Person:

Jones, Richard Norman

Purpose: One approach to identify genes that contribute to common complex ocular disorders such as primary open angle glaucoma (POAG) is to study the genetic determinates of endophenotypes that are defined by underlying pre-disposing heritable quantitative traits such as central corneal thickness (CCT). Collagen VIII is a major component of Descemet’s membrane and studies in mice have indicated that targeted inactivation of the genes encoding the collagen type 8 alpha1 (Col8a1) and collagen type 8 alpha2 (Col8a2) subunits (COL8A1 and COL8A2) results in thinning of the corneal stroma and of Descemet’s membrane. The purpose of this study is to evaluate COL8A1 and COL8A2 as candidate genes for thin CCT in human POAG patients. Methods: 100 Caucasian POAG patients were enrolled in this study. The entire COL8A1 and COL8A2 coding sequence was determined in 8 patients with CCT<513 µm (one standard deviation (36 microns) below the mean (550 microns) and 8 patients with CCT>586 µm (one standard deviation above the mean). Selected COL8A2 exons containing variants of interest were sequenced in the full POAG cohort. Association and quantitative trait analyses were performed. Results: Three patients with CCT less than 513 µm and advanced POAG were found to have missense changes in COL8A2; two patients had a previously identified mutation, R155Q and one had a novel change, P678L (p=0.0035, Fisher’s exact test). Missense changes were not found in any of the patients with CCT>513 µm and missense changes in the COL8A1 gene were not found in any patient. One common COL8A2 SNP, rs274754 was also statistically associated with CCT (p=0.018). Conclusions: In this study we have identified COL8A2 missense changes in a group of Caucasian patients with very thin CCT and advanced POAG. These results suggest that DNA sequence variants in the COL8A2 gene may be associated with thin corneas in some glaucoma patients. Further study of COL8A2 variants in other patient populations, especially those with thinner CCT such as African-Americans would provide further support for a role of COL8A2 in corneal thickness and in glaucoma.

Background: This manuscript describes a method for adjustment of nursing home quality indicators (QIs) defined using the Center for Medicaid & Medicare Services (CMS) nursing home resident assessment system, the Minimum Data Set (MDS). QIs are intended to characterize quality of care delivered in a facility. Threats to the validity of the measurement of presumed quality of care include baseline resident health and functional status, pattern of comorbidities, and facility case mix. The goal of obtaining a valid facility-level estimate of true quality of care should include adjustment for resident- and facility-level sources of variability. Methods: We present a practical and efficient method to achieve risk adjustment using restriction and indirect and direct standardization. We present information on validity by comparing QIs estimated with the new algorithm to one currently used by CMS. Results: More than half of the new QIs achieved a "Moderate" validation level. Conclusions: Given the comprehensive approach and the positive findings to date, research using the new quality indicators is warranted to provide further evidence of their validity and utility and to encourage their use in quality improvement activities.

Background: Delirium (acute confusion), is a common, morbid, and costly complication of acute illness in older adults. Yet, researchers and clinicians lack short, efficient, and sensitive case identification tools for delirium. Though the Confusion Assessment Method (CAM) is the most widely used algorithm for delirium, the existing assessments that operationalize the CAM algorithm may be too long or complicated for routine clinical use. Item response theory (IRT) models help facilitate the development of short screening tools for use in clinical applications or research studies. This study utilizes IRT to identify a reduced set of optimally performing screening indicators for the four CAM features of delirium. Methods: Older adults were screened for enrollment in a large scale delirium study conducted in Boston-area post-acute facilities (n = 4,598). Trained interviewers conducted a structured delirium assessment that culminated in rating the presence or absence of four features of delirium based on the CAM. A pool of 135 indicators from established cognitive testing and delirium assessment tools were assigned by an expert panel into two indicator sets per CAM feature representing (a) direct interview questions, including cognitive testing, and (b) interviewer observations. We used IRT models to identify the best items to screen for each feature of delirium. Results: We identified 10 dimensions and chose up to five indicators per dimension. Preference was given to items with peak psychometric information in the latent trait region relevant for screening for delirium. The final set of 48 indicators, derived from 39 items, maintains fidelity to clinical constructs of delirium and maximizes psychometric information relevant for screening. Conclusions: We identified optimal indicators from a large item pool to screen for delirium. The selected indicators maintain fidelity to clinical constructs of delirium while maximizing psychometric information important for screening. This reduced item set facilitates development of short screening tools suitable for use in clinical applications or research studies. This study represents the first step in the establishment of an item bank for delirium screening with potential questions for clinical researchers to select from and tailor according to their research objectives.

Background: Unplanned hospitalization often represents a costly and hazardous event for the older population. Objectives: To develop and validate a predictive model for unplanned medical hospitalization from administrative data. Research Design: Model development and validation. Subjects: A total of 3919 patients aged >=70 years who were followed for at least 1 year in primary care clinics of an academic medical center. Measures: Risk factor data and the primary outcome of unplanned medical hospitalization were obtained from administrative data. Results: Of 1932 patients in the development cohort, 299 (15%) were hospitalized during 1 year follow up. Five independent risk factors were identified in the preceding year: Deyo-Charlson comorbidity score >=2 [adjusted relative risk (RR) = 1.8; 95% confidence interval (CI): 1.4–2.2], any prior hospitalization (RR = 1.8; 95% CI: 1.5–2.3), 6 or more primary care visits (RR = 1.6; 95% CI: 1.3–2.0), age >=85 years (RR = 1.4; 95% CI: 1.1–1.7), and unmarried status (RR = 1.4; 95% CI: 1.1–1.7). A risk stratification system was created by adding 1 point for each factor present. Rates of hospitalization for the low- (0 factor), intermediate- (1–2 factors), and high-risk (>=3 factors) groups were 5%, 15%, and 34% (P < 0.0001). The corresponding rates in the validation cohort, where 328/1987 (17%) were hospitalized, were 6%, 16%, and 36% (P < 0.0001). Conclusions: A predictive model based on administrative data has been successfully validated for prediction of unplanned hospitalization. This model will identify patients at high risk for hospitalization who may be candidates for preventive interventions.

OBJECTIVES: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention. DESIGN: Quantitative and qualitative survey. SETTING: Academic primary care medicine and pre-anesthesia testing clinics. PARTICIPANTS: Fifty patients aged 70 and older, including 25 medical patients at high risk of hospitalization and 25 patients with planned major surgery. MEASUREMENTS: Fifteen- to 20-minute interviews involved open- and closed-ended questions guided by an in-depth script. Two planned study protocols were presented to each participant. Both involved serial neuropsychological assessments, blood testing, and magnetic resonance brain imaging (MRI); one added lumbar puncture (LP). Participants were asked whether they would be willing to participate in these protocols, rated barriers and incentives to participation, and were probed with open-ended questions. RESULTS: Of 50 participants (average age 78, 44% male, 40% nonwhite), 32 (64%) expressed willingness to participate in the LP-containing protocol, with LP cited as the strongest disincentive. Thirty-eight (76%) expressed willingness to participate in the protocol without LP, with phlebotomy and long interviews cited as the strongest disincentives. Altruism was a strong motivator for participation, whereas transportation was a major barrier. Study visits at home, flexible appointment times, assessments shorter than 75 minutes, and providing transportation and free parking were strategies developed to maximize study participation. CONCLUSION: Vulnerable elderly people expressed a high rate of willingness to participate in an 18-month prospective study. Participants identified incentives and barriers that enabled investigators to develop procedures to maximize recruitment and retention.

OBJECTIVES: To examine the association between persistent delirium and 1-year mortality in newly admitted post-acute care (PAC) facility patients with delirium who were followed regardless of residence.

DESIGN: Observational cohort study.

SETTING: Eight greater-Boston skilled nursing facilities specializing in PAC.

PARTICIPANTS: Four hundred twelve PAC patients with delirium at admission after an acute hospitalization.

MEASUREMENTS: Assessments were done at baseline and four follow-up times: 2, 4, 12, and 26 weeks. Delirium, defined using the Confusion Assessment Method, was assessed, as were factors used as covariates in analyses: age, sex, comorbidity, functional status, and dementia. The outcome was 1-year mortality determined according to the National Death Index and corroborated using medical record and proxy telephone interview.

RESULTS: Nearly one-third of subjects remained delirious at 6 months. Cumulative 1-year mortality was 39%. Independent of age, sex, comorbidity, functional status, and dementia, subjects with persistent delirium were 2.9 (95% confidence interval=1.9–4.4) times as likely to die during the 1-year follow-up as subjects whose delirium resolved. This association remained strong and significant in groups with and without dementia. Additionally, when delirium resolved, the risk of death diminished thereafter.

CONCLUSION: In patients who were delirious at the time of PAC admission, persistent delirium was a significant independent predictor of 1-year mortality.

Background— Delirium is a common outcome after cardiac surgery. Delirium prediction rules identify patients at risk for delirium who may benefit from targeted prevention strategies, early identification, and treatment of underlying causes. The purpose of the present prospective study was to develop a prediction rule for delirium in a cardiac surgery cohort and to validate it in an independent cohort.

Methods and Results— Prospectively, cardiac surgery patients ≥60 years of age were enrolled in a derivation sample (n=122) and then a validation sample (n=109). Beginning on the second postoperative day, patients underwent a standardized daily delirium assessment, and delirium was diagnosed according to the confusion assessment method. Delirium occurred in 63 (52%) of the derivation cohort patients. Multivariable analysis identified 4 variables independently associated with delirium: prior stroke or transient ischemic attack, Mini Mental State Examination score, abnormal serum albumin, and the Geriatric Depression Scale. Points were assigned to each variable: Mini Mental State Examination ≤23 received 2 points, and Mini Mental State Examination score of 24 to 27 received 1 point; Geriatric Depression Scale >4, prior stroke/transient ischemic attack, and abnormal albumin received 1 point each. In the derivation sample, the cumulative incidence of delirium for point levels of 0, 1, 2, and ≥3 was 19%, 47%, 63%, and 86%, respectively (C statistic, 0.74). The corresponding incidence of delirium in the validation sample was 18%, 43%, 60%, and 87%, respectively (C statistic, 0.75).

Conclusions— Delirium occurs frequently after cardiac surgery. Using 4 preoperative characteristics, clinicians can determine cardiac surgery patients’ risk for delirium. Patients at higher delirium risk could be candidates for close postoperative monitoring and interventions to prevent delirium.