The effect of missing data and imputation on the detection of bias in cognitive testing using differential item functioning methods.

BACKGROUND: Item response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies. METHODS: We used data from Visit 6 (2016-2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection. RESULTS: When missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation. CONCLUSIONS: Incorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing.

Assessing Bias in Cognitive Testing for Older Adults with Sensory Impairment: An Analysis of Differential Item Functioning in the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

OBJECTIVES: Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition. METHODS: Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5-4 kHz pure-tone average > 25 decibels). RESULTS: We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p = .04) and in BLSA: .62 logits (p = .02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p = .001) and Incidental Learning test in ARIC-NCS: .35 logits (p = .001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement. CONCLUSIONS: DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

Hearing loss is associated with cortical thinning in cognitively normal older adults.

BACKGROUND AND PURPOSE: Hearing loss (HL) is one of the most influential risk factors of dementia in older adults. However, its potential association with neurodegeneration is not well established. The association between HL and cortical thickness in cognitively normal older adults was evaluated. METHODS: In all, 982 cognitively normal older adults (age ≥65 years) were identified from the Health Promotion Center at the Samsung Medical Center from September 2008 to December 2014. The participants underwent pure-tone audiometry and brain magnetic resonance imaging. HL was evaluated according to a four-frequency (0.5, 1, 2, 4 kHz) pure-tone average. Participants were divided into three groups according to pure-tone average (normal hearing ≤15 dB, minimal HL 16-25 dB, mild-to-severe HL >25 dB). Cortical thickness in the HL groups was compared with that of the normal hearing group. RESULTS: In women, right ear HL was associated with cortical thinning: the minimal HL group showed cortical thinning in the left frontal and bilateral occipital areas and the mild-to-severe HL group showed cortical thinning in the bilateral frontal, right temporal and bilateral occipital areas compared to the normal hearing group. In men, there was no significant association between HL on either side and cortical thickness. CONCLUSION: In older women, right ear HL is associated with neurodegeneration even in a cognitively normal state. Therefore, managing HL especially in older women may be an effective strategy for dementia prevention.

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells.

The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

Slowing the progression of age-related hearing loss: Rationale and study design of the ASPIRIN in HEARING, retinal vessels imaging and neurocognition in older generations (ASPREE-HEARING) trial.

BACKGROUND: Age-related hearing loss (ARHL) is a leading cause of disability in the elderly. Low-grade inflammation and microvessel pathology may be responsible for initiating or exacerbating some of the hearing loss associated with aging. A growing body of evidence demonstrates an association of hearing loss with cognitive decline. A shared etiological pathway may include a role of inflammation, alongside vascular determinants. The ASPREE-HEARING study aims to determine whether low-dose aspirin decreases the progression of ARHL, and if so, whether this decrease in progression is also associated with retinal microvascular changes and/or greater preservation of cognitive function. DESIGN AND METHODS: A three year double-blind, randomized controlled trial of oral 100mg enteric-coated aspirin or matching placebo, enrolling 1262 Australians aged ≥70years with normal cognitive function and no overt cardiovascular disease. The primary outcome is the change in mean pure tone average hearing threshold (decibels) in the better ear, over a 3-year period. Secondary outcomes consist of changes in retinal microvascular indicators, and changes in cognitive function. Participants are recruited from a larger trial, ASPirin in Reducing Events in the Elderly (ASPREE), which is designed to assess whether daily low dose aspirin will extend disability-free life. DISCUSSION: ASPREE-HEARING will determine whether aspirin slows development or progression of ARHL, and will interrogate the relationship between inflammatory and microvascular mechanisms that may underlie the effects of aspirin on ARHL. This study will improve understanding of the patterns of comorbidity with, and the relationships between, aging and ARHL, alongside modeling the impacts of ARHL.

Association of hearing impairment with brain volume changes in older adults.

Hearing impairment in older adults is independently associated in longitudinal studies with accelerated cognitive decline and incident dementia, and in cross-sectional studies, with reduced volumes in the auditory cortex. Whether peripheral hearing impairment is associated with accelerated rates of brain atrophy is unclear. We analyzed brain volume measurements from magnetic resonance brain scans of individuals with normal hearing versus hearing impairment (speech-frequency pure tone average>25 dB) followed in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging for a mean of 6.4 years after the baseline scan (n=126, age 56-86 years). Brain volume measurements were performed with semi-automated region-of-interest (ROI) algorithms, and brain volume trajectories were analyzed with mixed-effect regression models adjusted for demographic and cardiovascular factors. We found that individuals with hearing impairment (n=51) compared to those with normal hearing (n=75) had accelerated volume declines in whole brain and regional volumes in the right temporal lobe (superior, middle, and inferior temporal gyri, parahippocampus, p<.05). These results were robust to adjustment for multiple confounders and were consistent with voxel-based analyses, which also implicated right greater than left temporal regions. These findings demonstrate that peripheral hearing impairment is independently associated with accelerated brain atrophy in whole brain and regional volumes concentrated in the right temporal lobe. Further studies investigating the mechanistic basis of the observed associations are needed.

Correlative study on the expression of p53 and DNA ploidy in acute nonlymphocytic leukemia.

We used the flow cytometric immunoassay to study the correlation between the rumor-suppressor gene product p53- and the DNA ploidy in 30 de novo cases of acute nonlymphocytic leukemia (ANLL). The results showed that 15 cases were positive expression for p53. As compared with p53 negative (p53) cases, the patients with positive p53 (p53+) had higher percentage of bone marrow blasts and lower peripheral leukocyte and platelet counts, which had no influence on the complete remission rate. Before treatment, DNA diploidy was seen in 18 cases including 12 p53- cases, and DNA aneuploidy in 12 cases including 9 p53+. After therapy, aneuploidy could be transformed into diploidy. Patients with P53+ or having aneuploidy in complete remission were at risk for early relapse. We believe that p53 may be involved in the process of leukemogenesis and progression of ANLL.

Functional status of pancreatic islet in acute leukemia.

Using enzymatic assay and radioimmunoassay, we studied the functional status of pancreatic islet in 50 patients with acute leukemia. Oral glucose tolerance test and insulin and C peptide release were made in 40 patients before and after treatment. 14 patients who revealed diabetic curve and delayed insulin and C peptide release before treatment showed normal values in 6 after therapy. Five patients with impaired glucose tolerance and decreased insulin and C peptide release before treatment showed normalization of these parameters following therapy. Five patients with normal pretreatment values disclosed abnormal post-treatment results. The remaining 16 patients displayed normal results both before and after therapy. Anti-insulin antibodies were negative, and glucagon level was normal in all the 50 patients. The red cell insulin receptor binding rate analysed in 47 patients was significantly higher than in controls (P < 0.001). We considered that the disturbed glucose metabolism in acute leukemia was not uncommon mainly due to the dysfunction of pancreatic islet beta cells as a result of islet damage by leukemic cells, the effect of corticosteroid and chemotherapy and the preexisting diabetes. Impaired glucose metabolism had no influence on therapeutic effect.

Pathological features of coronary atherosclerotic plaques in nonagenarians.

The atherosclerotic lesions from 4 major epicardial coronary arteries (left main, left anterior descending, left circumflex and right coronary arteries) of 23 nonagenarians patients were compared with that from 23 patients aged 60-69. The arteries were cut into transversely 5 mm long segments and were examined by microscope. The inside circumferences of the lumen were measured by computerized morphometric analysis. The results showed that the numbers of atherosclerotic plaques, percentages of narrowing of the coronary arterial lumen and circumferences of the arterial lumen in both groups were similar. But there were much more fibrous and resting (silent) or regressive plaques in the group aged 90-99 years as well as less lipid and active or progressive plaques than those in the group of 60-69 years. The above morphological findings may be correlated with the fact that there was a similar incidence of coronary heart disease but a less risk of acute myocardial infarction in patients aged 90-99 years than those aged 60-69 years.

[Malignant tumors in patients aged 60 and over--an analysis of 208 autopsy cases].

From the autopsy of 617 cases aged 60 and over, 208 cases with malignant tumor were found. The detection rate of malignant tumor was 35.8% in male and 26.4% in female. Malignant tumor was the cause of death in 26.0% of male patients and 19.3% of female ones. Malignant tumor was the second most common cause of death in the elders. The incidence of malignant tumors increased with age in male, but it peaked in the 70s age group in female. The top three most common malignant tumors were carcinoma of the lung(8.6%), stomach (5.9%), and liver (4.6%) in men, and that of the lung (7.9%), stomach (3.6%), and colon (2.9%) in women. It must be pointed out that the incidence of malignant tumor in three medical eras gradually increased. It was 19.8% in the period from 1952 to 1969, 23.5% from 1970 to 1979 and 26.0% from 1980 to 1992.

Etoposide-based combination chemotherapy in malignant histiocytosis.

We investigated the responses of patients with malignant histiocytosis (MH) to the treatment of epotoside-based regimen. Of 11 evaluable cases, 9 (81.8%) achieved complete remission and 1 partial remission. 7 complete remission cases (77.7%) received only one therapeutic course. The side effects were mild and well-tolerated. We conclude that etoposide-containing regimen is highly effective and can be used as first-line treatment for MH and is worthy of further study.

Plasma ammonia in patients with acute leukemia.

Plasma ammonia level (PAL) was studied in 43 cases of acute leukemia (AL). PAL was 39.21 +/- 26.2 mumol/L in normal controls and 38.8 +/- 16.6 mumol/L in leukemic patients before chemotherapy. High PAL was found in 40 cases after chemotherapy. Six cases showed clinical manifestations due to severe hyperammonemia, including dizziness, lethargy, confusion, coma and mental changes of various degree, and there was also respiratory alkalosis. After ammonia-trapping therapy, 4 of the 5 patients recovered. The authors believe that high PAL is not uncommon after chemotherapy in leukemic patients. Respiratory alkalosis and unexplained mental and neurologic changes following intensive chemotherapy are useful clues for the diagnosis of hyperammonemia syndrome. Early diagnosis and treatment with ammonia-trapping may improve the rates of remission and survival.

Intracellular destruction of salmonellae in genetically resistant mice.

Virulent Salmonella typhimurium, 2000 LD50, were injected intraperitoneally into inbred male A/J mice, genetically resistant to salmonella infection. Peritoneal exudate cells were harvested between 5 and 54 h after infection and examined by electronmicroscopy. Polymorphs were seen ingesting as well as digesting the pathogens as early as 5 h after infection. Macrophages were equally active in destroying the phagocytosed organisms throughout this period. In the meantime, the proliferation of salmonellae appeared to occur extracellularly in the peritoneal cavity as evidenced by their division.

[Preventive action of shen mai san on heatstroke in aged rats].

15-18 month-old Wistar rats were selected and placed in 41 degrees C chamber for 12 hours. 10% Shen Mai San granule was poured into the stomachs every 3 hours. The preventive effects of this drug on heatstroke were observed. The result showed that the mortality of animal was decreased, the exhaustions of myocardial creatine phosphate and cAMP contents were significantly mitigated. By the view point of western medicine, the mechanisms recorded in traditional Chinese medicine about the preventive actions of this drug on heatstroke were also discussed in this study. The authors considered that the effects of Shen Mai San on "strengthening pulmonary Qi", "strengthening Heart Qi", might be concerned in its efficiency to stabilize the energy store in myocardium, and it might be beneficial to prevent the elderly from heatstroke.

Confirmation of destruction of salmonellae within murine peritoneal exudate cells by immunocytochemical technique.

A procedure was developed with which peritoneal exudate cell (PEC) preparations were fixed in a glutaraldehyde-picric acid mixture, post-fixed with osmium tetroxide, embedded in LR White resin and then stained with immunogold probe. It provided tissue sections showing both well-defined ultrastructures as well as specifically labelled Salmonella O antigens by electron microscopy. Inbred, male C57BL/6 mice were injected intraperitoneally with 2 x 10(7) virulent Salmonella typhimurium. Peritoneal exudate cells were harvested at 16 and 20 hr after infection. Disintegrating intracellular bacteria were identified as salmonellae by the immunogold markers. Deposition of gold particles in the cytoplasm of phagocytes also indicated that intracellular debris contained digested pathogen. This investigation therefore confirms previous findings of the destruction of salmonellae within inflammatory polymorphs and macrophages.

Electronmicroscopic studies on the location of salmonella proliferation in the murine spleen.

Highly susceptible inbred male C57BL/6 mice were infected intraperitoneally with 2 x 10(7) cfu of a virulent Salmonella typhimurium strain. Tissue sections were taken from the spleen 2 and 3 days after infection for examination by electronmicroscopy. Rapid infiltration of polymorphs and macrophages was evident at the site of infection. These inflammatory phagocytes displayed avid destructive action against ingested bacteria. Bacterial multiplication occurred primarily in extracellular locations within sinusoids or in lesions containing disintegrating host cells.

Electron microscopic studies on the location of bacterial proliferation in the liver in murine salmonellosis.

Highly susceptible inbred male C57BL/6 mice were infected with 2 X 10(7) virulent Salmonella typhimurium by intraperitoneal inoculation. Samples of the liver were removed 2 or 3 days post-infection for examination by electron microscopy. Rapid infiltration of polymorphs and macrophages was observed in the site of infection. Visual evidence is presented to confirm the destruction of salmonellae within these inflammatory phagocytes as previously reported. The proliferation of the pathogens occurred in the extracellular locations of sinusoids and early lesions, and within hepatocytes.