randomization
Dotaz
Zobrazit nápovědu
Přes významné zlepšování metodologie epidemiologických studií a analýz zdravotnických databází, zůstávají v observačních epidemiologických studiích asociace mezi ovlivnitelnými expozicemi a nemocí do určité míry zkresleny. Princip mendelovské randomizace, tj. náhodné rozdělení rodičovských genů potomkům v meiose během formování gamet a při koncepci, představuje jednu z šancí metodologie hodnocení příčinné povahy některých zevních příčin nemocí. Při využití tohoto přístupu je zjištěná asociace mezi nemocí a studovaným genetickým polymorfizmem, který odráží biologickou spojitost mezi podezřelou expozicí a nemocí, obecně méně náchylná k fenoménu zavádění nebo k zpětnému zapříčinění, které může zkreslit interpretaci výsledků konvenčních pozorovacích studií. Autoři ilustrují explanační možnosti mendelovské randomizace na příkladech vztahů folát – homocystein – ICHS a izothiokyanát versus karcinom plic. I když využití principu mendelovské randomizace má svá omezení, poskytuje nové možnosti jak testovat příčinnou souvislost dějů a jasně ukazuje, jak prostředky vložené do projektu lidského genomu mohou přispět k poznání a potenciálním možnostem prevence nepříznivých účinků ovlivnitelných expozic na lidské zdraví.
Though the methodology and designs of epidemiological studies and analyses of medical databases have improved, associations between modifiable exposures and the disease in observational epidemiological studies remain partly biased. Mendelian randomization principle, which is the random distribution of parental genes to offspring in meiosis during gametogeneis and at conception, represents a chance for methodology of evaluation of the causal relations between the external cause and the disease. The use of this principle assumes the association between the disease and the genetic polymorphism which reflects the biological relation between the suspected exposure and the disease, and is generally less prone to the phenomenon of confounding and reverse causation that can impair the interpretation of results in conventional observational studies. Authors describe explanatory options of the Mendelian randomization principle using examples in folic acid – homocysteine – coronary heart disease, and isothiocyanate versus lung carcinoma. Though the use of Mendelian randomization principle has its limitations, it offers new possibilities to test causal relations and clearly shows that means invested into the Human genome project can contribute to the understanding and prevention of adverse effects of modifiable exposure to the human health.
Randomizovaná klinická studie je v současnosti považována za nejspolehlivější metodu pro porovnávání terapeutických efektů. Článek se snaží najít odpověď na otázku, zda je náhodné přidělování pacientů do terapeutických větví akceptovatelné z etického hlediska. Rámcem úvah je konflikt mezi individuálním pojetím etiky hájícím zájmy jednotlivých účastníků studie a kolektivním pojetím zdůrazňujícím především kvalitně navržené experimenty, které jako jediné mohou přinést spolehlivé odhady terapeutických efektů a jejichž závěry mohou změnit klinickou praxi a pomoci mnoha pacientům v budoucnosti. Jako možné vyústění tohoto konfliktu je nabídnuto následující řešení: Panuje-li v klinické veřejnosti nejistota ohledně superiority porovnávaných terapií, pak je nabídka účasti v randomizované studii nejen přijatelná, ale dokonce nutná s ohledem na práva jednotlivých pacientů a respekt k jejich autonomii. Je-li v takové situaci získán informovaný souhlas pacienta, pak užitím randomizace nejsou narušeny principy lékařské etiky. Rovněž je prezentováno několik alternativních plánů pro klinické studie.
Randomized clinical trial is currently thought to be the most reliable method for comparing therapeutic effects. The article tries to ansewer the question whether chance allocation of patients into various therapeutic arms is acceptable from the ethical point of view. It deals with the conflict between two concepts: of individual ethics mostly defending interests of individual participants of each trial, and collective ethics based on well-designed experiments that are the sole source of reliable estimation of therapeutic effect and their conclusions can change clinical practice and help patients in the future. The article suggests this possible solution: providing there is no prevailing consensus as for superiority of one of the compared therapies, the offer to participate in randomized clinical trial is not only acceptable but necessary in view of individual patients’ right and respect of their autonomy. If an informed consent is obtained the principles of medical ethics have not been violated. Finally, a few alternative trial designs are presented.
Wiley series in probability and statistics
1st ed. xvii, 259 s.
- Klíčová slova
- Zkoušky klinické, Randomizace,
- Konspekt
- Statistika
- NLK Obory
- statistika, zdravotnická statistika
- diagnostika
The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed.
In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.
Etické ohledy k účastníkům randomizované klinické studie vyžadují průběžné monitorování výsledků, které může vést k předčasnému zastavení studie. Opakované provádění statistických testů však zvyšuje šanci na nalezení falešně pozitivního výsledku. Proto je nutné použít speciální statistickou metodologii, která zajistí kontrolu nad stanovenou hladinou významnosti. Další možností, jak reagovat na průběžné výsledky, je změnit pravděpodobnosti přiřazování pacientů do jednotlivých terapeutických větví.
The ethical responsibility to the randomized study participants demands that the results be monitored during the course of the trial. The interim evaluation of the trial results may lead to the premature stopping. However, the repeated statistical testing inflates the probability of false positive error. Hence statistical adjustments are necessary. The probabilistic rules for the random allocation of patients may be changed during the course of the trial according to the observed responses.
- MeSH
- etika MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- monitorování léčiv MeSH
- statistika jako téma metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
- MeSH
- adipozita genetika MeSH
- celogenomová asociační studie statistika a číselné údaje MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- index tělesné hmotnosti MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory epidemiologie etiologie genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- metabolom genetika MeSH
- obezita komplikace epidemiologie genetika metabolismus MeSH
- poměr pasu a boků MeSH
- rizikové faktory MeSH
- sexuální faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Evropa MeSH
A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.
- MeSH
- celogenomová asociační studie MeSH
- cirkadiánní rytmus genetika MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * genetika epidemiologie MeSH
- lidé MeSH
- mendelovská randomizace * MeSH
- poruchy iniciace a udržování spánku genetika MeSH
- rizikové faktory MeSH
- spánek * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
