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.

Patient-reported outcome measures in dysphagia: a systematic review of instrument development and validation.

OBJECTIVE: Patient-reported outcome (PRO) measures are commonly used to capture patient experience with dysphagia and to evaluate treatment effectiveness. Inappropriate application can lead to distorted results in clinical studies. A systematic review of the literature on dysphagia-related PRO measures was performed to (1) identify all currently available measures and (2) to evaluate each for the presence of important measurement properties that would affect their applicability. DESIGN: MEDLINE via the PubMed interface, the Cumulative Index of Nursing and Allied Health Literature, and the Health and Psychosocial Instrument database were searched using relevant vocabulary terms and key terms related to PRO measures and dysphagia. Three independent investigators performed abstract and full text reviews. Each study meeting criteria was evaluated using an 18-item checklist developed a priori that assessed multiple domains: (1) conceptual model, (2) content validity, (3) reliability, (4) construct validity, (6) scoring and interpretation, and (7) burden and presentation. RESULTS: Of 4950 abstracts reviewed, a total of 34 dysphagia-related PRO measures (publication year 1987-2014) met criteria for extraction and analysis. Several PRO measures were of high quality (MADS for achalasia, SWAL-QOL and SSQ for oropharyngeal dysphagia, PROMIS-GI for general dysphagia, EORTC-QLQ-OG25 for esophageal cancer, ROMP-swallowing for Parkinson's Disease, DSQ-EoE for eosinophilic esophagitis, and SOAL for total laryngectomy-related dysphagia). In all, 17 met at least one criterion per domain. Thematic deficiencies in current measures were evident including: (1) direct patient involvement in content development, (2) empirically justified dimensionality, (3) demonstrable responsiveness to change, (4) plan for interpreting missing responses, and (5) literacy level assessment. CONCLUSION: This is the first comprehensive systematic review assessing developmental properties of all available dysphagia-related PRO measures. We identified several instruments with robust measurement properties in multiple diseases including achalasia, oropharyngeal dysphagia, post-surgical dysphagia, esophageal cancer, and dysphagia related to neurological diseases. Findings herein can assist clinicians and researchers in making more informed decisions in selecting the most fundamentally sound PRO measure for a given clinical, research, or quality initiative.

Rapid assessment of Malawi's civil registration and vital statistics system.

In 2010, Malawi adopted a National Registration Act, making the registration of births and deaths compulsory, and efforts to improve Malawi's civil registration and vital statistics (CRVS) system are underway. During a participatory-style workshop, stakeholders completed a rapid assessment of the national civil registration and vital statistics systems. While participants discussed and scored each item in a standard tool, the workshop focused on sharing of partners' roles and challenges. The workshop has enhanced receptiveness in collaboration, and an inter-ministerial technical working group has now been formed to develop a strategic plan and conduct a comprehensive assessment to guide future improvements.

En 2010, le Malawi a adopté l'état-civil national, rendant l'enregistrement des naissances et des décès obligatoire, et des efforts d'amélioration du système d'enregistrement de l'état-civil et des autres statistiques vitales du Malawi sont en cours. Lors d'un atelier participatif, les partenaires ont complété l'outil d'évaluation rapide du système de l'état-civil national et des statistiques vitales. Tandis que les participants discutaient et donnaient un score à chaque élément de l'outil, l'atelier s'est concentré sur le partage des rôles des partenaires et des défis auxquels ils étaient confrontés. L'atelier a renforcé la réceptivité des participants à la collaboration et un groupe de travail technique interministériel a maintenant été formé pour développer un plan stratégique et réaliser une évaluation plus complète afin de guider les améliorations à venir.

En el 2010, Malawi adoptó la Ley Nacional del Registro, por la cual se hace obligatorio el registro de los nacimientos y las defunciones, y están en curso iniciativas tendentes a mejorar el sistema de registro civil y estadísticas vitales. En un taller de tipo participativo, los interesados directos completaron un instrumento de evaluación rápida de los sistemas de registro civil y estadísticas vitales. Los participantes examinaron y calificaron cada elemento del instrumento, y el centro de interés del taller consistió en poner en común de las funciones y las dificultades encontradas de los asociados. El taller reforzó la receptividad durante el trabajo en colaboración y se conformó un grupo de trabajo interministerial, con el propósito de elaborar un plan estratégico y llevar a cabo una evaluación exhaustiva que permita orientar las futuras medidas de perfeccionamiento.

Vitamin D status and associated factors of deficiency among Jordanian children of preschool age.

BACKGROUND/OBJECTIVES: Vitamin D deficiency in children remains a global concern. Although literature exists on the vitamin D status and its risk factors among children in the Middle East, findings have yielded mixed results, and large, representative community studies are lacking. SUBJECTS/METHODS: In a nationally representative survey of 1077 Jordanian children of preschool age (12-59 months) in Spring 2010, we measured 25(OH)D3 concentrations by liquid chromatography-tandem mass spectrometry and calculated prevalence ratios for deficiency associated with various factors. RESULTS: RESULTS showed 19.8% (95% confidence interval (CI): 16.4-23.3%) deficiency (<12 ng/ml) and 56.5% (95% CI: 52.0-61.0%) insufficiency (<20 ng/ml). In adjusted models, prevalence of deficiency was higher for females compared with males (prevalence ratio (PR)=1.74, 95% CI: 1.22-2.47, P=0.002) and lower for children 24-35 months of age (PR=0.64, 95% CI: 0.44-0.92, P=0.018) compared with children 12-23 months of age. In rural areas, there was no difference in prevalence of vitamin D deficiency between those whose mothers had/did not have vitamin D deficiency (P=0.312); however, in urban areas, prevalence of vitamin D deficiency was 3.18 times greater among those whose mothers were vitamin D deficient compared with those whose mothers were not deficient (P=0.000). CONCLUSIONS: Vitamin D deficiency and insufficiency pose significant public health problems in Jordanian children with female children disproportionately affected. Strong associations between vitamin D status in children and urban residency and maternal vitamin D status suggest that the behaviors related to sun exposure in urban mothers likely also affect the sun exposure and thus vitamin D status of their children.

Micronutrient status in Jordan: 2002 and 2010.

BACKGROUND/OBJECTIVES: Two national surveys were conducted in Jordan in 2002 and 2010 to investigate the micronutrient status in women and children. To determine the prevalence of anemia, iron and folate deficiency among women and children in 2010 and compare with the prevalence of anemia and iron deficiency in 2002. SUBJECTS/METHODS: A nationally representative survey was conducted in 2002 (1023 women, 15-49 years of age; 1059 children, 12-59 months of age) and a second survey in 2010 (2035 women; 940 children). Venous blood samples were used to measure hemoglobin, ferritin and red blood cell folate (the latter on a subsample of 393 women). RESULTS: Among women in 2010, the prevalence of folate deficiency and insufficiency was 13.6% and 82.9%, respectively. Geometric mean serum ferritin was higher in 2010 compared with 2002 (21.3 ng/ml vs 18.3, P=0.01); there was no significant change in the prevalence of iron deficiency (35.1% vs 38.7%, P=0.17), iron deficiency anemia (19.1% vs 20.0%, P=0.61) or anemia (29.2% vs 29.3%, P=0.96). Among children, a significantly lower prevalence was observed in 2010 compared with 2002 for iron deficiency (13.7% vs 26.2% P<0.001) and iron deficiency anemia (4.8% vs 10.1%, P<0.001); a nonsignificant lower prevalence was observed for anemia (16.6% vs 20.2%, P=0.09). CONCLUSIONS: In 2010, approximately one of seven women was folate deficient and six out of seven were folate insufficient for the prevention of neural tube defects. Between 2002 and 2010, significant improvement was observed in the prevalence of iron deficiency in children, but not in women.

Effects of a large-scale micronutrient powder and young child feeding education program on the micronutrient status of children 6-24 months of age in the Kyrgyz Republic.

BACKGROUND/OBJECTIVES: To combat iron and other micronutrient deficiencies, the Ministry of Health of the Kyrgyz Republic launched a regional Infant and Young Child Nutrition (IYCN) program in 2009, which included promotion of home fortification with micronutrient powder (MNP) containing iron (12.5 mg elemental iron), vitamin A (300 µg) and other micronutrients. Every 2 months children aged 6-24 months were provided 30 sachets to be taken on a flexible schedule. The objective was to assess biochemical indicators of iron and vitamin A status among children aged 6-24 months at the baseline and follow-up surveys. SUBJECTS/METHODS: Cross-sectional representative cluster surveys were conducted in 2008 (n=571 children) and 2010 (n=541). Data collected included measurement of hemoglobin, serum ferritin, soluble transferrin receptor (sTfR), retinol-binding protein, C-reactive protein (CRP) and α1-glycoprotein acid (AGP). RESULTS: Among all children, declines were observed in the prevalence of: anemia, 50.6% versus 43.8% (P=0.05); total iron deficiency (either low ferritin or high sTfR), 77.3% versus 63.7% (P<0.01); and iron deficiency anemia, 45.5% versus 33.4% (P<0.01). Among children without inflammation as measured by CRP and AGP, similar declines were observed, but only declines in total iron deficiency and iron deficiency anemia reached statistical significance. Among all children and those without inflammation, the prevalence of vitamin A deficiency remained the same. CONCLUSIONS: One year after the introduction of home fortification with MNP, within a larger IYCN program, the prevalence of anemia, iron deficiency and iron deficiency anemia declined, but vitamin A deficiency remained unchanged.

Mycobacterium abscessus induces a limited pattern of neutrophil activation that promotes pathogen survival.

Mycobacterium abscessus is a rapidly growing mycobacterium increasingly detected in the neutrophil-rich environment of inflamed tissues, including the cystic fibrosis airway. Studies of the immune reaction to M. abscessus have focused primarily on macrophages and epithelial cells, but little is known regarding the neutrophil response despite the predominantly neutrophillic inflammation typical of these infections. In the current study, human neutrophils released less superoxide anion in response to M. abscessus than to Staphylococcus aureus, a pathogen that shares common sites of infection. Exposure to M. abscessus induced neutrophil-specific chemokine and proinflammatory cytokine genes. Although secretion of these protein products was confirmed, the quantity of cytokines released, and both the number and level of gene induction, was reduced compared to S. aureus. Neutrophils mediated killing of M. abscessus, but phagocytosis was reduced when compared to S. aureus, and extracellular DNA was detected in response to both bacteria, consistent with extracellular trap formation. In addition, M. abscessus did not alter cell death compared to unstimulated cells, while S. aureus enhanced necrosis and inhibited apoptosis. However, neutrophils augment M. abscessus biofilm formation. The response of neutrophils to M. abscessus suggests that the mycobacterium exploits neutrophil-rich settings to promote its survival and that the overall neutrophil response was reduced compared to S. aureus. These studies add to our understanding of M. abscessus virulence and suggest potential targets of therapy.

Vitamin D status and determinants of deficiency among non-pregnant Jordanian women of reproductive age.

BACKGROUND/OBJECTIVES: Vitamin D deficiency, a risk factor for osteomalacia and osteoporosis, is a re-emerging health problem globally. While sunlight is an important vitamin D source, previous investigations among women whose culture encourages skin covering have been small, not nationally representative, or both. We investigated serum 25-hydroxyvitamin D (25(OH)D(3)) status and factors associated with deficiency in a nationally representative survey of 2013 Jordanian women of reproductive age in Spring 2010. SUBJECTS/METHODS: We measured 25(OH)D(3) concentrations by liquid chromatography-tandem mass spectrometry and calculated prevalence ratios for deficiency associated with skin covering and other factors. RESULTS: Results showed 60.3% (95% CI: 57.1-63.4%) deficiency (<12 ng/ml) and 95.7% (95% CI: 94.4-96.8%) insufficiency (<20 ng/ml) among women. Prevalence of deficiency was 1.60 times higher for women who covered with a scarf/hijab (95% CI: 1.06-2.40, P = 0.024) and 1.87 times higher for women who wore full cover, or a niqab (95% CI: 1.20-2.93, P = 0.006), compared with the women who did not wear a scarf/hijab or niqab. Compared with rural women completing at least secondary education, prevalence of deficiency was 1.30 times higher for urban women of the same education level (95% CI: 1.08-1.57, P = 0.006), 1.18 times higher for urban women completing less than secondary education (95% CI: 0.98-1.43, P = 0.09), and 0.66 times lower for rural women completing less than secondary education (95% CI: 0.52-0.84, P = 0.001). CONCLUSION: Vitamin D deficiency and insufficiency pose significant public health problems in Jordanian women. Prevalence of deficiency is significantly higher among urban women and among women who cover with a scarf/hijab or niqab.

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists.

The Rookwood Driving Battery: normative older adult performance.

OBJECTIVES: The current study aimed to obtain older adult normative data on a neuropsychological battery in relation to functions underlying driving ability. The effect of age on performance on the battery was previously unknown; normative data revision was necessary to enable more appropriate use of the battery with older clients. DESIGN: Cross-sectional cohort study. METHODS: Volunteers were sought from healthy older people living independently in the community to complete the Rookwood Driving Battery. A group of 202 volunteers above the age of 70 were recruited from local social groups to complete the battery. Of these, 184 completed a screening test of cognitive integrity (Mini Mental State Examination, MMSE). The age ranged from 70 to 96 (mean age=81 years, SD=5.438). In the total sample, 155 (77%) were females. RESULTS: Results of the MMSE indicated that 161 (87.5%) of the group fell above a cut-off (25/30) typically used in epidemiological studies to identify age-related cognitive decline. Of these cognitively intact volunteers, performance was marked by higher battery error scores (mean=5.12, SD=3.75) than those observed in an earlier normative study using younger volunteers below 70 years of age (mean=1.41, SD=1.87). The two age groups differed significantly on all 10 battery subtests; in all cases the level of significance was .002 or less; for nine subtests, significance fell below .001. In the 'intact' older group, battery performance was observed to be closely related to score on the MMSE, a test of general cognitive integrity (r=.558, p=.01). CONCLUSIONS: Performance on the Rookwood Battery differs for the over 70s and under 70s. The authors suggest essential modifications in its use with older people.

Aging does not lessen the effectiveness of TGFbeta2-enhanced bone regeneration.

Controversy exists over the potency of bone healing in the aged skeleton, and there is concern that enhancement of bone regeneration after use of bone-stimulating growth factors may not be effective in the aged. In this study, 30 skeletally mature beagles (1-2 or 10-12 years old) had titanium implants placed bilaterally in the proximal humerus for a period of 4 weeks in a model of intramembranous bone regeneration. A bony defect made at the time of surgery created a 3-mm gap between the implant surface and the host bone. Some of the implants were treated with recombinant human TGFbeta2 (rhTGFbeta2) at various does (0.32-35 microg per implant), and some served as paired controls. The dose response was similar in young and old animals. The most effective dose, 35 microg, led to a 3-fold increase in the volume fraction of new bone within the gap in both the young (p = 0.001) and old (p = 0.002) animals. At this dose, there was a 5-fold increase in osteoblast surface. While age did not significantly affect the quantity of new bone formed as assessed by backscatter scanning electron microscopy, the older animals had thinner regenerated trabeculae that tended to be spaced more closely than the younger animals. Coupled with the finding that the increase in osteoid was greater in the old animals compared with the young animals, these qualitative differences suggest that there may have been a slight delay in the rate or a defect of mineralization in the old animals.

Locally delivered rhTGF-beta2 enhances bone ingrowth and bone regeneration at local and remote sites of skeletal injury.

The purposes of the present study were to determine if recombinant human transforming growth factor-beta-2 (rhTGF-beta2) enhances bone ingrowth into porous-coated implants and bone regeneration in gaps between the implant and surrounding host bone. The implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs in the presence of a 3-mm gap. In three treatment groups of animals, the test implant was treated with hydroxyapatite/tricalcium phosphate (HA/TCP) and rhTGF-beta2 in buffer at a dose per implant of 1.2 microg (n = 6), 12 microg (n = 7), or 120 microg (n = 7) and placed in the left humerus. In these same animals, an internal control implant treated only with HA/TCP and buffer was placed in the right humerus. In a non-TGF-beta treated external control group of animals (n = 7), one implant was treated with HA/TCP while the contralateral implant was not treated with the ceramic. In vitro analyses showed that approximately 15%, of the applied dose was released within 120 h with most of the release occurring in the first 24 h. The TGF-beta treated implants had significantly more bone ingrowth than the controls with the greatest effect in the 12 microg/implant group (a 2.2-fold increase over the paired internal control (P = 0.004) and a 4-fold increase over the external control (P < 0.001)). The TGF-beta treated implants had significantly more bone formation in the gap than the controls with the greatest effect in the 12 and 120 microg groups (1.8-fold increases over the paired internal controls (P = 0.003 and P = 0.012, respectively) and 2.8-fold increases over the external controls (P < 0.001 and P = 0.001, respectively)). Compared to the external controls, the internal control implants tended to have more bone ingrowth (1.9-fold increase, P = 0.066) and had significantly more bone formation in the gap (1.7-fold increase. P = 0.008). Thus, application of rhTGF-beta2 to a porous-coated implant-stimulated local bone ingrowth and gap healing in a weakly dose-dependent manner and stimulated bone regeneration in the 3-mm gap surrounding the contralateral control implant, a site remote from the local treatment with the growth factor.

Patient education in thyrotoxicosis.

The aim of the study was to assess the need for a thyrotoxicosis patient education programme and to evaluate a group education session. Patients with thyrotoxicosis were sent questionnaires on knowledge, satisfaction and mood. Patients showed limited knowledge about thyrotoxicosis. Newly diagnosed patients did not differ significantly from those who had been diagnosed more than a year previously. There was no significant relation between knowledge and other measures, but satisfaction was significantly correlated with mood. A further 82 patients were recruited to evaluate a group education session. Patients were randomly allocated either to receive a leaflet about thyrotoxicosis or to attend a group education session in addition to a leaflet. Comparison of the two groups showed a significant difference in anxiety (p = 0.02) but no significant difference in knowledge. Only 9 of 31 patients attended the group education session, and no significant differences were found between those who did and did not attend. Patients in the trial who all received leaflets, were more knowledgeable (p = 0.05) and more satisfied (p < 0.05), than those in the initial survey. Patients with thyrotoxicosis have limited knowledge about their condition. The offer of a group education programme had little effect on that knowledge but was associated with a reduction in anxiety. The provision of leaflets alone seemed to improve knowledge and satisfaction compared with no leaflets, but as this was not a randomised comparison, further evaluation is needed.

The effect of TGF-beta2 in various vehicles on incisional wound healing.

BACKGROUND: The isoforms of transforming growth factor beta (TGF-beta) have been shown to be deficient in models of impaired wound healing. Exogenous application of the growth factor to enhance healing as been investigated. TGF-beta1 has been shown to enhance incisional wound strength, but to be dependent on the vehicle used to carry the cytokine. Because TGF-beta2 has shown safety in human trials of chronic wound healing, this study evaluates TGF-beta2 in acute incisional healing using a variety of vehicles. METHODS: Using an acute incisional wound model in healthy rats, rhTGF-beta2 was suspended in various vehicles including fibrin sealant (normal commercial concentration), fibrin sealant (dilute concentration), phosphate buffered saline/serum albumin, and a carboxymethycellulose gel. A single dose of the agent was instilled into the incisions at the time of wound closure and breaking strength analyses and histology performed periodically from days 3-14. RESULTS: TGF-beta2 enhanced the gain of incisional strength in all vehicles during the first two weeks of healing. This was most noticeable by day three with the carboxymethycellulose gel, but by day 7 with the other vehicles. Like reports with TGF-beta1, TGF-beta2 accelerated the gain of wound strength by about three days by day 11. Normal density fibrin sealant delayed incisional healing; whereas, the other vehicles without TGF-beta2 had no significant effect. CONCLUSIONS: The use of TGF-beta2 appears to be of value in increasing incisional wound strength in the first 14 days post-wounding in healthy rats and this effect is demonstrated in a variety of vehicles. These data support the hypothesis that the "normal" incisional wound healing curve can he shifted to the left. Shortening the time for gain of incisional wound strength may have potential clinical use.

Tetrapeptide derived inhibitors of complexation of a class II MHC: the peptide backbone is not inviolate.

Major histocompatabilty (MHC) proteins rely heavily on peptide backbone recognition for ligation. Nonetheless, modifications to the polyamide backbone of a tetrapeptide ligand can be made without abrogating binding.