Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

Statistical Analysis with Missing Data

Principles and Practice of Sleep Medicine

We congratulate Drs. Kang and Schafer (KS henceforth) for a careful and thought-provoking contribution to the literature regarding the so-called “double robustness” property, a topic that still engenders some confusion and disagreement. The authors’ approach of focusing on the simplest situation of estimation of the population mean μ of a response y when y is not observed on all subjects according to a missing at random (MAR) mechanism (equivalently, estimation of the mean of a potential outcome in a causal model under the assumption of no unmeasured confounders) is commendable, as the fundamental issues can be explored without the distractions of the messier notation and considerations required in more complicated settings. Indeed, as the article demonstrates, this simple setting is sufficient to highlight a number of key points.

As noted eloquently by Molenberghs (2005), in regard to how such missing data/causal inference problems are best addressed, two “schools” may be identified: the “likelihood-oriented” school and the “weighting-based” school. As we have emphasized previously (Davidian, Tsiatis and Leon, 2005), we prefer to view inference from the vantage point of semi-parametric theory, focusing on the assumptions embedded in the statistical models leading to different “types” of estimators (i.e., “likelihood-oriented” or “weighting-based”) rather than on the forms of the estimators themselves. In this discussion, we hope to complement the presentation of the authors by elaborating on this point of view.

Throughout, we use the same notation as in the paper.

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Comment: Demystifying Double Robustness: A Comparison of Alternative Strategies for Estimating a Population Mean from Incomplete Data

Hot deck imputation is a method for handling missing data in which each missing value is replaced with an observed response from a “similar” unit. Despite being used extensively in practice, the theory is not as well developed as that of other imputation methods. We have found that no consensus exists as to the best way to apply the hot deck and obtain inferences from the completed data set. Here we review different forms of the hot deck and existing research on its statistical properties. We describe applications of the hot deck currently in use, including the U.S. Census Bureau’s hot deck for the Current Population Survey (CPS). We also provide an extended example of variations of the hot deck applied to the third National Health and Nutrition Examination Survey (NHANES III). Some potential areas for future research are highlighted.

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A Review of Hot Deck Imputation for Survey Non-response.

The model-based approach to inference from multivariate data with missing values is reviewed. Regression prediction is most useful when the covariates are predictive of the missing values and the probability of being missing, and in these circumstances predictions are particularly sensitive to model misspecification. The use of penalized splines of the propensity score is proposed to yield robust model-based inference under the missing at random (MAR) assumption, assuming monotone missing data. Simulation comparisons with other methods suggest that the method works well in a wide range of populations, with little loss of efficiency relative to parametric models when the latter are correct. Extensions to more general patterns are outlined.

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Robust Likelihood-based Analysis of Multivariate Data with Missing Values

Objective: To explore the neurochemical basis of REM sleep behavior disorder (RBD) in multiple-system atrophy (MSA). Methods: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of REM atonia loss by the percentage of REM sleep with tonically increased electromyographic (EMG) activity and the percentage of REM sleep with phasic EMG bursts. PET with (+)-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ) was employed to measure the density of striatal monoaminergic terminals and SPECT with (−)-5-[ 123 I]iodobenzovesamicol ([ 123 I]IBVM) to measure the density of thalamic cholinergic terminals. Data in the patient group were compared with data from 15 normal control subjects scanned with [ 11 C]DTBZ and 12 with [ 123 I]IBVM. Results: Age and gender distributions were similar in patient and normal control groups. The MSA subjects showed decreased mean [ 11 C]DTBZ binding in the striatum ( p 123 I]IBVM binding in the thalamus ( p 11 C]DTBZ binding was inversely correlated with the severity of REM atonia loss ( p = 0.003). Thalamic [ 123 I]IBVM binding, however, was not correlated to the severity of REM atonia loss. Conclusion: Decreased nigrostriatal dopaminergic projections may contribute to RBD in MSA.

REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA

Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing.

Objective: To determine the percentage of sporadic olivopontocerebellar atrophy (sOPCA) patients who later develop multiple system atrophy (MSA). Methods: Observations of the course of 51 sOPCA patients 20 years of age or older initially evaluated in an ataxia clinic over 14 years and followed at 3- to 6-month intervals for 3 months to 10 years (median 2.5 years, interquartile range 5 months to 4 years). Results: Seventeen patients evolved to develop MSA, whereas the remaining 34 manifested only progressively worsening cerebellar ataxia. The features of the MSA cases included autonomic failure and parkinsonism in 10 patients, autonomic failure without parkinsonism in six, and parkinsonism without autonomic failure in one. Using survival analysis methods, the authors estimated that 24% of subjects in this population will evolve to MSA within 5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at onset of symptoms and a shorter time from onset of symptoms to first presentation in a neurology specialty clinic were both highly predictive of evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to 5 years after they had met diagnostic criteria for MSA. The estimated median survival time from time of transition was 3.5 years. In contrast, death occurred in only one of the 34 patients with sOPCA who did not evolve to MSA. Autopsy examination of all six patients with MSA who died confirmed the diagnosis. Conclusions: Approximately one-fourth of sporadic olivopontocerebellar atrophy patients will evolve to multiple system atrophy within 5 years, and this transition carries a poor prognosis for survival. Older age at onset of ataxia and earlier presentation in a neurologic specialty clinic predicted transition to MSA.

Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy.

Objective: To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA). Methods: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea–hypopnea index during sleep. SPECT with (−)-5-[ 123 I]iodobenzovesamicol ([ 123 I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [ 123 I]IBVM and 15 normal control subjects utilizing [ 11 C]DTBZ. Results: Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [ 123 I]IBVM binding in the thalamus ( p 11 C]DTBZ binding in the striatum ( p 123 I]IBVM binding was inversely correlated with the severity of OSA ( p = 0.011). Striatal [ 11 C]DTBZ binding was not correlated with the severity of OSA ( p = 0.19). Conclusion: Decreased pontine cholinergic projections may contribute to OSA in MSA.

Hyonggin An

Papers

Robust Likelihood-based Analysis of Multivariate Data with Missing Values

REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA

Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing.

Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy.

Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA.