THE USE OF MULTIVARIATE ANALYSIS OF COVARIANCE IN EVALUATING THE COMPARABILITY OF LABORATORY DETERMINATIONS IN COOPERATIVE STUDIES

The role of clinical chemistry has traditionally been to evaluate acutely ill or hospitalized patients. Traditional statistical methods have serious drawbacks in that they use univariate techniques. To demonstrate alternative methodology, a multivariate analysis of covariance model was developed and applied to the data from the Cooperative Study of Sickle Cell Disease.^ The purpose of developing the model for the laboratory data from the CSSCD was to evaluate the comparability of the results from the different clinics. Several variables were incorporated into the model in order to control for possible differences among the clinics that might confound any real laboratory differences.^ Differences for LDH, alkaline phosphatase and SGOT were identified which will necessitate adjustments by clinic whenever these data are used. In addition, aberrant clinic values for LDH, creatinine and BUN were also identified.^ The use of any statistical technique including multivariate analysis without thoughtful consideration may lead to spurious conclusions that may not be corrected for some time, if ever. However, the advantages of multivariate analysis far outweigh its potential problems. If its use increases as it should, the applicability to the analysis of laboratory data in prospective patient monitoring, quality control programs, and interpretation of data from cooperative studies could well have a major impact on the health and well being of a large number of individuals. ^

IMPROVING QUANTITATIVE TREATMENT RESPONSE MONITORING WITH DEFORMABLE IMAGE REGISTRATION

Quantitative imaging with 18F-FDG PET/CT has the potential to provide an in vivo assessment of response to radiotherapy (RT). However, comparing tissue tracer uptake in longitudinal studies is often confounded by variations in patient setup and potential treatment induced gross anatomic changes. These variations make true response monitoring for the same anatomic volume a challenge, not only for tumors, but also for normal organs-at-risk (OAR). The central hypothesis of this study is that more accurate image registration will lead to improved quantitation of tissue response to RT with 18F-FDG PET/CT. Employing an in-house developed “demons” based deformable image registration algorithm, pre-RT tumor and parotid gland volumes can be more accurately mapped to serial functional images. To test the hypothesis, specific aim 1 was designed to analyze whether deformably mapping tumor volumes rather than aligning to bony structures leads to superior tumor response assessment. We found that deformable mapping of the most metabolically avid regions improved response prediction (P<0.05). The positive predictive power for residual disease was 63% compared to 50% for contrast enhanced post-RT CT. Specific aim 2 was designed to use parotid gland standardized uptake value (SUV) as an objective imaging biomarker for salivary toxicity. We found that relative change in parotid gland SUV correlated strongly with salivary toxicity as defined by the RTOG/EORTC late effects analytic scale (Spearman’s ρ = -0.96, P<0.01). Finally, the goal of specific aim 3 was to create a phenomenological dose-SUV response model for the human parotid glands. Utilizing only baseline metabolic function and the planned dose distribution, predicting parotid SUV change or salivary toxicity, based upon specific aim 2, became possible. We found that the predicted and observed parotid SUV relative changes were significantly correlated (Spearman’s ρ = 0.94, P<0.01). The application of deformable image registration to quantitative treatment response monitoring with 18F-FDG PET/CT could have a profound impact on patient management. Accurate and early identification of residual disease may allow for more timely intervention, while the ability to quantify and predict toxicity of normal OAR might permit individualized refinement of radiation treatment plan designs.

Vancomycin: Predictive risk factors for nephrotoxicity and implication for monitoring

The increased use of vancomycin in hospitals has resulted in a standard practice to monitor serum vancomycin levels because of possible nephrotoxicity. However, the routine monitoring of vancomycin serum concentration is under criticism and the cost effectiveness of such routine monitoring is in question because frequent monitoring neither results in increase efficacy nor decrease nephrotoxicity. The purpose of the present study is to determine factors that may place patients at increased risk of developing vancomycin induced nephrotoxicity and for whom monitoring may be most beneficial.^ From September to December 1992, 752 consecutive in patients at The University of Texas M. D. Anderson Cancer Center, Houston, were prospectively evaluated for nephrotoxicity in order to describe predictive risk factors for developing vancomycin related nephrotoxicity. Ninety-five patients (13 percent) developed nephrotoxicity. A total of 299 patients (40 percent) were considered monitored (vancomycin serum levels determined during the course of therapy), and 346 patients (46 percent) were receiving concurrent moderate to highly nephrotoxic drugs.^ Factors that were found to be significantly associated with nephrotoxicity in univariate analysis were: gender, base serum creatinine greater than 1.5mg/dl, monitor, leukemia, concurrent moderate to highly nephrotoxic drugs, and APACHE III scores of 40 or more. Significant factors in the univariate analysis were then entered into a stepwise logistic regression analysis to determine independent predictive risk factors for vancomycin induced nephrotoxicity.^ Factors, with their corresponding odds ratios and 95% confidence limits, selected by stepwise logistic regression analysis to be predictive of vancomycin induced nephrotoxicity were: Concurrent therapy with moderate to highly nephrotoxic drugs (2.89; 1.76-4.74), APACHE III scores of 40 or more (1.98; 1.16-3.38), and male gender (1.98; 1.04-2.71).^ Subgroup (monitor and non-monitor) analysis showed that male (OR = 1.87; 95% CI = 1.01, 3.45) and moderate to highly nephrotoxic drugs (OR = 4.58; 95% CI = 2.11, 9.94) were significant for nephrotoxicity in monitored patients. However, only APACHE III score (OR = 2.67; 95% CI = 1.13,6.29) was significant for nephrotoxicity in non-monitored patients.^ The conclusion drawn from this study is that not every patient receiving vancomycin therapy needs frequent monitoring of vancomycin serum levels. Such routine monitoring may be appropriate in patients with one or more of the identified risk factors and low risk patients do not need to be subjected to the discomfort and added cost of multiple blood sampling. Such prudent selection of patients to monitor may decrease cost to patients and hospital. ^

THE DISCHARGED PSYCHIATRIC PATIENT: POST-HOSPITAL ADJUSTMENT AND FACTORS AFFECTING REHOSPITALIZATION

Discharged psychiatric patients were studied six months post-discharge to determine those demographic, social and clinical characteristics affecting positive or negative adjustment and the degree to which the use of mental health services and medication compliance mediated the effects. With the exception of those with primary or secondary diagnoses of OBS, substance abuse or mental retardation, sixty-three psychiatric subjects between the ages of eighteen and sixty-four were chosen from all admissions into the hospital and interviewed six months after discharge using a specially designed questionnaire.^ The subjects' adjustment to community living was found to be marginal. Although not engaged in destructive activities, over half were living with their family members who supported them financially and emotionally. Most were unemployed and had been so for a long time. Others worked sporadically and frequently changed residences. Most did have substantial social ties with extended family and with friends with whom they interacted regularly, but one-fourth were socially isolated. Almost three-quarters continued to obtain regular mental health services after discharge and followed medication instructions under the supervision of their physician. The use of mental health services after discharge and the use of medication did not appear to affect the subjects' community adaption or their rate of rehospitalization.^ Forty percent of those discharged were rehospitalized by the end of the follow-up period. Four levels of risk of rehospitalization emerged. The highest risk was associated with a history of five or more prior hospitalizations, living alone, and social isolation. One third or more of the subjects expressed a need for more counseling, leisure time activities, case-manager assistance, vocational guidance, supervised housing, and placement into a transitional residential treatment program.^ Recommendations were made to enhance the ability to predict recidivism, to develop interorganizational casework management programs linking the patient and family to the community mental health system and to create computerized tracking and monitoring programs that systematically report patient treatment regimen and progress cross-sectionally and longitudinally. ^