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      Mastering variation: variance components and personalised medicine

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          Various sources of variation in observed response in clinical trials and clinical practice are considered, and ways in which the corresponding components of variation might be estimated are discussed. Although the issues have been generally well‐covered in the statistical literature, they seem to be poorly understood in the medical literature and even the statistical literature occasionally shows some confusion. To increase understanding and communication, some simple graphical approaches to illustrating issues are proposed. It is also suggested that reducing variation in medical practice might make as big a contribution to improving health outcome as personalising its delivery according to the patient. It is concluded that the common belief that there is a strong personal element in response to treatment is not based on sound statistical evidence. © 2015 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

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          Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

          Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. ( number, NCT00334711 [].). Copyright 2006 Massachusetts Medical Society.
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            Cluster trials in implementation research: estimation of intracluster correlation coefficients and sample size.

            The cluster randomized trial with a concurrent economic evaluation is considered the gold standard evaluative design for the conduct of implementation research evaluating different strategies to promote the transfer of research findings into clinical practice. This has implications for the planning of such studies, as information is needed on the effects of clustering on both effectiveness and efficiency outcomes. This paper describes the design considerations specific to implementation research studies, focusing particularly on the estimation of sample size requirements and on the need for reliable information on intracluster correlation coefficients for both effectiveness and efficiency outcomes. Copyright 2001 John Wiley & Sons, Ltd.
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              How Intermountain trimmed health care costs through robust quality improvement efforts.

              It has been estimated that full implementation of the Affordable Care Act will extend coverage to thirty-two million previously uninsured Americans. However, rapidly rising health care costs could thwart that effort. Since 1988 Intermountain Healthcare has applied to health care delivery the insights of W. Edwards Deming's process management theory, which says that the best way to reduce costs is to improve quality. Intermountain achieved such quality-based savings through measuring, understanding, and managing variation among clinicians in providing care. Intermountain created data systems and management structures that increased accountability, drove improvement, and produced savings. For example, a new delivery protocol helped reduce rates of elective induced labor, unplanned cesarean sections, and admissions to newborn intensive care units. That one protocol saves an estimated $50 million in Utah each year. If applied nationally, it would save about $3.5 billion. "Organized care" along these lines may be central to the long-term success of health reform.

                Author and article information

                Stat Med
                Stat Med
                Statistics in Medicine
                John Wiley and Sons Inc. (Hoboken )
                28 September 2015
                30 March 2016
                : 35
                : 7 , Papers from the 35th Annual Conference of the International Society for Clinical Biostatistics ( doiID: 10.1002/sim.v35.7 )
                : 966-977
                [ 1 ] Competence Centre for Methodology and StatisticsLuxembourg Institute of Health L‐1445 StrassenLuxembourg
                Author notes
                [* ] Correspondence to: Stephen Senn, Competence Centre for Methodology and Statistics, Luxembourg Institute of Health, L‐1445 Strassen, Luxembourg.

                E‐mail: stephen.senn@

                SIM6739 SIM-14-0786.R1
                © 2015 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Pages: 12
                Funded by: European Union FP7 programme
                Award ID: 602552
                Special Issue Paper
                Special Issue Papers
                Custom metadata
                30 March 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:07.10.2016


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