Assessing genome-wide significance for the detection of differentially methylated regions.

DNA methylation plays an important role in human health and disease, and methods for the identification of differently methylated regions are of increasing interest. There is currently a lack of statistical methods which properly address multiple testing, i.e. control genome-wide significance for differentially methylated regions. We introduce a scan statistic (DMRScan), which overcomes these limitations. We benchmark DMRScan against two well established methods (bumphunter, DMRcate), using a simulation study based on real methylation data. An implementation of DMRScan is available from Bioconductor. Our method has higher power than alternative methods across different simulation scenarios, particularly for small effect sizes. DMRScan exhibits greater flexibility in statistical modeling and can be used with more complex designs than current methods. DMRScan is the first dynamic approach which properly addresses the multiple-testing challenges for the identification of differently methylated regions. DMRScan outperformed alternative methods in terms of power, while keeping the false discovery rate controlled.

Parity, hormones and breast cancer subtypes - results from a large nested case-control study in a national screening program.

BACKGROUND: Breast cancer comprises several molecular subtypes with different prognoses and possibly different etiology. Reproductive and hormonal factors are associated with breast cancer overall, and with luminal subtypes, but the associations with other subtypes are unclear. We used data from a national screening program to conduct a large nested case-control study. METHODS: We conducted a nested case-control study on participants in the Norwegian Breast Cancer Screening Program in 2006 - 2014. There was information on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) for 4748 cases of breast cancer. Breast cancer subtypes were defined as luminal A-like (ER+ PR+ HER2-), luminal B-like (ER+ PR- HER2- or ER+ PR+/PR-HER2+), HER2-positive (ER- PR- HER2+) and triple-negative (ER- PR- HER2-). Conditional logistic regression was used to estimate odds ratios (ORs) of breast cancer associated with age at first birth, number of pregnancies, oral contraceptive use, intrauterine devices and menopausal hormone therapy. Analyses were adjusted for age, body mass index, education, age at menarche, number of pregnancies and menopausal status. RESULTS: Number of pregnancies was inversely associated with relative risk of luminal-like breast cancers (p-trend ≤0.02), and although not statistically significant, with HER2-positive (OR = 0.60, 95% CI 0.31-1.19) and triple-negative cancer (OR = 0.70, 95% CI 0.41-1.21). Women who had ≥4 pregnancies were at >40% lower risk of luminal-like and HER2-positive cancers than women who had never been pregnant. However, there was a larger discrepancy between tumor subtypes with menopausal hormone use. Women who used estrogen and progesterone therapy (EPT) had almost threefold increased risk of luminal A-like cancer (OR = 2.92, 95% CI 2.36-3.62) compared to never-users, but were not at elevated risk of HER2-positive (OR = 0.88, 95% CI 0.33-2.30) or triple-negative (OR = 0.92, 95% CI 0.43 - 1.98) subtypes. CONCLUSIONS: Reproductive factors were to some extent associated with all subtypes; the strongest trends were with luminal-like subtypes. Hormone therapy use was strongly associated with risk of luminal-like breast cancer, and less so with risk of HER2-positive or triple-negative cancer. There are clearly some, but possibly limited, etiologic differences between subtypes, with the greatest contrast between luminal A-like and triple-negative subtypes. TRIAL REGISTRATION: Not applicable.

Cause-specific mortality and cancer morbidity in 390 male workers exposed to high purity talc, a six-decade follow-up.

BACKGROUND: This study updates information on mortality and cancer morbidity in a cohort of Norwegian talc workers. METHODS: Follow-up was extended with 24 years, covering 1953-2011. Comparisons were made with the general population and between subgroups within the cohort. RESULTS: Standardized mortality ratio for non-malignant respiratory disease (NMRD) was 0.38 (95%CI: 0.18, 0.69) and for diseases of the circulatory system (CVD) 0.98 (95%CI: 0.82, 1.16). A non-significantly increased NMRD risk was observed at high dust exposures. There were no deaths from pneumoconiosis. CONCLUSIONS: With the clear limitations of a small cohort, our results do hint at an effect of talc dust on mortality from NMRD other than pneumoconiosis, covered by a strong and persisting healthy worker effect. Also, an effect on CVD mortality, masked by a healthy worker selection into the cohort cannot be ruled out. Excess mortality from pneumoconiosis seen in other studies, may reflect exposure to quartz and, possibly, bias due to comparability problems.

Cutaneous head and neck melanoma (CHNM): A population-based study of the prognostic impact of tumor location.

BACKGROUND: Most studies of cutaneous head and neck melanomas (CHNM) have reported poorer survival in CHNM compared with other sites, especially on the scalp/neck. OBJECTIVE: We sought to compare patient and tumor characteristics between CHNM and cutaneous trunk and extremity melanomas and between CHNM locations (face/ear vs scalp/neck, anterior vs posterior), and to study prognostic factors in patients with CHNM. METHODS: We studied all CHNM (n = 1074) from 8120 cases of cutaneous melanomas diagnosed in Norway in 2008 to 2012. RESULTS: Compared with cutaneous trunk and extremity melanomas, CHNM were more frequently found in men, more often nodular and lentigo maligna cutaneous melanomas, and diagnosed at higher T stage (P ≤ .01). CHNM located on posterior sites were diagnosed at significantly higher T stage, and were significantly more often diagnosed with ulceration and at more advanced stage compared with CHNM located on anterior sites (P < .001). T stage and clinical stage were the only significant prognostic factors for melanoma-specific and overall death in the multivariable analysis (P < .001). LIMITATIONS: Low number of cases and the relatively high frequency of missing values are limitations. CONCLUSION: More advanced CHNM were diagnosed on posterior compared with anterior locations, but location was not a significant prognostic factor for cutaneous melanoma-specific or overall death in the multivariable models.

Shear bond strength of resin bonded zirconia and lithium disilicate - effect of surface treatment of ceramics and dentin.

Objectives:The purpose of the study was to investigate the effect of ceramic surface pretreatment, effect of resin cement and dentin surface roughness on shear bond strength. Methodology: Zirconia rods (n = 140) were randomly assigned to air born particle abrasion with aluminum oxide (Al2O3) or hot etching with potassium hydrogen difluoride (KHF2). Lithium disilicate rods (LDS; n = 50) etched with hydrofluoric acid served as reference material. In Part 1 of the study, ceramic rods were cemented to bovine dentin using 5 dual-polymerizing resin cements (Variolink Esthetic, Multilink Automix (Ivoclar Vivadent), Duo-Link (BISCO Dental), Panavia F2.0 (Kuraray Dental), RelyX Unicem (3 M)). Shear bond strength was tested and fracture morphology determined. In Part 2 of the study, test groups with the highest frequency of adhesive fractures between cement and dentin were selected for further bond strength testing with different surface roughness of dentin; ground with P1200 or P80 silicon carbide paper. Dentin samples were fractured vertically to the cemented surface and the adherence between cement and dentin was studied. Results: The results of Part 1 showed that hot etching of zirconia significantly improved bond strength to Duo-Link cement. In Part 2, RelyX Unicem showed significantly higher bond strength to P1200 compared to P80 ground dentin. For Variolink Esthetic, bond strengths to P1200 and P80 ground dentin were similar. Adhesive fracture between cement and dentin dominated. Conclusions: A smooth dentin surface (P1200) improved bond strength to RelyX Unicem. Surface roughness was not important for Variolink Esthetic.

Validating 4 Staging Systems for Cutaneous Squamous Cell Carcinoma Using Population-Based Data: A Nested Case-Control Study.

Importance: Cutaneous squamous cell carcinoma (cSCC) has metastatic potential, but the prognostic value of current staging systems in nonselected patients is uncertain. Objective: To assess the effect of risk factors for metastasis and to evaluate validity and usefulness of 4 staging systems for cSCC using population-based data. Design, Setting, and Participants: This was a nationwide, population-based, nested case-control study. The Cancer Registry of Norway, which receives compulsory data on all cancers in the Norwegian population of approximately 5.2 million inhabitants. All patients diagnosed as having a primary invasive cSCC in the period 2000 to 2004 (n = 6721) were identified. Of these, 112 patients were diagnosed with metastasis within 5 years. As control patients, 112 patients with cSCC without metastases, matched for sex and age at diagnosis, were identified by random. Clinical data and biopsy specimens of primary cSCC were collected for all 224 patients. The biopsies were reexamined histologically by an experienced pathologist using well-established criteria for cSCC, yielding 103 patients with metastasis (cases) and 81 cSCC without metastasis (controls). Main Outcomes and Measures: The ability of 4 cSCC staging systems (ie, the American Joint Committee on Cancer, 7th edition [AJCC 7] staging system, the staging system used by Breuninger et al, the Brigham and Women's Hospital [BWH] staging system, and the AJCC, 8th edition [AJCC 8] staging systems) to identify patients who developed metastasis with 5 years of follow-up. External validation was performed by logistic regression, discrimination (sensitivity, specificity, proportion correctly classified, concordance index), and calibration (R2, Hosmer-Lemeshow test, plots) statistics. Results: Of 6721 patients; 3674 (54.7%) were men and 3047 (45.3%) were women, with a mean age at diagnosis of 78 years. Of the 103 patients with cSCC diagnosed with metastasis within 5 years, 60 [58.3%] were men, and mean [SD] age 72.7 [13.5] years. Of the 81 patients with cSCC without metastasis, 51 [63.0%] were men, and mean [SD] age 74.6 [11.7] 15 years. The staging systems distinguished poorly to moderately between patients who developed metastasis and those who did not. The ability to cluster patients with similar outcomes within the same staging category was low, particularly when using the AJCC 7 system. Using the AJCC 7 system, the risk of metastasis for T2 patients was 3-fold, compared with T1 patients (OR, 2.96; 95% CI, 1.43-6.15). In the system used by Breuninger et al, high-risk categories for diameter and tumor thickness and the BWH system's T2b category collected relatively homogeneous groups. In the systems used by Breuninger et al and Brigham-Women's Hospital, risk of metastasis was significantly elevated with increasing stage or risk category. Using the system by Breuninger et al, the risk of metastasis was less than 3-fold for tumors in the high-risk category of the combined variable (OR, 2.72; 95% CI, 1.29-5.74). The BWH system gave ORs for metastasis at 4.6 (95% CI, 2.23-9.49) and 21.31 (95% CI, 6.07-74.88) for the T2a and T2b categories, respectively. Conclusions and Relevance: Using population-based data, 4 current staging systems for cSCC were unsatisfactory in identifying nonselected cSCC patients at high risk for metastasis. The system used by Breuninger gave the best results.

High mortality due to cutaneous melanoma in Norway: a study of prognostic factors in a nationwide cancer registry.

PURPOSE: The purpose of this study was to examine why Norway has the highest rate of mortality due to cutaneous melanoma (CM) in Europe. The Norwegian Malignant Melanoma Registry (NMMR) enables the study of clinical and histopathological characteristics of patients who die due to CM. RESULTS: The NMMR and the Norwegian Cause of Death Registry provided data on the clinical and histopathological factors as well as the date and cause of death, through June 2015 for all first invasive CMs diagnosed in 2008-2012 (n=8087). Cox regression was used to estimate associations between clinical and pathological factors and CM-specific death. Multiple imputation was used to handle missing data. RESULTS: The CMs were equally distributed between men (49.9%) and women (50.1%), and the median follow-up was 4.0 years (range: 0.08-7.5 years). Trunk was the most common anatomic site (48%), superficial spreading melanoma was the dominant melanoma subtype (68.2%), median Breslow thickness was 1.0 mm, ulceration was present in 23% of CMs, and 91.8% of cases were in a local clinical stage at diagnosis. Compared to women, men were diagnosed at a higher age, with thicker and more-often-ulcerated tumor, and more often were in advanced clinical stages. During follow-up, 1015 patients died due to CM, representing 52.8% of all deaths. The nodular subtype made up the dominant proportion of fatal CM cases (55.3% in women, 64.6% in men). Sex, age, anatomic site (trunk), T-stage, ulceration, clinical stage, and having a second primary CM were associated with increased risk of CM-specific death. CONCLUSION: Our data suggest that the high rate of mortality due to CM observed in Norway is attributable to the more advanced stage of the disease at diagnosis. Most high-risk cases occurred in male patients ≥70 years of age. Efforts to improve awareness and secondary prevention of CM, including warning signs of all melanoma subtypes, are required urgently and should be targeted toward men in particular.

Number of Risky Lifestyle Behaviors and Breast Cancer Risk.

BACKGROUND: Lifestyle factors are associated with overall breast cancer risk, but less is known about their associations, alone or jointly, with risk of specific breast cancer subtypes. METHODS: We conducted a case-control subjects study nested within a cohort of women who participated in the Norwegian Breast Cancer Screening Program during 2006-2014 to examine associations between risky lifestyle factors and breast cancer risk. In all, 4402 breast cancer cases subjects with information on risk factors and hormone receptor status were identified. Conditional logistic regression was used to estimate odds ratios (ORs), with 95% confidence intervals (CIs), in relation to five risky lifestyle factors: body mass index (BMI) of 25 kg/m² or greater, three or more glasses of alcoholic beverages per week, ever smoking, fewer than four hours of physical activity per week, and ever use of menopausal hormone therapy. Analyses were adjusted for education, age at menarche, number of pregnancies, and menopausal status. All statistical tests were two-sided. RESULTS: Compared with women with no risky lifestyle behaviors, those with five had 85% (OR = 1.85, 95% CI = 1.42 to 2.42, P trend < .0001) increased risk of breast cancer overall. This association was limited to luminal A-like (OR = 2.20, 95% CI = 1.55 to 3.12, P trend < .0001) and luminal B-like human epidermal growth factor receptor 2 (HER2)-positive (OR = 1.66, 95% CI = 0.61 to 4.54, P trend < .004) subtypes. Number of risky lifestyle factors was not associated with increased risk of luminal B-like HER2-negative, HER2-positive, or triple-negative subtypes (P trend > .18 for all). CONCLUSIONS: Number of risky lifestyle factors was positively associated with increased risk for luminal A-like and luminal B-like HER2-positive breast cancer.

Prediagnostic serum calcium and albumin and ovarian cancer: A nested case-control study in the Norwegian Janus Serum Bank Cohort.

BACKGROUND: Women with higher serum calcium may be more likely to be diagnosed and die of ovarian cancer. We evaluated that finding in a large, prospective cohort. METHODS: We conducted a nested case-control study using a population-based biobank from Norway. We compared 202 ovarian cancer cases and 202 controls, matched for age, date at blood draw, and county of residence, with respect to serum calcium and albumin, adjusted for anthropometric variables. We evaluated risks using the entire follow-up period as well as 2-15 years and 16-25 years ("early" and "late", respectively). RESULTS: For the entire follow-up, risk was significantly increased in the highest tertile of albumin and for high albumin and calcium jointly. Risks for ovarian cancer differed markedly by follow-up time. In early follow-up, women in the highest tertile of serum calcium had a 2.5-fold increased risk, adjusted for height and body mass index (OR=2.47, 95% C.I. 1.12-5.45) with a significant dose-response (p=0.024). Risk was not elevated in late follow-up (OR=0.62, 95% C.I. 0.27-1.36). Similarly, in early follow-up, women in the highest tertile of serum albumin had an increased risk (OR=2.55, 95% C.I.1.22-5.49) with a significant dose-response (p=0.009). Conversely, risk was not increased in late follow-up (OR=1.36, 95% C.I. 0.65-2.83). CONCLUSIONS: These data confirm a prospective association between higher serum calcium and ovarian cancer. An association in early, but not late, follow-up suggests that the higher calcium reflects the presence of existing cancer. A positive association with serum albumin is novel and should be interpreted cautiously.

Cardiorespiratory fitness and risk of site-specific cancers: a long-term prospective cohort study.

Based on self-reported physical activity, there is epidemiologic evidence for a beneficial relation between physical activity and colon cancer in men, but findings for other cancers are inconclusive. Measured cardiorespiratory fitness (CRF) can provide knowledge about the cancer-preventive value of physical activity. We aimed to assess relationships between CRF and risk of site-specific cancers. A cohort of 1997 healthy Norwegian men, aged 40-59 years at inclusion in 1972-1975, was followed for cancer throughout 2012 using data from the Cancer Registry of Norway. CRF was measured by a maximal exercise bicycle test at inclusion. Relationships between CRF and site-specific cancers were estimated using Cox regression, adjusted for age, body mass index, and smoking. During follow-up, 898 cancer cases were diagnosed in 758 men. When comparing men in CRF tertile 1 with men in tertiles 2 and 3, respectively, we found decreased risk of proximal colon cancer in tertile 2 (HR: 0.30, 95% CI: 0.13-0.73) and decreased risk of cancers of lung (0.39 95% CI: 0.22-0.66), pancreas (0.32 95% CI: 0.10-1.00), and bladder (HR: 0.40 95% CI: 0.21-0.74) in tertile 3. Furthermore, a significant trend for lower risk by increasing CRF tertile was found for cancers of proximal colon, lung, and bladder (P-value for trend <0.05). For other cancer sites, no significant association was found. Our results indicate that high midlife CRF may have cancer-preventive value.

Alcohol, Physical Activity, Smoking, and Breast Cancer Subtypes in a Large, Nested Case-Control Study from the Norwegian Breast Cancer Screening Program.

Background: To what extent alcohol, smoking, and physical activity are associated with the various subtypes of breast cancer is not clear. We took advantage of a large population-based screening cohort to determine whether these risk factors also increase the risk of the poor prognosis subtypes.Methods: We conducted a matched case-control study nested within the Norwegian Breast Cancer Screening Program during 2006-2014. A total of 4,402 breast cancer cases with risk factor and receptor data were identified. Five controls were matched to each case on year of birth and year of screening. Conditional logistic regression was used to estimate ORs of breast cancer subtypes adjusted for potential confounders.Results: There were 2,761 luminal A-like, 709 luminal B-like HER2-negative, 367 luminal B-like HER2-positive, 204 HER2-positive, and 361 triple-negative cancers. Current alcohol consumption was associated with breast cancer risk overall [OR 1.26; 95% confidence interval (CI), 1.09-1.45] comparing 6+ glasses a week to never drinkers. However, this risk increase was found only for luminal A-like breast cancer. Smoking 20+ cigarettes a day was associated with an OR of 1.41 (95% CI, 1.06-1.89) overall, with significant trends for luminal A-like and luminal B-like HER2-negative cancer. Current physical activity (4+ hours/week compared with none) was associated with 15% decreased risk of luminal A-like cancer, but not clearly with other subtypes.Conclusions: In this large study, alcohol, smoking, and physical activity were predominantly associated with luminal A-like breast cancer.Impact: Alcohol, smoking, and physical activity were associated with luminal A-like breast cancer subtype. Cancer Epidemiol Biomarkers Prev; 26(12); 1736-44. ©2017 AACR.

A protocol for prospective studies of 25-hydroxyvitamin D, leptin and body mass index in relation to cutaneous melanoma incidence and survival.

INTRODUCTION: The incidence and mortality rates of cutaneous melanoma (CM) are increasing among fair-skinned populations worldwide. Ultraviolet radiation (UVR) is the principal risk factor for CM, but is also the main source of 25-hydroxyvitamin D (25(OH)D), which has been associated with reduced risk and better prognosis of some cancer types. However, both low and high 25(OH)D levels have been associated with increased risk of CM. Obesity as measured by body mass index (BMI) is associated with risk of several cancers and has also been suggested as a risk factor for CM, and may also be related to insufficient 25(OH)D and/or high leptin levels. Moreover, contracting a CM diagnosis has been associated with increased risk of developing second cancer. We aim to study whether low prediagnostic serum levels of 25(OH)D, high prediagnostic levels of BMI and high serum leptin levels influence CM incidence, Breslow thickness and CM mortality, and risk of second cancer and survival after a CM diagnosis. METHODS AND ANALYSIS: Cohort and nested case-control studies will be carried out using the population-based Janus Serum Bank Cohort (archival prediagnostic sera, BMI, smoking and physical activity), with follow-up from 1972 to 2014. Additional data will be received from the Cancer Registry of Norway, the national Cause of Death Registry, Statistics Norway (education and occupation) and exposure matrices of UVR. Time-to-event regression models will be used to analyse the cohort data, while the nested case-control studies will be analysed by conditional logistic regression. A multilevel approach will be applied when incorporating group-level data. ETHICS AND DISSEMINATION: The project is approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and in the news media.

Measured cardiorespiratory fitness and self-reported physical activity: associations with cancer risk and death in a long-term prospective cohort study.

Physical activity is inversely associated with risk of some cancers. The relation with cancer-specific death remains uncertain. Mainly, studies on relationships between physical activity and cancer are based on self-reported physical activity (SPA). Hereby, we examined whether measured cardiorespiratory fitness (CRF) is associated with cancer risk, mortality, and case fatality. We also describe relationships between SPA and these outcomes, and between CRF and SPA. A cohort of 1997 healthy Norwegian men, aged 40-59 years at inclusion in 1972-75, was followed throughout 2012. At baseline, CRF was objectively measured. SPA (leisure time and occupational) was obtained through a questionnaire. Relationships between CRF or SPA, and the outcomes were estimated using Cox regression, adjusted for age, body mass index (BMI), and smoking. Pearson correlation coefficients evaluated agreements between CRF and SPA. During follow-up, 758 men were diagnosed with cancer and 433 cancer deaths occurred. Analyses revealed lower cancer risk (Hazard ratio [HR] 0.85, 95% confidence intervals [CI]: 0.68-1.00), mortality (HR 0.68, 95% CI: 0.53-0.88), and case fatality (HR 0.74, 95% CI: 0.57-0.96), in men with high CRF compared to low CRF. Light leisure time SPA was associated with lower cancer risk (HR 0.70, 95% CI: 0.56-0.86) and mortality (HR 0.64 95% CI: 0.49-0.83), whereas strenuous occupational SPA was associated with higher risks (HR 1.42, 95% CI: 1.13-1.78 and HR 1.45, 95% CI: 1.09-1.93). Correlations between CRF and SPA were 0.351 (P < 0.001) and -0.106 (P < 0.001) for leisure time and occupational SPA, respectively. A high midlife CRF may be beneficial for cancer risk, cancer mortality, and case fatality.

Vitamin D intake, month the mammogram was taken and mammographic density in Norwegian women aged 50-69.

BACKGROUND: The role of vitamin D in breast cancer etiology is unclear. There is some, but inconsistent, evidence that vitamin D is associated with both breast cancer risk and mammographic density (MD). We evaluated the associations of MD with month the mammogram was taken, and with vitamin D intake, in a population of women from Norway--a country with limited sunlight exposure for a large part of the year. METHODS: 3114 women aged 50-69, who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006/07, completed risk factor and food frequency (FFQ) questionnaires. Dietary and total (dietary plus supplements) vitamin D, calcium and energy intakes were estimated by the FFQ. Month when the mammogram was taken was recorded on the mammogram. Percent MD was assessed using a computer assisted method (Madena, University of Southern California) after digitization of the films. Linear regression models were used to investigate percent MD associations with month the mammogram was taken, and vitamin D and calcium intakes, adjusting for age, body mass index (BMI), study year, estrogen and progestin therapy (EPT), education, parity, calcium intakes and energy intakes. RESULTS: There was no statistical significant association between the month the mammogram was taken and percent MD. Overall, there was no association between percent MD and quartiles of total or dietary vitamin D intakes, or of calcium intake. However, analysis restricted to women aged <55 years revealed a suggestive inverse association between total vitamin D intake and percent MD (p for trend = 0.03). CONCLUSION: Overall, we found no strong evidence that month the mammogram was taken was associated with percent MD. We found no inverse association between vitamin D intake and percent MD overall, but observed a suggestive inverse association between dietary vitamin D and MD for women less than 55 years old.

Discontinuing inappropriate medication in nursing home residents (DIM-NHR Study): protocol of a cluster randomised controlled trial.

INTRODUCTION: Nursing home residents often have a high number of comorbidities resulting in polypharmacy. Inappropriate prescribing is therefore likely to occur, which in turn is expected to worsen cognitive impairment, to increase the fall risk and to decrease residents' quality of life. The objective of the 'Discontinuing Inappropriate Medication in Nursing Home Residents' (DIM-NHR) study is to examine the efficacy and cost-effectiveness of the Multidisciplinary Multistep Medication Review (3MR) that is aimed at optimising prescribing and discontinuing inappropriate medication. METHODS: A cluster randomised controlled trial will be conducted. Elderly care physicians and their wards (clusters) will be randomised. Data will be collected at baseline and 4 months after the 3MR has taken place. Six hundred nursing home residents will be recruited of whom more than half are expected to suffer from dementia. The 3MR will be based on consensus criteria and the relevant literature and will be performed by the patient's elderly care physician in collaboration with a pharmacist. ANALYSIS: Primary outcomes-the difference in proportion of residents who successfully discontinued inappropriate medication between the intervention and control group at follow-up. Secondary outcomes-undertreatment, exposure to anticholinergic and sedative medicines, neuropsychiatric symptoms, cognitive function, falls, hospital admission, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Participant burden will be kept at a minimum. The elderly care physician will remain free to adjust medication when symptoms relapse or adverse events occur, rendering serious adverse events highly unlikely. Study findings will be published in peer-reviewed journals and a 3MR toolkit will be developed. TRIAL REGISTRATION NUMBER: This study has been registered at http://www.ClinicalTrials.gov (trial registration number: NCT01876095).