Analytic methods for factors, dimensions and endpoints in clinical trials for Alzheimer's disease.

Alzheimer's disease (AD) is a complex disease process, so finding a single biomarker to track in clinical trials has proven difficult. This paper describes and contrasts statistical methods that might be used with biomarkers in clinical trials for AD, highlighting their differences, limitations and interpretations. The first method is traditional regression, within which one dependent variable, the Best Empirically Supported Indicator (BESI), must be identified. In this approach one biomarker (e.g., the ratio of tau to Abeta42 from CSF) is the indicator for an individual's disease status, and change in that status. The second approach is an exploratory factor analysis (EFA) to consolidate a multitude of candidate dependent variables into a sample-dependent, mathematically-optimized smaller set of 'factors'. The third method is latent variable (LV) modeling of multiple indicators of an entity (e.g., "disease burden"). The LV approach can yield a complex 'dependent variable', the Best Measurement Model Indicator (BMMI). A measurement model represents an entity that several dependent variables reflect or measure, and so can include many 'dependent variables', and estimate their relative contributions to the underlying entity. The selection of a single BESI is an artifact of regression that limits the investigator's ability to utilize all relevant variables representing the entity of interest. EFA results in sample-specific combination of biomarkers that might not generalize to a new sample - and fit of the EFA results cannot be tested. Latent variable methods can be useful to construct powerful, efficient statistical models that optimally combine diverse biomarkers into a single, multidimensional dependent variable that can generalize across samples when they are theory-driven and not sample-dependent. This paper shows that EFA can work to uncover underlying structure, but that it does not always yield solutions that 'fit' the data. It is not recommended as a method to build BMMIs, which will be useful in establishing diagnostic criteria, creating and evaluating benchmarks, and monitoring progression in clinical trials.

Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency.

OBJECTIVES: To describe the interrelationships of thyroid functions based on trimester-specific concentrations in healthy, iodine-sufficient pregnant women across trimesters, and postpartum. METHODS: Circulating total 3,5,3'- triidothyronine (T(3)) and thyroxine (T(4)) concentrations were determined simultaneously using liquid chromatography tandem mass-spectrometry (LC/MS/MS). Free thyroxine (FT(4)), thyroid-stimulating hormone (TSH), and thyroglobulin (Tg) were measured using immunoassay techniques. Linear mixed effects models and correlations were calculated to determine trends and associations, respectively, in concentrations. RESULTS AND CONCLUSIONS: Trimester-specific T(3), FT(4), TSH, and Tg concentrations were significantly different between the first and third trimesters (all p < 0.05); second and third trimester values were not significantly different for FT(4), TSH, and Tg (all p > 0.25) although T3 was significantly higher in the third, relative to the second trimester. T(4) was not significantly different at any trimester (all p > 0.80). With two exceptions, analyte concentrations tended not to be correlated at each trimester and at 1-year postpartum. One exception was that T(3) and T(4) tended to be associated (all p < 0.05) at all time points except the third trimester (rho = 0.239, p > 0.05). T(4) and FT(4) concentrations tended to correlate positively during pregnancy (rho 0.361-0.382, all p < 0.05) but not postpartum (rho = 0.179, p > 0.05). Trends suggest that trimester-specific measurements of T(3), FT(4), Tg, and possibly TSH are warranted.

Frequency of behavioral symptoms characterizes agitation in Alzheimer's disease.

This study describes two well-characterized groups of Alzheimer's disease (AD) patients with similar levels of cognitive functioning, but with different overall behavioral disturbance levels. We sought to determine the nature of this difference-whether AD patients with higher levels of behavioral disturbance (n = 148) differ from less disturbed AD patients (n = 235) in terms of (a) the range of symptoms exhibited, (b) the frequency of occurrence of these symptoms, or (c) both of these. We defined and operationalized 'diversity of behaviors' and 'frequency' with respect to the item-level responses on the Cohen-Mansfield agitation inventory (CMAI). We found that, in these two samples of AD patients, differences occurred in the frequency of 10 out of 21 behaviors, rather than in a variety of endorsed behaviors. These 10 behaviors, observed at different frequencies in both groups, may be useful for monitoring change in studies of drugs or behavioral interventions for behavioral disturbance in persons with AD.

Interobserver disagreements on clinical dementia rating assessment: interpretation and implications for training.

The Clinical Dementia Rating (CDR) is a widely used semiobjective instrument for staging dementia severity. A global CDR score is reported that is derived from individual scores in six domains. In this study, we examined both agreement and disagreement, among raters and with a gold standard, to identify domain-specific and global dementia severity level ratings that would most benefit from further training or greater emphasis in future training. We found that raters-in-training experienced the most difficulty with rating normal and questionable dementia. They also had the most trouble scoring the memory domain. When they disagreed with the gold standard, they nearly always gave higher ratings. A third, extremely experienced group of raters were uniform in their high levels of agreement on each domain and the global CDR and tended to give lower ratings if they disagreed with the gold standard. Analysis of the agreement and disagreement patterns suggested that greater emphasis on the memory, home and hobbies, and orientation domains during CDR training, and increasing the information provided for the judgment and problem solving domain on the standardized CDR worksheets, could improve the consistency of raters and increase the efficiency with which they are trained to use the CDR.

Qualifying change: a method for defining clinically meaningful outcomes of change score computation.

OBJECTIVES: To identify clinically meaningful change in longitudinal assessment. DESIGN: A novel approach that qualifies item-level change over time by the degree to which it is clinically meaningful. SETTING: The classification method was tested by applying it to changes over 12 months in the frequency ratings of the items of a behavioral assessment instrument that is used commonly in clinical trials with Alzheimer's disease (AD) patients. PARTICIPANTS: Responses from a cohort of 235 well characterized, community-dwelling subjects with AD were analyzed by this method. MEASUREMENTS: The approach allowed us to describe the proportions of items that emerged, ceased, worsened, and improved between the baseline and 12-month visits. RESULTS AND CONCLUSIONS: One-year change in the behavioral symptoms of persons with AD was used to exemplify the methodology. This approach can be used in other populations and with other measurements and was designed for analyses of clinical trial data. This method uses item-level changes to generate global impressions of clinically meaningful change; it also facilitates the definition of change that can be used in the clinical setting.

Prevalence of symptoms on the CERAD behavior rating scale for dementia in normal elderly subjects and Alzheimer's disease patients.

The authors sought to define "abnormal" levels for total scores on the CERAD Behavioral Rating Scale for Dementia (BRSD) and for 37 BRSD items by comparing 242 patients with Alzheimer's disease (AD) and 64 normal elderly control subjects (NEC). BRSD total scores for NEC ranged as high as 52 (out of a maximum 167), and although item prevalence rates were higher for AD patients, not all of these differences were significant. Many symptoms were observed in < or = 10% of AD subjects. Lower Mini-Mental State Examination scores were not consistently associated with lower or higher levels of endorsement across all items. Over 6 and 12 months, endorsement rates were relatively stable for both groups. The authors conclude that assessment of behavior in long-term studies will be needed to quantify "abnormal" levels, and that item-level BRSD information could be important in clinical trials.

Treatment of agitation in AD: a randomized, placebo-controlled clinical trial.

BACKGROUND: Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs. OBJECTIVE: To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients. METHODS: A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden. RESULTS: Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments. CONCLUSIONS: Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.