Surrogate Criteria Research Articles

Validation study of a portable monitoring device for identifying OSA in a symptomatic patient population

Obstructive sleep apnoea syndrome (OSAS) is a common disorder associated with early atherosclerosis, diabetes mellitus, ischaemic heart disease and cerebrovascular disease. The gold standard for confirming OSAS is based on an attended overnight polysomnography (PSG) in a sleep laboratory; however lack of health-care resources creates long waiting times for patient access to this diagnostic test. This study evaluated the ability of a portable sleep-monitoring device to identify patients in Hong Kong with suspected OSAS. Patients with symptoms of OSAS were invited to use the ARES (apnoea risk evaluation system) concurrently with an attended inpatient PSG. Several sets of AHI were generated by the ARES provider based on different oxygen desaturation criteria and surrogate parameters of arousal. The results were compared against PSG to determine the optimal sensitivity and specificity. There were 141 patients who completed the study successfully. Results of AHI from the ARES study were presented in the order of different scoring criteria--4% oxygen desaturation alone, obstructive events with 3% oxygen desaturation and obstructive events with 1% desaturation plus surrogate arousal criteria. The sensitivity was 0.84 (95% confidence interval (CI): 0.77-0.90), 0.89 (95% CI: 0.89-0.94) and 0.97 (95% CI: 0.94-0.99), respectively. The specificity was 1, 1 and 0.63 (95% CI: 0.55-0.71), respectively. The receiver operating curve had an area of 0.96, 0.97 and 0.98, respectively. The kappa coefficient varied from 0.24 to 0.55 for agreement of severity between PSG and ARES. The likelihood ratio positive and the likelihood ratio negative were 2.61, infinity, infinity and 0.16, 0.11, 0.05, respectively, in the order of oxygen desaturation described earlier. The ARES device has reasonable sensitivity and specificity for diagnosing severe OSAS in symptomatic Chinese patients. There is moderate agreement between ARES and PSG in the diagnosis of severe disease, but less agreement in patients with mild/moderate disease.

Homeostasis Model Assessment (HOMA) as Surrogate Insulinization Criteria in Patients With Type 2 Diabetes

Type 2 diabetes mellitus is a metabolic disorder that results from defects in both insulin secretion and insulin action. Questions remain about when insulin therapy is indicated; thus, the aim of this study was to evaluate homeostasis model assessment beta-cell (HOMAbetacell) values as surrogate criteria for insulin therapy indication in patients with type 2 diabetes. A prospective study was performed involving 189 type 2 diabetic patients with deficient metabolic control assessed by clinical and laboratory parameters. All patients received nutritional intervention and combination therapy with metformin and glimepiride. Patients who did not respond were admitted to the next phase, which consisted of glimepiride + metformin + rosiglitazone oral therapy and revaluation after 3 months. Comparisons between responders and nonresponders in this phase were made in order to achieve differences in metabolic parameters and beta cell function. Of 189 patients studied, 150 (79.36%) were considered full responders in the first phase of this study. The remaining 39 patients were admitted in the second trial phase, in which 20 patients (51.28%) responded to triple oral therapy, while the other 19 (49.72%) required insulin therapy. Significant differences were found in fasting and postprandial glycemia (P < 0.001; P < 0.004) between the non-insulin-requiring group (200 +/- 12.0 mg/dL; 266.05 +/- 17,67 mg/dL) and the insulin-requiring group (291.5 +/- 17.6 mg/dL; 361.6 +/- 26.1 mg/dL). Likewise, significant differences were observed in homeostasis model assessment insulin resistance (HOMAIR) and HOMAbetacell values (P < 0.002; P < 0.04) between non-insulin-requiring patients (7.7 +/- 0.8; 24.5 +/- 1.3%) and insulin-requiring patients (12.6 +/- 1.2; 19.4 +/- 2.4%). Finally, significant differences were observed when comparing body mass index (non-insulin-requiring group, 29.2 +/- 0.4 kg/m, versus insulin-requiring group, 27.1 +/- 0.9 kg/m; P < 0.05). HOMAbetacell determination in clinical practice is a useful tool to determine when insulin therapy should be started for type 2 diabetic patients.

How to Anticipate the Assessment of the Public Health Benefit of New Medicines?

How to Anticipate the Assessment of the Public Health Benefit of New Medicines?

Multiple objective optimal control of integrated urban wastewater systems

Integrated modelling of the urban wastewater system has received increasing attention in recent years and it has been clearly demonstrated, at least at a theoretical level, that system performance can be enhanced through optimized, integrated control. However, most research to date has focused on simple, single objective control. This paper proposes consideration of multiple objectives to more readily tackle complex real world situations. The water quality indicators of the receiving water are considered as control objectives directly, rather than by reference to surrogate criteria in the sewer system or treatment plant. A powerful multi-objective optimization genetic algorithm, NSGA II, is used to derive the Pareto optimal solutions, which can illustrate the whole trade-off relationships between objectives. A case study is used to demonstrate the benefits of multiple objective control and a significant improvement in each of the objectives can be observed in comparison with a conventional base case scenario. The simulation results also show the effectiveness of NSGA II for the integrated urban wastewater system despite its complexity.

Controlling failure using structural fuses for predictable progressive failure of composite laminates

Structural fuses have been used to bias and control failures in structural applications where predictability of the progressive failure or collapse response is important. Tailoring structural fuses by trial and error in large structures that have numerous possible load and failure paths is not possible because the optimum failure sequence is not known a priori. Using nondeterministic methods to tailor structural fuses is computationally expensive. A procedure for developing deterministic measures to optimize structural fuses is presented here. The progressive failure of composite laminates is used for demonstration. Structural fuses are optimized using a reliability optimization. The failure response characteristics of the laminate with optimum structural fuses are used to identify deterministic measures that correlate with high progressive failure predictability. The deterministic measures are validated by using them as surrogate design criteria in a deterministic optimization to optimize structural fuses that control failure and improve progressive failure predictability. The improvement in predictability of the deterministic optimum design achieved by using optimized structural fuses is better than that obtained by optimizing the ply angles of the laminate explicitly for predictability.

Prevalence of the metabolic syndrome in an incident dialysis population

The National Heart, Lung, and Blood Institute's National Cholesterol Education Program 2001 Adult Treatment Panel III report defined the metabolic syndrome as having at least 3 of the following 5 criteria: abdominal obesity, elevated triglyceride levels, low high-density lipoprotein cholesterol levels, an elevated blood pressure, and an elevated fasting glucose. Evidence is accumulating to suggest that the metabolic syndrome predisposes to cardiovascular disease (CVD). End-stage kidney disease (ESKD) patients requiring dialysis have a substantially elevated risk of CVD morbidity and mortality. Dialysis patients' increased risk can be partially explained by traditional and nontraditional risk factors. The prevalence of the metabolic syndrome in dialysis patients is unknown. This retrospective, cross-sectional study of 202 incident dialysis patients examined the prevalence of the metabolic syndrome at the time of renal replacement therapy initiation. The study group was compared with all incident dialysis patients in 2002 on file with the U.S. Renal Data System. Females represented 39.1% of the study population. Blacks composed 34.7% of the study group. Diabetes was the etiology of ESKD in 44.6% of our patients. Surrogate criteria were used for the Adult Treatment Panel III risk factors of abdominal obesity and elevated fasting glucose levels. Overall, the prevalence of the metabolic syndrome was 69.3% in our population and was especially prevalent among diabetic, female, and white ESKD patients. Study limitations included the use of surrogate markers for 2 criteria of the metabolic syndrome and dependence on the Medical Evidence Report (Form 2728) for baseline characteristics. In summary, the metabolic syndrome is highly prevalent in incident dialysis patients.

A prospective assessment of bowel habit in irritable bowel syndrome in women: Defining an alternator

Irritable bowel syndrome (IBS) is subtyped as IBS with diarrhea (IBS-D) or IBS with constipation (IBS-C) based on Rome II guidelines. The remaining group is considered as having mixed IBS (IBS-M). There is no standard definition of an alternator (IBS-A), in which bowel habit changes over time. Our aim was to use Rome II criteria to prospectively assess change in bowel habit for more than 1 year to understand IBS-A. Female patients (n=317) with IBS entering a National Institutes of Health treatment trial were studied at baseline with questionnaires and 2-week daily diary cards of pain and stool frequency and consistency. Studies were repeated at the end of treatment (3 months) and at four 3-month intervals for one more year. Algorithms to classify subjects into IBS-D, IBS-C, and IBS-M groups used diary card information and modified Rome II definitions. Changes in bowel habit at 3-month intervals were then assessed using these surrogate diary card measures. At baseline, 36% had IBS-D, 31% IBS-M, and 34% IBS-C. Except for stool frequency, there were no differences between groups. While the proportion of subjects in each subgroup remained the same over the year, most individuals (more than 75%) changed to either of the other 2 subtypes at least once. IBS-M was the least stable (50% changed out by 12 weeks). Patients were more likely to transition between IBS-M and IBS-C than between IBS-D and IBS-M. Notably, only 29% switched between the IBS-D and IBS-C subtypes over the year. While the proportion of subjects in each of the IBS subtypes stays the same, individuals commonly transition between subtypes, particularly between IBS-M and IBS-C. We recommend that IBS-A be defined as at least one change between IBS-D and IBS-C by Rome II criteria over a 1-year period.

A randomized trial comparing conventional dose (70.2GyE) and high-dose (79.2GyE) conformal radiation in early stage adenocarcinoma of the prostate: Results of an interim analysis of PROG 95–09

This trial was designed to test the hypothesis that increasing the radiation dose delivered conformally to men with early stage prostate cancer above conventional levels improves disease free outcome. From January 1996 to December 1999 393 patients with biopsy proven T1b-T2b prostate cancer and a PSA of <15ng/ml were recruited at two centers onto an IRB approved protocol. 75.3% had Gleason scores of 6 or less, 15.3% Gleason 7, and 8.4% Gleason 8–10. 61.2% had T1c tumors. The median age at diagnosis was 67 years and the median PSA was 6.3. Patients were randomized to receive an initial boost to the prostate alone using conformal protons (either lateral or perineal fields) of either 19.8 or 28.8 Gray equivalent (GyE). All patients then received 50.4Gy at 1.8Gy per fraction using 3-D conformal photons to the prostate, seminal vesicles, and peri-prostatic tissues. 197 patients were randomized to a total dose of 70.2 GyE (conventional dose) and 196 to 79.2 GyE (high dose). Of those assigned to high dose 12 received less than 77 GyE (5.6%). Of those assigned to conventional dose only 5 received doses above 71 GyE (2%). Median follow-up is 4 years. No patient received adjunctive androgen suppression therapy with their radiation. Local failure was defined using both direct and surrogate criteria: clinically through palpation, histologically after rebiopsy of a clinically benign prostate with a rising PSA, or biochemically by a PSA of >1ng/ml 2 or more years after treatment without rebiopsy. Biochemical failure was determined using the ASTRO definition. This trial originated with the Proton Radiation Oncology Group and received statistical and data management support from the American College of Radiology. The distribution of PSA nadirs of either <0.5 or <1.0ng/ml was 36.7% and 73% after 70.2 GyE and 50% and 79.9% after 79.2 GyE. The cumulative incidence estimates of the five-year local failure rate using the surrogate of a PSA >1ng/ml 2 or more years after radiation were 63.6% (95% CI = 54.5% to 72.8%) for the 70.2 GyE group and 36.3% (95% CI = 26.5% to 46.0%) for the 79.2 GyE group (p ≤ 0.0001). The five-year biochemical failure rates were 37.3% (95% CI = 28.4% to 46.3%) for the conventional dose group and 19.1% (95% CI = 11.1% to 27.1%) for the high dose group (p = 0.00001). This difference held true when only those with low risk disease were examined (T1b-2a, PSA <10, Gleason <6, n = 227, 58% of total). The 5-year biochemical failure rate was 34.9% in the conventional dose arm and only 17.2% in the high dose arm (p = 0.002). It was also significant for intermediate risk patients (39.5% vs 21.3% p = 0.01). At this time, there was no difference in the overall survival rates between the treatment arms (p = 0.83). Only 2% of patients receiving conventional dose and 1.5% receiving high dose radiation experienced acute urinary or rectal morbidity of RTOG grade >3. The respective proportions for those experiencing any grade 2 acute morbidity was 62 and 69%. So far only 1.5% and 0.5% respectively have experienced late morbidity of RTOG grade >3. This randomized controlled trial shows an advantage in terms of freedom from biochemical failure for men with low and intermediate risk prostate cancer receiving high dose versus conventional dose conformal radiation. This advantage was achieved without any associated increase in either acute or late urinary or rectal morbidity

Dynamically-Based Criteria for the Identification of Optimal Bioreserve Networks

The use of “surrogate” design criteria (such as size or connectedness) to evaluate potential bioreserve network alternatives is attractive because they can be relatively straightforward to measure. However, to promote the persistence of a focal species, a higher level of biological detail may be used to derive specific design criteria for the species of interest. But just as for surrogate criteria, no single best criterion is likely to arise. Here, a set of mechanistic equations describing the dynamics of hawks and voles in a hypothetical landscape is used to derive design criteria for a reserve network. Multiobjective Integer Programming (MOIP) then identifies reserve network alternatives that reflect the tradeoffs between the objectives. When choosing from only five potential patches for inclusion in the network, in four of five cases a single design optimized the design objectives simultaneously. When choosing from ten patches, in all five cases there were conflicts between the objectives, but in two of five cases, there were optimal intermediate solutions along the tradeoff surface between the objectives. When resources allow, a more detailed description of the species of conservation interest may be used to develop reserve design criteria that are likely to promote persistence. MOIP can then be used to evaluate potential compromises between the criteria.

Experimental and clinical methods in the development of anti-Alzheimer drugs.

Methodology used for the development of anti-Alzheimer's disease (AD) drugs raises specific problems which are rarely examined in the literature. While the general development scheme is similar to that required for most drugs, some specific aspects must be analyzed, highly dominated by the dual goal of pharmacology, i.e., to obtain both symptomatic and etiopathogenic drugs. During preclinical studies, aged or lesioned animals are mainly useful for symptomatic drugs, whereas transgenic models or neurodegeneration-induced techniques would probably lead to etiopathogenic drugs potentially slowing down the process of AD. The first administrations of a new compound to human beings raise the question of the activity measurement techniques. Psychometry remains the most informative procedure to detect and analyze the activity of the drugs on the different components of cognition. Electrophysiology and neuroimaging need some complementary studies before they can be proposed as surrogate criteria in phase III trials. At this stage of development, American and the recently published European guidelines are of great help while insisting on long-term (6 months) placebo controlled trials with the use of the triple efficacy criterion: an objective cognition scale, a global assessment, and the opinion of the caregiver. In the long term, pharmacoepidemiology and pharmacoeconomy will have to confirm the rationale of this recent progress in the methodology of anti-AD drug development.

Development of Surrogate Methodologies for Operational Performance Measurement: Empirical Studies

A series of studies is described demonstrating the feasibility of linking reliable surrogate performance tests to real-life measures of performance. First, we illustrate dose equivalency, where deficits in computerized performance tests were related to graded dosages of alcohol and where prediction equations of blood alcohol level were established. Secondly, surrogate criteria composed of standardized aptitude tests (known to be predictive of operational performances) were administered to a sample tested on the same computer-based cognitive tests. This performance loss, in connec- tion to alcohol, was indexed to cognitive performances on the computer tests through their composite relation to intelligence tests. These laboratory-based relations were then linked to several studies of real-world performances by applying the integrative surrogate metric. An explanation is given of how the composite is developed and used to form units that are common from study to study and familiar to the reader.

Plasma and tissue concentrations of fluconazole and their correlation to breakpoints.

The prediction of clinical outcome during antifungal therapy is an issue of paramount importance in clinical research, because no consistently reliable parameters are available. Minimum inhibitory concentration (MIC) values and breakpoint interpretation may serve as surrogate criteria until standardized in vitro antifungal susceptibility testing is developed, especially for fluconazole. With reproducible susceptibility testing methods for Candida species now available, tentative fluconazole interpretive breakpoints derived from MIC values determined by the National Committee on Clinical Laboratory Standards (NCCLS) M27-T broth macrodilution method are open for public comment. Besides the in vitro susceptibility of the fungus, clinical response to antifungal therapy with fluconazole depends to a great extent on the daily dose and corresponding plasma and tissue concentrations. Promising results from a few dose-finding studies in non-neutropenic patients show that fluconazole doses of up to 1000 mg day-1 result in higher clinical response rates than lower dosages. Therapeutic success depends substantially on achieving fluconazole plasma and tissue levels that are sufficiently higher than MIC values indicated by in vitro testing. However, this simplified concept must be related to the clinical situation and it is essential to consider the immunological status and underlying disease of the patient. Misinterpretation of MIC values may result in selection of an antifungal agent for life-threatening infections that does not provide optimal efficacy or toleration.

Plasma and tissue concentrations of fluconazole: discussion of the breakpoint problem

The reliable prediction of the clinical outcome during antifungal therapy is an issue of paramount priority in clinical research, since there are no appropriate parameters available. MIC values and in the future breakpoints may serve as surrogate criteria if further standardization of in vitro antifungal susceptibility testing especially for fluconazole leading to improved interlaboratory reproducibility of the test results can be provided. With reproducible susceptibility testing methods for Candida species now being available, tentative fluconazole interpretative breakpoints derived from MICs determined by the NCCLS M27-T broth macrodilution methodology are now open for public commentary. Besides the proven susceptibility of the fungus, clinical response to antifungal therapy with fluconazole also depends to a great extent on the daily dosage and the corresponding plasma and tissue concentrations as well as the immunological status and the underlying disease of the patient. The promising results of a relatively small number of dose finding studies with fluconazole in non-neutropenic patients indicate that with daily doses up to 1000 mg/die higher clinical response rates compared to those under lower dosages can be achieved. In view of future valid breakpoints, higher corresponding plasma and tissue levels of fluconazole should be achieved on which the therapeutic success depends substantially. However, this simplified concept needs several adjustments. Misinterpretation of MIC values and breakpoints may have as a consequence that patients with often life-threatening fungal infections may not be treated with an efficacious and better tolerated agent.

Total intravenous anesthesia is best for neurological surgery.

We believe that today balanced TIVA represents the best anesthetic technique for neurological surgery. Freely acknowledging that this point of view is unproven (36) with regard to the hard criterion of patient outcome on leaving the hospital, we submit that the intermediate or surrogate criteria discussed make a convincing case for preferring TIVA to volatile-based anesthetic techniques. Until a study demonstrating hard outcome differences between the two techniques is achieved, we will continue to encourage the use of TIVA in neuroanesthesia, based on its practical (anesthetic depth, neuromonitoring, surgical field) and theoretical (homeostasis, metabolism, antinociception, neuroprotection) advantages.