hamartoma tumor syndrome and reliable methods for assessing neurobehavioral change

BackgroundIndividuals with PTEN hamartoma tumor syndrome (PHTS) demonstrate a distinct neurobehavioral profile suggesting primary disruption of frontal lobe symptoms, with more severe cognitive deficits in those with associated autism spectrum disorder (ASD) that extend to other areas of neurobehavioral function as well (e.g., adaptive behavior, sensory deficits). The current study sought to characterize longitudinal neurobehavioral profiles in individuals with PHTS who completed serial assessments (2–3 evaluations) over a 2-year time period.MethodsComprehensive neurobehavioral evaluations were conducted on 92 participants (age range 6–21) with PHTS and/or ASD. Spaghetti plots and linear mixed effects models were used to visualize the individual patient profiles and group trends and examine the group differences in cognitive/behavioral test scores over time. Practice-adjusted reliable change indices (RCIs) and standardized regression-based change scores (SRBs) were calculated for those measures in the battery with adequate sample sizes and test–retest reliabilities for future use in assessing neurobehavioral change in children and young adults with PHTS.ResultsWide individual differences were observed at baseline across all measures. Encouragingly, baseline differences between patient groups persisted at the same magnitude over a 2-year time period with no differences in longitudinal neurobehavioral profiles within any one group. Test–retest reliabilities were generally high, ranging from 0.62 to 0.97, and group mean change from baseline to 12 months was small (range − 3.8 to 3.7). A Microsoft Excel calculator was created that clinicians and researchers can use to automatically calculate RCI and SRB thresholds at both 80% and 90% confidence intervals using test scores from a given child or young adult with PHTS.ConclusionsOur results suggest that the neurobehavioral phenotypes observed in individuals with PHTS remain relatively stable over time, even in those with ASD. The RCIs and SRBs provided can be used in future research to examine patient outcomes at the individual level as well as to detect negative deviations from the expected trajectory that can be used to inform intervention strategies.

Neuropathic pain correlates with worsening cognition in people with human immunodeficiency virus.

Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants in the prospective, observational CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort underwent standardized clinical evaluations for clinical examination findings of distal sensory polyneuropathy, reporting distal neuropathic pain and neurocognitive performance at study entry (baseline) and an average of 12 years later. Change in neuropathic pain and neuropathy status from baseline to follow-up was by self-report and repeat examination, and change in neurocognitive performance was assessed using a previously published summary regression-based change score. Relationships between incident or worsened neuropathic pain and neurocognitive change were evaluated using uni- and multivariable regressions, including age at baseline and other relevant covariates. Participants were 385 people with HIV, 91 (23.6%) females, mean ± standard deviation (SD) age at baseline 43.5 (7.81) years, ethnicity 44.9% African American, 10.6% Hispanic, 42.6% non-Hispanic white and 1.82% other. Baseline median (interquartile range) nadir CD4 was 175 (34 309) cells/µl and current CD4 was 454 (279 639). Incident or worsened distal neuropathic pain occurred in 98 (25.5%) over the follow-up period. People with HIV with incident or worsened distal neuropathic pain had significantly worsened neurocognitive performance at follow-up compared to those without incident or worsened distal neuropathic pain (summary regression-based change score mean ± SD -0.408 ± 0.700 versus -0.228 ± 0.613; P = 0.0158). This effect remained significant when considering viral suppression on antiretroviral therapy, incident diabetes and other covariates as predictors. Overall neurocognitive change related to neuropathic pain was driven primarily by changes in the domains of executive function and speed of information processing. Those with incident distal neuropathy signs did not have neurocognitive worsening, nor did individuals who used opioid analgesics or other pain-modulating drugs such as amitriptyline. Worsened neurocognitive performance in people with HIV was associated with worsened neuropathic pain but not with changes in physical signs of neuropathy, and this was not attributable to therapies for pain or depression or to differences in viral suppression. This finding implies that incident or worsened pain may signal increased risk for neurocognitive impairment, and deserves more investigation, particularly if better pain management might stabilize or improve neurocognitive performance.

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years

BackgroundNeurocognitive (NC) impairment in people with HIV (PWH) is associated with important adverse outcomes, but no markers exist to predict long-term NC decline. We evaluated depressed mood and markers of persistent inflammation, oxidative stress and altered amyloid processing (all common in PWH) as predictors of NC worsening over 12 years. MethodsPWH were enrolled and followed longitudinally in the CNS HIV Antiretroviral Effects Research (CHARTER) study at six US sites. At entry we quantified biomarkers in blood of inflammation: (interleukin-6 [IL-6], C-reactive protein [CRP], monocyte chemoattractant protein type 1 [MCP-1], D-dimer, soluble sCD14 (sCD14), soluble tumor necrosis factor receptor – type II [sTNFR-II], neopterin, and soluble CD40 ligand [sCD40L], oxidative stress (protein carbonyls, 8-oxo-2'-deoxyguanosine [8-oxo-dG]) and altered amyloid processing [amyloid beta (Aβ)-42, soluble amyloid precursor protein-α (sAPPα)] using commercial immunoassays. The Beck Depression Inventory-II (BDI-II) assessed depressed mood at entry. NC decline over 12 years was evaluated using the published and validated summary (global) regression-based change score (sRBCS). A factor analysis reduced dimensionality of the biomarkers. Univariable and multiple regression models tested the relationship between baseline predictors and the outcome of neurocognitive decline. ResultsParticipants were 191 PWH, 37 (19.4%) women, 46.6% African American, 43.5% non-Hispanic white, 8.83% Hispanic, 15.7% white, 1.6% other; at study entry mean (SD) age 43.6 (8.06) years, estimated duration of HIV infection (median, IQR) 9.82 [4.44, 14.5] years, nadir CD4 104/μL (19,205), current CD4 568/μL (356, 817), and 80.1% had plasma HIV RNA <50 c/mL. Participants were enrolled between 2003 and 2007; median (IQR) duration of follow-up 12.4 [9.69, 16.2] years. Three biomarker factors were identified: Factor (F)1 (IL-6, CRP), F2 (sTNFR-II, neopterin) and F3 (sCD40L, sAPPα). Participants with higher F1, reflecting worse systemic inflammation at baseline, and higher F3, had greater decline in global neurocognition (r ​= ​−0.168, p ​= ​0.0205 and r ​= ​−0.156, p ​= ​0.0309, respectively). Of the F1 components, higher CRP levels were associated with worse decline (r ​= ​−0.154, p ​= ​0.0332), while IL-6 did not (r ​= ​−0.109, p ​= ​0.135). NC change was not significantly related to F2, nor to demographics, nadir and current CD4, viral suppression or baseline NC comorbidity ratings. Individuals with worse depressed mood at entry also experienced more NC decline (r ​= ​−0.1734, p ​= ​0.0006). Together BDI-II (p ​= ​0.0290), F1 (p ​= ​0.0484) and F3 (p ​= ​0.0309) contributed independently to NC decline (p ​= ​0.0028); their interactions were not significant. Neither CRP nor IL-6 correlated significantly with depression. ConclusionsPWH with greater systemic inflammation and more depression at entry had greater NC decline over 12 years. Understanding the basis of this inflammatory state might be particularly important. These findings raise the possibility that targeted anti-inflammatory or antidepressant therapies may help prevent NC worsening in PWH with depression and inflammation.

Development and Preliminary Validation of Standardized Regression-Based Change Scores as Measures of Transitional Cognitive Decline.

An increasing focus in Alzheimer's disease and aging research is to identify transitional cognitive decline. One means of indexing change over time in serial cognitive evaluations is to calculate standardized regression-based (SRB) change indices. This paper includes the development and preliminary validation of SRB indices for the Uniform Data Set 3.0 Neuropsychological Battery, as well as base rate data to aid in their interpretation. The sample included 1,341 cognitively intact older adults with serial assessments over 0.5-2years in the National Alzheimer's Coordinating Center Database. SRB change scores were calculated in half of the sample and then validated in the other half of the sample. Base rates of SRB decline were evaluated at z-score cut-points, corresponding to two-tailed p-values of .20 (z=-1.282), .10 (z=-1.645), and .05 (z=-1.96). We examined convergent associations of SRB indices for each cognitive measure with each other as well as concurrent associations of SRB indices with clinical dementia rating sum of box scores (CDR-SB). SRB equations were able to significantly predict the selected cognitive variables. The base rate of at least one significant SRB decline across the entire battery ranged from 26.70% to 58.10%. SRB indices for cognitive measures demonstrated theoretically expected significant positive associations with each other. Additionally, CDR-SB impairment was associated with an increasing number of significantly declined test scores. This paper provides preliminary validation of SRB indices in a large sample, and we present a user-friendly tool for calculating SRB values.

Heterogeneous Response of Chemotherapy-Related Cognitive Decline in Patients with Breast Cancer: A Prospective Study.

A significant proportion of adjuvant-treated breast cancer patients experience cognitive decline, challenging the person's ability to return to normal activities after treatment. However, not every patient experiences cognitive problems, and even in patients with impairments, determining clinically important cognitive decline remains challenging. Our objective was to explore differences in neuropsychological performance following adjuvant chemotherapy (CT) in patients with breast cancer. We conducted a prospective observational study in an Oncology Breast Clinic and assessed neuropsychological performance before and after adjuvant CT and in non-CT-treated women with breast cancer and healthy controls (HCs). Standardised between-group differences and regression-based change scores were calculated. CT-treated patients (n = 66) performed significantly different from non-CT-treated patients (n = 39) and HCs (n = 56). There was a significant effect on verbal fluency (p = .0013). CT performed significantly worse than non-CT and HC [effect size (ES) = .89, p < .001 and ES = .61, p ≤ .001, respectively] and from HCs with regard to proactive interference (ES = .62, p ≤ .001). Regression-based scores revealed more severe cognitive decline in the CT-treated group [24.24% (16/66)] than in the non-CT-treated group [15.20% (6/39)] and HC group [7.14% (4/56)]. Patients who underwent CT and showed cognitive decline were less educated and older, with significantly lower baseline scores. CT-treated patients showed more vulnerability on cognitive control and monitoring than non-CT-treated breast cancer patients and HCs. Older patients with less education and lower baseline cognitive performance represent a group at risk for cognitive decline following CT. Identification of patients at risk for decline could improve targeted support and rehabilitation.

Reliable change indices for the 37-item version of the MMSE in Spanish older adults

Objective The aim of this study was to establish reliable change and regression-based change score norms on the 37-item version of MMSE in older Spanish adults at the three-year follow-up. Method All subjects of this research were selected from the Neurological Disorders in Central Spain (NEDICES), a prospective population-based cohort study of older adults (65 years and over). Of the 4208 individuals free from neurological disorders in this cohort, 2073 participants completed the MMSE-37 at baseline and at the three-year follow-up. Reliable Change Indices were computed for the 80, 90% and 95 confidence intervals (CIs). Multiple regression analyses were used to derive equations for predicting MMSE-37 post-test scores taking into account baseline scores, time to follow-up and sociodemographic factors. Results The MMSE-37 obtained a marginal test-retest reliability (.70). The results showed significant effects of education, age, and sex on the MMSE-37 change scores. After correcting for regression to the mean, at least a 6-point change on MMSE-37 (three-years follow-up) is required to be classified as reliable (90% CI). Conclusions These findings demonstrate that the MMSE-37 is a reliable test-retest measure whose change scores are significantly influenced by sociodemographic factors. Importantly, small changes on this measure require a cautious interpretation.

Short-term practice effects in mild cognitive impairment: Evaluating different methods of change

ABSTRACTPractice effects are improvements on cognitive tests as a result of repeated exposure to testing material. However, variability exists in the literature about whether patients with amnestic mild cognitive impairment (MCI) display practice effects, which may be partially due to the methods used to calculate these changes on repeated tests. The purpose of the current study was to examine multiple methods of assessing short-term practice effects in 58 older adults with MCI. The cognitive battery, which included tests of memory (Hopkins Verbal Learning Test–Revised and Brief Visuospatial Memory Test–Revised) and processing speed (Symbol Digit Modalities Test and Trail Making Test Parts A and B), was administered twice across one week. Dependent t tests showed statistically significant improvement on memory scores (ps < .01, ds = 0.8–1.3), but not on processing speed scores. Despite this, the sample showed no clinically meaningful improvement on any cognitive scores using three different reliable change indices. Regression-based change scores did identify relatively large groups of participants who showed smaller than expected practice effects, which may indicate that this method is more sensitive in identifying individuals who may portend a declining trajectory. Practice effects remain a complex construct, worthy of continued investigation in diverse clinical conditions.

Is the HIV Dementia Scale a Reliable Tool for Assessing HIV-related Neurocognitive Decline?

Background: The HIV Dementia scale (HDS) has been recommended as a cross-sectional screen for HIVassociated neurocognitive disorder (HAND) but its longitudinal usefulness has not been optimally established. Method: 55 HIV+ participants underwent baseline and follow-up HDS screening after an average of 3.9 (SD=1.1) months. They had completed standard neuropsychological (NP) evaluations within the last 6-18 months to calculate a baseline HAND rate (49.1%) and gold standard cognitive change performance: 12.7% showed mild to moderate decline compared to normative standards for NP change; 80% confidence interval; 1-tailed, the rest of the sample was cognitively stable. After normalizing HDS raw-scores, standard regression-based change scores were developed to quantify HDS-based decline, which corrected for practice effect, regression towards the mean, and yielded individual predictions of neurocognitive change. Clinically significant decline was defined as a z-score outside the 80% confidence interval; 1-tailed. Baseline HIV disease and laboratory data were collected. Results: The magnitude of HDS reliability was very large r=0.76 (p<0.0001). HDS-testing found that 21.8% significantly declined. Compared to gold standard NP decline, the HDS showed 57% sensitivity and 82% specificity. Only participants (n=4) that declined moderately (median HDS-change z-score=-2 SD below mean of zero; at least 3-4 points decline in raw HDS-score) were congruently identified. Standard regression-based change scores did not operate optimally at smaller magnitudes of decline. HAND diagnosis (gold standard) at baseline (p<0.03) and more severe HAND were associated with greater chance of decline (p<0.03). No baseline HIV biomarkers were associated with decline. Conclusions: The HDS is a reliable screen to detect at least moderate neurocognitive decline in individuals with MND and HAD. Other screening instruments are needed to detect milder levels of neurocognitive decline. Alternatively, non-parametric statistical modelling is needed to improve predictions of individual cognitive change on such scales that typically have a restricted range of values.

Persistent Cognitive Changes in Breast Cancer Patients 1 Year Following Completion of Chemotherapy

Numerous studies have shown that there are acute cognitive side-effects of chemotherapy for breast cancer. Presumably, patients are more concerned about chronic treatment effects. This report from a prospective longitudinal study compares cognitive functioning in 56 breast cancer patients 1 year after chemotherapy to that of 56 healthy individuals. Neuropsychological test scores were combined into verbal memory, visual memory, working memory, and processing speed scores, as well as an overall summary score, and analyzed using multi-level growth modeling. Frequency of cognitive decline was assessed using regression-based change scores. There was significant rebound in the overall summary score from end of treatment to 1-year follow-up as well as a substantial reduction in the frequency of cognitive decline. However, more than one-third of the breast cancer patients who showed cognitive decline immediately following completion of chemotherapy showed persistent cognitive decline 1 year later. Furthermore, recovery was not seen in all cognitive domains. In fact, the rebound was significant only for working memory. Longer multi-site studies are recommended to explore the risk factors for and the permanence of these longer-term cognitive effects.

Normative Data in Women Aged 85 and Older: Verbal Fluency, Digit Span, and the CVLT-II Short Form

Individuals aged 85 years and above (i.e., the oldest old) represent the fastest growing segment of the US population and are at increased risk of developing dementia. This represents an important challenge for the clinical neuropsychologist, as the extant normative data on neuropsychological measures remain relatively limited for this age group. Therefore the aim of the present study was to characterize the performance effects of age and education in a large, well-characterized sample of women between the ages of 85 and 95 years on the California Verbal Learning Test-II (CVLT-II) Short Form (Delis, Kramer, Kaplan, & Ober, 2000), verbal fluency tasks, and the WAIS-III Digit Span Test (Wechsler, 1997). In order to minimize the likelihood that women with an incipient neurodegenerative process were included in the final normative sample, we applied regression-based change scores to identify and exclude women who evidenced a statistically significant decline on a global cognitive screening measure over a 20-year interval. The results of our analysis indicate varying influence of age and education on these measures and we provide tables with descriptive statistics stratified by both age and education. Findings from the present normative study are discussed within the context of “robust” longitudinal normative data.

Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy

To rigorously evaluate the time course of cognitive change in a cohort of individuals with HIV-associated neurocognitive disorders (HAND) initiating combination antiretroviral therapy (CART), and to investigate which demographic, laboratory, and treatment factors are associated with neuropsychological (NP) outcome (or "any NP improvement"). Study participants included 37 HIV+ individuals with mild to moderate NP impairment who initiated CART and underwent NP testing at 12, 24, 36, and 48 weeks thereafter. NP change was assessed using a regression-based change score that was normed on a separate NP-stable group thereby controlling for regression toward the mean and practice effect. Mixed-effect regression models adjusting for loss to follow-up were used to evaluate the time course of cognitive change and its association with baseline and time-varying predictors. In persons with HAND initiating CART, cognitive improvement happens soon after initiation (13% at week 12), but more often 24, 36, and up to 48 weeks after initiation (up to 41%), with fewer than 5% demonstrating significant worsening. In multivariate analyses, unique predictors of NP improvement included more severe baseline NP impairment and higher CART CNS penetration index. Greater viral load decrease was associated with NP improvement only in univariate analyses. Clinically meaningful neuropsychological improvement seemed to peak around 24-36 weeks after combination antiretroviral therapy initiation and was prolonged over the 1-year study period. This study also provides new evidence that benefit may be maximized by choosing antiretroviral medications that reach therapeutic concentrations in the CNS.