Study Design Bias Research Articles

Are Nested Case-Control Studies Biased?

It has been recently asserted that the nested case-control study design, in which case-control sets are sampled from cohort risk sets, can introduce bias ("study design bias") when there are lagged exposures. The bases for this claim include a theoretical and an "empirical evaluation" argument. We examined both of these arguments and found them to be incorrect. We describe an appropriate empirical evaluation method to explore the performance of nested case-control study designs and analysis methods from an existing cohort. This empirical evaluation approach relies on simulating case-control outcomes from risk sets in the cohort from which the case-control study is to be performed. Because it is based on the underlying cohort structure, the empirical evaluation can provide an assessment that is tailored to the specific characteristics of the study under consideration. The methods are illustrated using samples from the Colorado Plateau uranium miners cohort.

Reporting, access, and transparency: Better infrastructure of clinical trials

Open access to information in medical science and adequate reporting of clinical trials may allow investigators and editors to recognize bias in study designs and avoid unnecessary duplication of efforts. Unfortunately, most of clinical trials are very expensive and are often supported by industries that may have financial reasons to hide or partially disclose results. However, investigators and editors have a greater interest in publishing results that can immediately change clinical practice rather than negative results, thus contributing to facilitate publication biases. Several years ago, legislation in several countries mandated the registration of clinical trials as an effective means of promoting information access and full transparency in medical research. However, comprehensive registers have not been adequately supported by law, particularly in Europe, where legislation has ironically contributed to fragmented research, and dampened its competitiveness and productivity. In this context, appropriate strategies help to protect the independence of academic research and ensure full transparency in medical science.

Cosmic Implications of NXY-059

The SAINT studies on NXY-0591,2 have reinvigorated debate over the momentous issues of neuroprotection and the development of novel stroke therapeutics. Some may argue there is little new ground that NXY-059 has unearthed and, in fact, the clinical trials merely confirm that as a strategy, neuroprotection has not been shown to be effective. Editorials in high-profile journals have sent out the clarion call to terminate research on neuroprotection given decades of work, which has uniformly led to failure after failure in clinical studies.3 These sentiments are premature and ignore studies showing that hypothermia improves outcome in patients after cardiac arrest, a major cause of global cerebral ischemia.4,5 Proof for the neuroprotection concept has therefore already been established. Despite decades of neutral clinical trials, there still remains optimism among the stroke academic community. A majority of university-affiliated stroke neurologists in the United States in a recent survey still believe neuroprotection is a viable therapeutic strategy, although admittedly, that survey was conducted between the SAINT I and SAINT II publications.6 However, the question whether neuroprotection will ever work in stroke has been overshadowed by the larger issue of whether animal studies, which serve as the foundation for the development of stroke therapeutics, are even relevant to our patients with acute stroke. In the discussion section of the SAINT II article, the authors write, “it is possible that the animal models of acute focal infarction are not relevant to the patient population; they certainly are insufficient to guarantee a positive clinical-trial result.” Have all prior neuroprotective agents failed in clinical studies because rodent stroke is not relevant to human stroke? This is a key question. Substantial reductions in infarct size in rodents with stroke treated with various types of purported neuroprotective agents would seem to support this view. There …

Requirements for applying a case–control study model and clinical significance of changes in the visual analogue scale score in abdominal pain

We greatly appreciated the detailed epidemiologic explanation of a case–control study but we do not believe that our study design biases the results presented. One of their arguments was that reduced pain and bleeding at the trocar site in the fibrin sealant group was not related to the different mesh fixation technique but only to the laparoscopic procedure. On the contrary, the use of fibrin sealant marks a major difference between the two techniques that explains the statistical differences in terms of postoperative pain and bleeding. The fibrin sealant device may be introduced only through a 5-mm trocar on the right flank instead of a 10mm trocar required by a stapling device. In the staple technique we have to suture the fascial defect of all 10-mm trocar sites to avoid postoperative incisional hernias [1], as recommended by several authors. Unfortunately, this practice is known to determine pain or discomfort during the first postoperative week, as frequently observed also in cases of laparoscopic repair of incisional hernias with mesh fixation by fascial suture [2], but the pain generally disappears after the first month. So, in our long experience of 16 years and around 4,000 laparoscopic hernia repair using transabdominal preperitoneal (TAPP) technique, we have encountered only two cases (0.05%) of chronic pain. Moreover, it is commonly noted that 10-mm port sites are more prone to postoperative bleeding than are 5-mm ones. Second, the visual analogue scale (VAS) is one of the most commonly used methods of measuring postoperative pain. Of course, VAS consists of a 10-cm line anchored by two extremes of pain; patients are asked to make a mark on the line that represents their level of perceived pain intensity. (Findings suggest that ratings of 0–4 mm can be considered pain free, and 5–44 mm as mild pain [2].) In keeping with current literature, we determine as positive (i.e., with pain) the cases of patients that placed their mark above 4 (i.e., 4 cm). This statistical test was correctly used in our study to compare the patient pain of the two groups and we believe that there are no convincing reasons that make other analytical methods proposed superior to or more accurate than this one [3].

Statins and congestive heart failure

Despite many post hoc analyses of cardiovascular databases in recent years suggesting a benefit of statins in the prevention and treatment of congestive heart failure (HF), a prospective study of statin therapy on two clinically relevant end points--HF morbidity and survival--had not been reported until 2007. However, a large-scale prospective trial, Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), has just reported its primary results. These results somewhat surprisingly show no survival benefit in a group of patients with ischemic systolic HF given low-dose rosuvastatin. In addition to this uncertainty generated by the results of CORONA, there remains additional uncertainty in the existing, predominantly retrospective data on statins because of the potential bias in study designs, use of post hoc subgroup analyses, and lack of mechanistic data. This review critically evaluates the recent literature in this area.

Strategies for discovering novel cancer biomarkers through utilization of emerging technologies

The introduction of technologies such as mass spectrometry and protein and DNA arrays, combined with our understanding of the human genome, has enabled simultaneous examination of thousands of proteins and genes in single experiments, which has led to renewed interest in discovering novel biomarkers for cancer. The modern technologies are capable of performing parallel analyses as opposed to the serial analyses conducted with older methods, and they therefore provide opportunities to identify distinguishing patterns (signatures or portraits) for cancer diagnosis and classification as well as to predict response to therapies. Furthermore, these technologies provide the means by which new, single tumor markers could be discovered through use of reasonable hypotheses and novel analytical strategies. Despite the current optimism, a number of important limitations to the discovery of novel single tumor markers have been identified, including study design bias, and artefacts related to the collection and storage of samples. Despite the fact that new technologies and strategies often fail to identify well-established cancer biomarkers and show a bias toward the identification of high-abundance molecules, these technological advances have the capacity to revolutionize biomarker discovery. It is now necessary to focus on careful validation studies in order to identify the strategies and biomarkers that work and bring them to the clinic as early as possible.

Authorship roles of oncology investigators with or without financial relationships to industry

6564 Background: Financial ties between clinical investigators and industry are common. This proximity between investigators and industry has raised concerns about bias in study design, conduct and reporting. We hypothesized that authors with such ties are more likely than other authors to play key scientific roles in oncology trials, and therefore to be in positions of disproportionate influence. We also examined whether this association varies by funding source. Methods: Data were abstracted from all trials (n=219) of drugs or biologicals published in JCO between 1/1/06 and 6/30/07. Article-level data included funding source, age group (adult vs. pediatric), phase, single vs. multicenter, country (US vs. other), and number of authors. Author-level data (n=2,719) included financial ties (e.g., employment, consulting) and performance of key scientific roles (i.e., conception/design, analysis/interpretation, or manuscript writing). Associations between financial ties and performance of key roles, adjusting for article-level covariates, were tested using generalized linear mixed models to account for clustering of authors within articles. Results: 122 studies (56%) had industry funding. 782 authors (29%) reported at least one financial tie to industry, and 1,733 authors (64%) reported performing at least one key role. Authors with financial ties were more likely than other authors to report performing a key role (OR=4.2, 99% CI=3.0–6.0, p<0.0001; Table). This relationship was stronger in industry-sponsored trials (OR=5.0, CI=3.3–7.5, p<0.0001) than in non-industry trials (OR=2.3, CI=1.1–4.6, p=0.002). This difference was explained by the higher prevalence of authors with employment relationships, most of whom reported playing key scientific roles, among industry trials. Conclusion: Authors with financial ties to industry are more likely than authors without such ties to play key roles in conception and design, analysis and interpretation, and reporting of oncology clinical trials. Relationship between authors' financial ties to industry and performance of key scientific roles Financial Tie Key Scientific Role Total Yes No Yes 620 (79%) 162 (21%) 782 No 1,113 (57%) 824 (43%) 1,937 Total 1,733 986 2,719 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Roche

Empirical Evaluation of Complex Epidemiologic Study Designs: Workplace Exposure and Cancer

To test whether a frequently used cohort-nested case-control study design exaggerated exposure-response relationships because of unrecognized study design bias. Our aim was to evaluate empirically the performance of this complex study design. We applied the design from one such study to a closely related cohort using randomly selected probands as cases. Values for average exposures were assigned to probands equal to, greater than, and less than those assigned to controls (matches). Under certain lag scenarios, the nested study design produced higher average exposure in probands compared with their matches, even when this was clearly not the case. Empirical evaluation demonstrated that the study design produced a biased case-control lagged exposure difference under the null hypothesis and could not distinguish qualitatively between null and alternate hypotheses. Empirical evaluation provided a useful check on results generated from a complex study design. It gave useful insight into the behavior of the index study design that was not otherwise readily deducible.

The Effects of Study Design and Spectrum Bias on the Evaluation of Diagnostic Accuracy of Confocal Scanning Laser Ophthalmoscopy in Glaucoma

To assess the effects of study design and spectrum bias on the evaluation of diagnostic accuracy of confocal scanning laser ophthalmoscopy (CSLO) in glaucoma. Analysis 1 included 67 eyes with glaucomatous visual field loss and 56 eyes of normal volunteers. Estimates of diagnostic accuracy in this analysis were compared to those obtained from analysis 2, which included a cohort of patients with suspected glaucoma, but without visual field loss at the time of CSLO imaging. For analysis 2, 40 eyes with progressive glaucomatous optic disc change were included in the glaucoma group and 43 eyes without any evidence of progressive damage to the optic nerve that were observed untreated for an average time of 9.01 +/- 3.09 years were included in the normal group. Areas under the receiver operating characteristic (ROC) curves (AUC) were used to evaluate diagnostic accuracy of CSLO parameters. There was a statistically significant difference between the performance of the parameter with largest AUC, discriminant function Bathija, in analysis 1 (AUC = 0.91) compared with its performance in analysis 2 (AUC = 0.71; P = 0.002). For the contour-line-independent parameter glaucoma probability score, a statistically significant difference was also observed in the performance obtained in analysis 1 (AUC = 0.89) compared with analysis 2 (AUC = 0.65; P < 0.001). Estimates of diagnostic accuracy of CSLO in glaucoma can be largely different depending on the population studied and the reference standard used to define disease. Diagnostic accuracy estimates obtained from case-control studies including well-defined groups of subjects with or without disease may not be applicable to the clinically relevant population.

Development of Korean Exposure Factors Handbook for Exposure Assessment

P-601 Introduction: In exposure assessments, researchers need to various exposure factors data that are likely to influence exposure. If the values of the exposure factors are not obtained, it will eventually have a sensitively influence on the predicted human exposure, and the decisions for the risk management would cause increase of uncertainty. Therefore, the purpose of this study is to develop Exposure Factors Handbook reflecting physiological and behavioral characteristics of Korean populations. The Korean Exposure Factors Handbook provides recommended values for use in exposure assessment as well as confidence ratings. Also this study is to construct on-line information offer system to the exposure assessor that how the data may be used to assess exposure. Methods: Based on the Exposure Factors Handbook of the U.S EPA, we first selected exposure factors. The investigation exposure factors include body weight, life expectancy, surface area, inhalation rate, soil ingestion rate, food consumption, showering and bathing, time-activity factors, population mobility, residence volume and residential exchange. The next step, we reviewed all domestic scientific study and nations statistic databases relating to exposure factors. The examination was based on scientific criteria (e.g. representativeness of the population, current information, adequacy of data collection period, minimal bias in study design, etc). After a thorough review, we classified the exposure factors in terms of both existence of available data deriving exposure factors and possibility of investigation during study period. If there is available data deriving exposure factors, we construct the database and progress data processing to fit the study purpose. The other way, we conduct direct measurement of exposure factors. Results: The study period of the project is 3 years. The first phase of a project, we suggest recommended values on four exposure factors, body weight, life expectancy, surface area and population mobility using precedence study data which was good available data evaluated in terms quality and relevance. This year, we are conducting the second phase of a project. We are investigating inhalation rate, water consumption and reanalyzing national food consumption survey data. Discussion: A comparison between some results of the recommend values for the exposure factors and the results of the US EPA revealed a difference. Therefore, it is considered to be adequate to use Korean data for domestic exposure assessment. Under the sponsorship of Ministry of Environment, Korean Exposure Factors Handbook is provided useful information to exposure assessor.

Evidence-based medicine

Evidence-based medicine (EBM) is the application of current, best-available clinical evidence to health care decisions for individual patients. EBM consists of five major steps: asking a clinical question, systematic retrieval of the best-available evidence, critical appraisal of the evidence, application of results, and evaluation of performance. This systematic approach allows the clinician to assess and grade the validity of a study and its applicability to the clinical question at hand. A sound knowledge of study design and study bias helps the clinician astutely evaluate the literature and design a study of his/her own. The five steps of EBM, categorizing and grading evidence, and major principles of study design are discussed in this chapter.

Case-Control Genetic Association Studies in Gastrointestinal Disease: Review and Recommendations

As our knowledge of genetic variation grows, our ability to use this information to unravel the mysteries of human disease expands. Identification of genes and inexpensive methods to sequence them has resulted in a rising interest in evaluating specific variants and whether they may result in clinical manifestations or symptoms. Genetic variants include restriction fragment length polymorphisms, variable number tandem repeats, DNA microsatellites, and single nucleotide polymorphisms. Using these variants, genetic association studies, also referred to as candidate gene association or genotype-disease association studies are being performed by clinical and basic researchers alike. They are relatively easy to perform, but as a result of their deceivingly simple design, can be conducted or interpreted poorly. A positive association between a genotype and a GI disease of interest may be because the genotype causes (or increases susceptibility to) the disease, but may also be the result of the genotype being in linkage disequilibrium with the actual disease susceptibility gene, or be a false positive due to chance or bias in study design. An excellent understanding of the genetic and methodological issues surrounding these studies is therefore essential. We provide an overview of terminology and provide insight into the complexities underlying these studies. Recommendations for reporting the results of a genetic association study are provided to assist with study planning and manuscript preparation.

Does the potential for selection bias in semen quality studies depend on study design? Experience from a study conducted within an infertility clinic

The low participation rates in human semen quality studies raises concern for the potential of differential participation based on semen quality (or a surrogate). To explore the potential for differential participation, we compared semen analysis results from study subjects with those of non-study subjects. We obtained semen analysis results from 235 study subjects and retrospectively obtained results from a subset of 235 infertility clinic patients that were not study subjects but met the same eligibility criteria. The study was conducted at the Massachusetts General Hospital Infertility Clinic. All semen samples (study subjects and non-study subjects) were analysed for sperm concentration and motility by computer-aided semen analysis (CASA), and morphology was assessed using strict criteria. Semen analysis parameters for the non-study subjects were compared with the semen analysis results from study subjects. For all semen characteristics (sperm concentration, total sperm count, sperm motility and morphology), there were only marginal (non-significant) differences between study subjects and non-study subjects. Among men from an infertility clinic, we found no strong evidence of differential participation based on semen quality. This is reassuring since the potential for selection bias is of concern in semen quality studies. However, the potential for selection bias in other study designs remains unclear.

Nicotinamide Attenuates Focal Ischemic Brain Injury: Meta-Analysis or Mechanism of Protection

HomeStrokeVol. 35, No. 12Nicotinamide Attenuates Focal Ischemic Brain Injury: Meta-Analysis or Mechanism of Protection Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBNicotinamide Attenuates Focal Ischemic Brain Injury: Meta-Analysis or Mechanism of Protection Hiroshi Yao, MD, Fumiko Sadanaga-Akiyoshi, MD, Setsuro Ibayashi, MD and Mitsuo Iida, MD Hiroshi YaoHiroshi Yao Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author , Fumiko Sadanaga-AkiyoshiFumiko Sadanaga-Akiyoshi Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author , Setsuro IbayashiSetsuro Ibayashi Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author and Mitsuo IidaMitsuo Iida Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author Originally published1 Dec 2004https://doi.org/10.1161/01.STR.0000147159.56641.dfStroke. 2004;35:2757–2758To the Editor:We read with great interest the recent article by Macleod et al.1 They have shown a highly significant neuroprotective effect of nicotinamide on experimental stroke using the technique of systematic review or meta-analysis. The message is clear, and we believe this approach is useful and fairly robust in terms of statistical power. However, I would like to point out a possible pitfall of their overview. Nicotinamide, vitamin B3, is the precursor of nicotinamide adenine dinucleotide (NAD+), and it may act as a poly(ADP-ribose) polymerase (PARP) inhibitor. When ischemia-induced DNA strand breakage is too extensive, the overactivation of PARP may lead to intracellular NAD+ depletion and subsequent secondary energy failure (ie, ATP depletion).2 ATP levels can be dramatically increased following ischemia-reperfusion by nicotinamide.3 This scenario is generally accepted to explain the neuroprotective action of nicotinamide. However, it is also well known that high doses of nicotinamide (250 mg/kg in our case4) increase regional cerebral blood flow, and many studies have ignored cerebral blood flow. Therefore, we cannot jump into a conclusion that nicotinamide is a pure neuroprotectant independent of vasodilative action. If one does not consider divergent mechanisms of the beneficial effects of a candidate drug, such a promising drug based on animal experiments may fail to work under clinical settings, even though pooling of animal data reveals undoubtedly obvious neuroprotection.1 Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004; 35: 1203–1208.LinkGoogle Scholar2 Pieper AA, Verma A, Zhang J, Snyder SH. Poly(ADP-ribose)polymerase, nitric oxide and cell death. Trends Pharmacol Sci. 1999; 20: 171–181.CrossrefMedlineGoogle Scholar3 Klaidman L, Morales M, Kem S, Yang J, Chang M-L, Adams JD. Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology. 2003; 69: 150–157.CrossrefMedlineGoogle Scholar4 Sasanaga-Akiyoshi F, Yao H, Tanuma S, Nakahara T, Hong JS, Ibayashi S, Uchimura H, Fujishima M. Nicotinamide attenuates focal ischemic brain injury in rats: with special reference to changes in nicotinamide and NAD+ levels in ischemic core and penumbra. Neurochem Res. 2003; 28: 1227–1234.CrossrefMedlineGoogle ScholarstrokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & WilkinsResponse:Macleod Malcolm, , MRCP, PhD, O’Collins Tori, , BSci, Howells David, , PhD, and Donnan Geoff, , MD01122004The comments of Yao and colleagues serve to further illustrate the potential uses of systematic review and meta-analysis in the context of the interpretation of data from animal studies in stroke.Studies in focal cerebral ischemia may report measurement of cerebral blood flow (CBF). In most cases, they find no significant differences between control and treated groups, and use this to infer that any protective effect seen is not a consequence of changes in CBF. However, power calculations for such comparisons are seldom if ever reported; it may be that a true difference in CBF is missed because studies are underpowered for this comparison (ie, there is a type II or “false negative” error).Analyses such as ours can illuminate the impact of study quality and study design on the estimate of efficacy. Equally, where data are available the same technique could be used to give a more precise estimate of the effect of a drug on CBF. This would reduce the probability of a type II error, and thereby reduce the risk that protection due to an effect on CBF might be incorrectly attributed to some other drug property.It is likely that systematic review and meta-analysis can provide further insights both into the limits to the efficacy of individual drugs and into more generic determinants of outcome in experimental stroke. We are currently developing an international collaborative approach to establish priorities for future research and to develop a standard set of methodologies which might be used. Previous Back to top Next FiguresReferencesRelatedDetails December 2004Vol 35, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000147159.56641.dfPMID: 15564567 Originally publishedDecember 1, 2004 PDF download Advertisement

Virtual colonoscopy: Good results and not so good results—why the difference?

Virtual colonoscopy: Good results and not so good results—why the difference?

Response:

HomeStrokeVol. 35, No. 12Nicotinamide Attenuates Focal Ischemic Brain Injury: Meta-Analysis or Mechanism of Protection Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBNicotinamide Attenuates Focal Ischemic Brain Injury: Meta-Analysis or Mechanism of Protection Hiroshi Yao, MD, Fumiko Sadanaga-Akiyoshi, MD, Setsuro Ibayashi, MD and Mitsuo Iida, MD Hiroshi YaoHiroshi Yao Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author , Fumiko Sadanaga-AkiyoshiFumiko Sadanaga-Akiyoshi Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author , Setsuro IbayashiSetsuro Ibayashi Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author and Mitsuo IidaMitsuo Iida Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Fukuoka, Japan Search for more papers by this author Originally published1 Dec 2004https://doi.org/10.1161/01.STR.0000147159.56641.dfStroke. 2004;35:2757–2758To the Editor:We read with great interest the recent article by Macleod et al.1 They have shown a highly significant neuroprotective effect of nicotinamide on experimental stroke using the technique of systematic review or meta-analysis. The message is clear, and we believe this approach is useful and fairly robust in terms of statistical power. However, I would like to point out a possible pitfall of their overview. Nicotinamide, vitamin B3, is the precursor of nicotinamide adenine dinucleotide (NAD+), and it may act as a poly(ADP-ribose) polymerase (PARP) inhibitor. When ischemia-induced DNA strand breakage is too extensive, the overactivation of PARP may lead to intracellular NAD+ depletion and subsequent secondary energy failure (ie, ATP depletion).2 ATP levels can be dramatically increased following ischemia-reperfusion by nicotinamide.3 This scenario is generally accepted to explain the neuroprotective action of nicotinamide. However, it is also well known that high doses of nicotinamide (250 mg/kg in our case4) increase regional cerebral blood flow, and many studies have ignored cerebral blood flow. Therefore, we cannot jump into a conclusion that nicotinamide is a pure neuroprotectant independent of vasodilative action. If one does not consider divergent mechanisms of the beneficial effects of a candidate drug, such a promising drug based on animal experiments may fail to work under clinical settings, even though pooling of animal data reveals undoubtedly obvious neuroprotection.1 Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004; 35: 1203–1208.LinkGoogle Scholar2 Pieper AA, Verma A, Zhang J, Snyder SH. Poly(ADP-ribose)polymerase, nitric oxide and cell death. Trends Pharmacol Sci. 1999; 20: 171–181.CrossrefMedlineGoogle Scholar3 Klaidman L, Morales M, Kem S, Yang J, Chang M-L, Adams JD. Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology. 2003; 69: 150–157.CrossrefMedlineGoogle Scholar4 Sasanaga-Akiyoshi F, Yao H, Tanuma S, Nakahara T, Hong JS, Ibayashi S, Uchimura H, Fujishima M. Nicotinamide attenuates focal ischemic brain injury in rats: with special reference to changes in nicotinamide and NAD+ levels in ischemic core and penumbra. Neurochem Res. 2003; 28: 1227–1234.CrossrefMedlineGoogle ScholarstrokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & WilkinsResponse:Macleod Malcolm, , MRCP, PhD, O’Collins Tori, , BSci, Howells David, , PhD, and Donnan Geoff, , MD01122004The comments of Yao and colleagues serve to further illustrate the potential uses of systematic review and meta-analysis in the context of the interpretation of data from animal studies in stroke.Studies in focal cerebral ischemia may report measurement of cerebral blood flow (CBF). In most cases, they find no significant differences between control and treated groups, and use this to infer that any protective effect seen is not a consequence of changes in CBF. However, power calculations for such comparisons are seldom if ever reported; it may be that a true difference in CBF is missed because studies are underpowered for this comparison (ie, there is a type II or “false negative” error).Analyses such as ours can illuminate the impact of study quality and study design on the estimate of efficacy. Equally, where data are available the same technique could be used to give a more precise estimate of the effect of a drug on CBF. This would reduce the probability of a type II error, and thereby reduce the risk that protection due to an effect on CBF might be incorrectly attributed to some other drug property.It is likely that systematic review and meta-analysis can provide further insights both into the limits to the efficacy of individual drugs and into more generic determinants of outcome in experimental stroke. We are currently developing an international collaborative approach to establish priorities for future research and to develop a standard set of methodologies which might be used. Previous Back to top Next FiguresReferencesRelatedDetails December 2004Vol 35, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000147159.56641.dfPMID: 15564567 Originally publishedDecember 1, 2004 PDF download Advertisement

Invited commentary

Wilhelmi and colleagues from Hannover Medical School have presented an echocardiographic assessment of long-term survivors of heart transplantation. Their results corroborate those demonstrated by other surveys, ie, (1) general “preservation” of left ventricular morphology and systolic function beyond the first decade and (2) a significant incidence of left atrial dysfunction, right ventricular enlargement and tricuspid regurgitation. The main problem with isolated surveys of graft left ventricular function after transplantation is the inherent bias in the survey method, ie, their authors are most often interested in the characteristics of current survivors rather than also in those that died. The study design biases the cohort in favor of normal graft function because significant graft dysfunction is fatal in short order. A more important statistic is the actuarial freedom from graft LV dysfunction at 10 years. This is a challenging calculation because one may not know when to include patients for whom LV dysfunction was a finding proximate to a fatal incidence of infection or rejection. The bias, in any case, allows little to be said about results and little to act upon. In designing clinical surveys, it is important to see the forest through the trees, ie, (1) the actuarial freedom from death at 10 years following transplantation is only 38%–42% in four recent reports and (2) the actuarial freedom from significant CAD decreases steadily with years post-transplantation and is 50%–70% at 10 years. In the present era, surveys of standard clinical databases should be designed to detect trends and suggest properly conducted studies of factors pertinent to survival and quality of life. The effectiveness of OKT3 induction, CMV prophylaxis, Ca++ channel blockers, and lipid-lowering agents were first suspected from such databases. The future dataset may include the plethora of both donor and recipient genotypes (beyond the major histocompatibility complex) pertinent to the immunological response. An example is the donor interleukin-4 promoter gene, which was recently presented by Bijlsma and colleagues from Utrecht. An analysis of their polymorphisms may pinpoint the most important immunological processes and thus suggest therapeutic interventions if not better donor/recipient matching. The authors’ data on right ventricular (RV) and tricuspid valve function suggest the “other evil” facing long-term survivors of transplantation. Twenty nine percent of patients had impaired RV function, often associated with significant tricuspid regurgitation. This finding may be consistent with the fact that, despite “well-preserved” left ventricular function, 23 out of their 65 patients were in NYHA Class III or IV. Prior studies, particularly by Chan and colleagues at Stanford, show that TR is common and, although initially asymptomatic, ultimately becomes so and may well require valve replacement. The time has come to understand the causes of this problem. If the problem relates primarily to the technique of bi-atrial anastomosis, the alternative technique should be used. If the problem is due primarily to the technique of endomyocardial biopsy, we should be compulsive in modifying the catheter sheath (as has been previously suggested), increasing the precision of the technique using echocardiographic guidance, and in continuing to seek sensitive and specific noninvasive methods of detecting acute rejection.

Anti-angiogenic therapy: rationale, challenges and clinical studies.

Physiological angiogenesis occurs during embryogenesis, wound healing and reproductive functions in adults. Abnormal angiogenesis takes place in certain chronic diseases (diabetes, psoriasis, rheumatoid arthritis, etc.) and tumours. Genetic changes and local stresses including hypoxia, glucose deprivation and oxidative stress play a pivotal role in angiogenesis switch, which is necessary for tumour development and is rate-limiting for tumour progression. Angiogenesis is tightly regulated by pro- and anti-angiogenic growth factors with a series of complex and interrelated steps. Activated endothelial cells (ECs) migrate as a solid cord and, subsequently, form lumina; the sprout tips then anastomose to form vessel loops or networks. One of the final events is the laying down of a basement membrane and the structural support of pericytes. The molecular alterations that sustain angiogenesis represent novel targets for rationally designed anti-cancer treatment strategies. Inhibition of angiogenesis presents certain advantages on conventional therapies, such as the direct accessibility from the circulation, and the potential low rate of drug resistance related to the genetic stability of ECs. Certain anti-angiogenic compounds were found to have potent anticancer property in in vivo experimental studies. Nevertheless, in contrast to preclinical studies, the first generation of anti-angiogenic drugs tested in clinical trials have shown a moderate activity in advanced disease partly due to suboptimal schedules of therapy or biases in study design.

What can we learn from clinical trials of anticonvulsant drugs in epilepsy?

Any physician who intends to utilize the available antiepileptic drugs (AEDs) judiciously, cannot do so without being well versed on their pharmacological properties and the large body of evidence that is continuously accumulating on their relative efficacy and tolerability in different types of epilepsy. While informal observations such as retrospective surveys and case reports can be useful under special circumstances, prospective randomized clinical studies represent by far the most important tool by which objective information can be obtained about the clinical value of existing drugs. Even randomized trials, however, can produce misleading conclusions because of inherent weaknesses or bias in study design, analysis, and interpretation. Common deficiencies identified in some of the most recent drug trials in epilepsy include 1) inclusion of inappropriately heterogeneous patient groups (for example, patients with partial and primarily generalized seizures); 2) low statistical power due to insufficient sample size (for trials designed to show therapeutic equivalence); 3) inappropriate titration rates or suboptimal dosages or dosing schedules (often favouring the sponsor's product over the comparator); 4) insufficient duration of treatment; and 5) utilization of endpoints of questionable clinical significance. In part, some of the above shortcomings can be ascribed to the fact that most clinical drug trials are designed to address regulatory needs rather than to provide the type of information required for rational prescribing. Physicians need to be alerted about the importance of these issues, and they should make every possible effort to interpret critically the medical literature on which they rely to guide and support their therapeutic decisions.

The allometry of density within the space used by populations of mammalian Carnivora

The relationship between body mass and population density has been used to develop theory of how energy is used in ecosystems. The usual allometric density slope, –0.75, was reduced to near zero among species of mammalian Carnivora after Smallwood and Schonewald and Blackburn and Gaston adjusted density estimates by the sizes of the corresponding study areas. In this paper, I restricted the allometric analysis to density estimates made at or near the threshold area, which is the species-specific minimum area likely to support a population. I excluded densities estimated from subpopulations and "megapopulations", thereby removing biases of study design that had previously confused the allometry of population density. Density at threshold area declined with increasing body mass. The population's mass density did not relate to threshold area, within which carnivore species averaged 9 kg/km2. The spatial intensity of oxygen consumption did not relate to body mass, but assuming that species with smaller threshold areas occur at more locations than species with larger threshold areas, one must conclude that smaller bodied species use more energy from the environment than do larger bodied species. Furthermore, threshold area and density at threshold area were most responsive to female brain mass, which provides an ecological allometry that links spatial scale, sensory perception, parental care, life-history attributes, basal metabolic rate, and body mass.