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1. Reliability of radiologists' first impression when interpreting a screening mammogram.

Author

Woloschak, GE, Gandomkar, Z, Siviengphanom, S, Suleiman, M, Wong, D, Reed, W, Ekpo, EU, Xu, D, Lewis, SJ, Evans, KK, Wolfe, JM, Brennan, PC, Woloschak, GE, Gandomkar, Z, Siviengphanom, S, Suleiman, M, Wong, D, Reed, W, Ekpo, EU, Xu, D, Lewis, SJ, Evans, KK, Wolfe, JM, and Brennan, PC

Abstract

Previous studies showed that radiologists can detect the gist of an abnormality in a mammogram based on a half-second image presentation through global processing of screening mammograms. This study investigated the intra- and inter-observer reliability of the radiologists' initial impressions about the abnormality (or "gist signal"). It also examined if a subset of radiologists produced more reliable and accurate gist signals. Thirty-nine radiologists provided their initial impressions on two separate occasions, viewing each mammogram for half a second each time. The intra-class correlation (ICC) values showed poor to moderate intra-reader reliability. Only 13 radiologists had an ICC of 0.6 or above, which is considered the minimum standard for reliability, and only three radiologists had an ICC exceeding 0.7. The median value for the weighted Cohen's Kappa was 0.478 (interquartile range = 0.419-0.555). The Mann-Whitney U-test showed that the "Gist Experts", defined as those who outperformed others, had significantly higher ICC values (p = 0.002) and weighted Cohen's Kappa scores (p = 0.026). However, even for these experts, the intra-radiologist agreements were not strong, as an ICC of at least 0.75 indicates good reliability and the signal from none of the readers reached this level of reliability as determined by ICC values. The inter-reader reliability of the gist signal was poor, with an ICC score of 0.31 (CI = 0.26-0.37). The Fleiss Kappa score of 0.106 (CI = 0.105-0.106), indicating only slight inter-reader agreement, confirms the findings from the ICC analysis. The intra- and inter-reader reliability analysis showed that the radiologists' initial impressions are not reliable signals. In particular, the absence of an abnormal gist does not reliably signal a normal case, so radiologists should keep searching. This highlights the importance of "discovery scanning," or coarse screening to detect potential targets before ending the visual search.

Published
2023

2. Global Radiomic Features from Mammography for Predicting Difficult-To-Interpret Normal Cases.

Author

Siviengphanom, S, Gandomkar, Z, Lewis, SJ, Brennan, PC, Siviengphanom, S, Gandomkar, Z, Lewis, SJ, and Brennan, PC

Abstract

This work aimed to investigate whether global radiomic features (GRFs) from mammograms can predict difficult-to-interpret normal cases (NCs). Assessments from 537 readers interpreting 239 normal mammograms were used to categorise cases as 120 difficult-to-interpret and 119 easy-to-interpret based on cases having the highest and lowest difficulty scores, respectively. Using lattice- and squared-based approaches, 34 handcrafted GRFs per image were extracted and normalised. Three classifiers were constructed: (i) CC and (ii) MLO using the GRFs from corresponding craniocaudal and mediolateral oblique images only, based on the random forest technique for distinguishing difficult- from easy-to-interpret NCs, and (iii) CC + MLO using the median predictive scores from both CC and MLO models. Useful GRFs for the CC and MLO models were recognised using a scree test. The CC and MLO models were trained and validated using the leave-one-out-cross-validation. The models' performances were assessed by the AUC and compared using the DeLong test. A Kruskal-Wallis test was used to examine if the 34 GRFs differed between difficult- and easy-to-interpret NCs and if difficulty level based on the traditional breast density (BD) categories differed among 115 low-BD and 124 high-BD NCs. The CC + MLO model achieved higher performance (0.71 AUC) than the individual CC and MLO model alone (0.66 each), but statistically non-significant difference was found (all p > 0.05). Six GRFs were identified to be valuable in describing difficult-to-interpret NCs. Twenty features, when compared between difficult- and easy-to-interpret NCs, differed significantly (p < 0.05). No statistically significant difference was observed in difficulty between low- and high-BD NCs (p = 0.709). GRF mammographic analysis can predict difficult-to-interpret NCs.

Published
2023

3. Focussed hydrothermal alteration in upper crustal oceanic faults on Macquarie Island

Author

Lewis, SJ

Abstract

Macquarie Island is an uplifted exposure of oceanic lithosphere lying deep within the Southern Ocean, less than ten kilometres east of the dextral transpressional boundary which separates the Indo-Australian and Pacific plates (54¬¨‚àû 30' S, 158¬¨‚àû 55' E). The island is a geological oddity; essentially an intra-oceanic ophiolite residing in its primary marine basin. Macquarie Island hosts a diverse spectrum of igneous rock types from all stratigraphic levels of the ocean crust, with pillow basalts and sheeted dolerite dykes most abundant. These upper crustal rocks were formed in the Late Miocene during slow crustal accretion and rifting (spreading rate ~ 20 mm per year) at the relict Proto-Macquarie Spreading Ridge (PMSR). Typical of many slow-spreading (magma-poor) mid-ocean ridges, tectonic activity played a dominant but episodic role in the geological evolution of Macquarie Island. Faults, fractures, and brittle shear zones are widespread across the island, and discrete igneous rock domains commonly have faulted margins. Many discontinuities were originally formed during arnagmatic extension at the PMSR, although more recent transpressive tectonism (< 10 Ma) has further modified or reactivated most of these structures. An extensive array of neotectonic faults have also formed during ongoing uplift and deformation (post-spreading). The Major Lake, Caroline Cove, and Sellick Bay Faults are prominent structural zones which cut sharply across upper crustal rocks in central and southern Macquarie Island. These steeply dipping fault systems are oriented subparallel (NW to NNE-strike) and are regularly spaced across the island (~ 10 km apart). Each fault forms a major geological boundary separating distinct lithologic domains which host disparate rock types (pillow basalts, sheeted dykes, and their transitional volcanic‚ÄövÑvÆintrusive packages) and regional alteration assemblages (recharge-related). Variably influenced by multiple episodes of extensional and strike-slip tectonic activity, all of these significant crustal discontinuities initially developed during seafloor-spreading at the PMSR. However, their orientations are largely oblique to the ENE trend of the palaeo-rift axis, suggesting that they may have formed structural accommodation zones during the waning stages of slow extension, or that they were related to active tectonism at a proximal ridge‚ÄövÑvÆtransform intersection. Structurally focussed zones of intensely altered volcanic rocks and sheeted dolerite dykes are intimately associated (spatially and genetically) with the Major Lake, Caroline Cove, and Sellick Bay Faults. Consistent geological and hydrothermal relationships attest to their critical role as crustal pathways and fracture conduits for hydrothermal systems. These major oceanic structures host highly distinctive hydrothermal assemblages which mainly consist of semi- to pervasively altered basaltic wall rocks, abundant hydrothermal veins and breccias, and patchy domains of massive sulfide mineralisation. The alteration zones comprise (in total) six focussed hydrothermal facies, which are here defined as: (1) the vein and breccia, quartz-chlorite (VQC) facies; (2) the massive and veined, chlorite-quartz-pyrite (CQP) fades; (3) the vein-dominated, prehnite-zeolite (VPZ) fades; (4) the foliated, massive chlorite (FMC) fades; (5) the pervasive, Fe-oxyhydroxide overprint (PFO) facies; and (6) the narrow, focussed quartz vein (NQV) fades. The formation of a single diagnostic facies dominated peak hydrothermal conditions in each major structure; the VQC fades in the Major Lake Fault, the CQP facies in the Caroline Cove Fault, and the VPZ fades in the Sellick Bay Fault. In addition, both the VQC and CQP fades are partially overprinted by smaller-scale alteration assemblages that post-dated peak hydrothermal activity, i.e., the FMC and PFO fades. The dominant fault-hosted alteration facies are highly anomalous, multi-component hydrothermal assemblages. They each have significantly different alteration minerals, hydrothermal textures, and physical attributes compared to regional igneous rock domains, i.e., non-fault zone crustal blocks. Multiple episodes of superimposed fluid‚ÄövÑvÆrock interaction produced these distinctive fault-hosted assemblages, with focussed hydrothermal activity mostly post-dating the main period of axial magmatism at the PMSR (crustal accretion). However, high-temperature fluid circulation was strongly influenced (initiated and sustained) by small-scale dyke pulses, mostly injected at deeper crustal levels than the present fault exposures. Rapid fluid discharge from the basement reservoir was probably also initiated (in part) by discrete tectonic events, such as oblique extension localised along specific fault segments. The physical manifestations of these relict fluid flow events are now well exposed at six key sites on Macquarie Island, where they afford an unparalleled opportunity to study the processes and products of structurally focussed hydrothermal activity in the ocean crust. The Major Lake Fault Zone (MLFZ) is one of the best preserved and most extensive oceanic discontinuities on Macquarie Island. Mainly oriented NNW along its ~ 4 km-long strike, the MLFZ separates upper greenschist and lower amphibolite facies rocks of the Sandell Bay and Lusitania Bay Dyke Swarms (in the southern footwall) from zeolite facies pillow basalts in the northern hangingwall. The fault is the main structural host of quartz + chlorite-dominated alteration (VQC facies) and is also associated with late-stage foliated, massive 'chlorite' (FMC) fades. Furthermore, five planar alteration zones representing the narrow (< 1-2 m-wide), focussed quartz vein (NQV) facies are situated in the regional footwall package ~ 1-1.5 km south of the MLFZ. There are four discrete VQC facies sites at ~ 750 m-spaced intervals along the length of the Major Lake Fault, forming 1-15 m-wide and 80-150 m-long alteration zones. The distinctive spatial segmentation of VQC fades zones likely reflects small-scale hydrothermal upflow systems, locally controlled by basement structures such as obliquely intersecting faults or slight variations in the orientation of the MLFZ, e.g., structural step-overs, kinked zones or offsets. In contrast, the FMC fades is only well exposed at a single 10 m-wide and 55 m-long outcrop segment in the central deformation corridor of the MLFZ (although its true strike extent and physical dimensions are uncertain due to the effects of surface cover and erosion). The VQC fades comprises a multi-stage paragenetic association of hydrothermally derived alteration minerals. Quartz, chlorite and albite are dominant components, whereas epidote and pyrite occur sporadically in altered basalts and dolerites. The main VQC phases are reflected by moderate to strong enrichments in whole-rock Si and Fe concentrations, consistently depleted levels of Ca (due to igneous plagioclase alteration, e.g., the conversion of labradorite to albite), and highly elevated loss-on-ignition values (enhanced volatile contents). The earliest alteration stage is characterised by selectively pervasive chlorite alteration, which is widespread throughout the primary igneous groundmass. Chlorite also forms narrow veinlets and inEtlls many vuggy cavities. Importantly, chlorites in the VQC fades are compositionally diverse and extend from Mg-rich to Fe-rich varieties (Fe # range = 0.29 to 0.64), with many also containing > 1 wt. % Mn (strongly suggestive of a fluid mixing origin). Hydrothermal fluids mostly ranged from 220¬¨‚àû-260¬¨‚àû C (mean = 237¬¨‚àû C) during the precipitation of chlorite (paragenetic Stage I). In contrast, fluids were up to ~ 50¬¨‚àû C hotter during the later formation of discrete quartz veins, intricate quartz stockwork arrays, and irregularly shaped patches of massive quartz alteration (Stage II). However, this diagnostic quartz-bearing stage precipitated across a much broader thermal range (176¬¨‚àû-309¬¨‚àû C), with fluid temperature variations of up to ~ 80¬¨‚àû C occurring between discrete sites and different quartz sub-stages along the MLFZ. The distribution and abundance of pyrite trace elements in the VQC facies also varies at different outcrop sites, and are moderately well correlated with quartz precipitation temperatures. The most significant trace element enrichments are for Co, Ni, Cu, Zn, and Pb. Highly elevated levels of these elements mainly occur in pyrites associated with the lower temperature range of VQC quartz (‚Äöv¢¬ß220¬¨‚àû C), whereas only Se concentrations are consistently enriched at higher temperature sites on the MLFZ. In contrast, sulfur isotope compositions of VQC facies pyrite are not site-specific. Their 834S values encompass the known range of seafloor-hosted sulfides (-1 ‚ÄövÑ‚àû to +11.9 ‚ÄövÑ‚àû) although most are within +1 to +4 ‚ÄövÑ‚àû, indicating that sulfur was mainly derived from leached magmatic crust. The Caroline Cove Fault Zone (CCFZ) is variably exposed for ~ lkm along-strike at the south-western extremity of Macquarie Island. This NNW to NNE-oriented structure is dominated by abundant small-scale normal- and sinistral-oblique faults. Clay-bearing gouge and breccia zones (neotectonic) occur commonly in the central deformation corridor, clearly post-dating the main period of hydrothermal alteration. The CCFZ cuts across regional pillow basalts with zeolite and lower greenschist facies assemblages, and also partly forms the north-eastern boundary of the massive and veined, chlorite-quartz-pyrite (CQP) facies. The diagnostic CQP facies outcrops exclusively at Caroline Cove (northern end of the CCFZ), where it forms a fault-bound wedge of intensely altered volcanic rocks ~ 200 m-long and up to 80 m-wide (strike extent limited by neotectonic faulting and surface cover). Sporadic occurrences of the foliated, massive outcrop segment in the central deformation corridor of the MLFZ (although its true stri...

Published
2023
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6. Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones

Author

Swain, CTV, Drummond, AE, Boing, L, Milne, RL, English, DR, Brown, KA, Van Roekel, EH, Dixon-Suen, Suzanne, Lynch, MJ, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, Lynch, BM, Swain, CTV, Drummond, AE, Boing, L, Milne, RL, English, DR, Brown, KA, Van Roekel, EH, Dixon-Suen, Suzanne, Lynch, MJ, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, and Lynch, BM

Published
2022

7. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author

Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM

Abstract

OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r

Published
2022

8. Linking Physical Activity to Breast Cancer: Text Mining Results and a Protocol for Systematically Reviewing Three Potential Mechanistic Pathways

Author

Lynch, BM, Milne, RL, English, DR, Brown, KA, Drummond, AE, Swain, CT, van Roekel, EH, Moore, MM, Gaunt, TR, Martin, RM, Lewis, SJ, Lynch, BM, Milne, RL, English, DR, Brown, KA, Drummond, AE, Swain, CT, van Roekel, EH, Moore, MM, Gaunt, TR, Martin, RM, and Lewis, SJ

Abstract

Epidemiologic research suggests that physical activity is associated with a reduced risk of breast cancer, but the causal nature of this link is not clear. Investigating mechanistic pathways can provide evidence of biological plausibility and improve causal inference. This project will examine three putative pathways (sex steroid hormones, insulin signaling, and inflammation) in a series of two-stage systematic reviews. Stage 1 used Text Mining for Mechanism Prioritisation (TeMMPo) to identify and prioritize relevant biological intermediates. Stage 2 will systematically review the findings from studies of (i) physical activity and intermediates and (ii) intermediates and breast cancer. Ovid MEDLINE, EMBASE, and SPORTDiscus will be searched using a combination of subject headings and free-text terms. Human intervention and prospective, observational studies will be eligible for inclusion. Meta-analysis will be performed where possible. Risk of bias will be assessed using the Cochrane Collaboration tool, or the ROBINS-I or ROBINS-E tool, depending on study type. Strength of evidence will be assessed using the GRADE system. In addition to synthesizing the mechanistic evidence that links physical activity with breast cancer risk, this project may also identify priority areas for future research and help inform the design and implementation of physical activity interventions.See related reviews by Swain et al., p. 16 and Drummond et al., p. 28.

Published
2022

9. Mammography-based Radiomics in Breast Cancer: A Scoping Review of Current Knowledge and Future Needs.

Author

Siviengphanom, S, Gandomkar, Z, Lewis, SJ, Brennan, PC, Siviengphanom, S, Gandomkar, Z, Lewis, SJ, and Brennan, PC

Abstract

RATIONALE AND OBJECTIVES: Breast cancer is a highly complex heterogeneous disease. Current validated prognostic factors (e.g., histological grade, lymph node involvement, receptor status, and proliferation index), as well as multigene tests (e.g., Oncotype DX and PAM50) are helpful to describe breast cancer characteristics and predict the chance of recurrence risk and survival. Nevertheless, they are invasive and cannot capture a complete heterogeneity of the entire breast tumor resulting in up to 30% of patients being either over- or under-treated for breast cancer. Furthermore, multigene testings are time consuming and expensive. Radiomics is emerging as a reliable, accurate, non-invasive, and cost-effective approach of using quantitative image features to classify breast cancer characteristics and predict patient outcomes. Several recent radiomics reviews have been conducted in breast cancer, however, specific mammography-based radiomics studies have not been well discussed. This scoping review aims to assess and summarize the current evidence on the potential usefulness of mammography-based (i.e., digital mammography, digital breast tomosynthesis, and contrast-enhanced mammography) radiomics in predicting factors that describe breast cancer characteristics, recurrence, and survival. MATERIALS AND METHODS: PubMed database and eligible text reference were searched using relevant keywords to identify studies published between 2015 and December 19, 2020. Studies collected were screened and assessed based on the inclusion and exclusion criteria. RESULTS: Eighteen eligible studies were included and organized into three main sections: radiomics predicting breast cancer characteristics, radiomics predicting breast cancer recurrence and survival, and radiomics integrating with clinical data. Majority of publications reported retrospective studies while three studies examined prospective cohorts. Encouraging results were reported, suggesting the potential clinical value o

Published
2022

14. X-ray Phase-Contrast Computed Tomography for Soft Tissue Imaging at the Imaging and Medical Beamline (IMBL) of the Australian Synchrotron

Author

Arhatari, BD, Stevenson, AW, Abbey, B, Nesterets, YI, Maksimenko, A, Hall, CJ, Thompson, D, Mayo, SC, Fiala, T, Quiney, HM, Taba, ST, Lewis, SJ, Brennan, PC, Dimmock, M, Hausermann, D, Gureyev, TE, Arhatari, BD, Stevenson, AW, Abbey, B, Nesterets, YI, Maksimenko, A, Hall, CJ, Thompson, D, Mayo, SC, Fiala, T, Quiney, HM, Taba, ST, Lewis, SJ, Brennan, PC, Dimmock, M, Hausermann, D, and Gureyev, TE

Abstract

The Imaging and Medical Beamline (IMBL) is a superconducting multipole wiggler-based beamline at the 3 GeV Australian Synchrotron operated by the Australian Nuclear Science and Technology Organisation (ANSTO). The beamline delivers hard X-rays in the 25–120 keV energy range and offers the potential for a range of biomedical X-ray applications, including radiotherapy and medical imaging experiments. One of the imaging modalities available at IMBL is propagation-based X-ray phase-contrast computed tomography (PCT). PCT produces superior results when imaging low-density materials such as soft tissue (e.g., breast mastectomies) and has the potential to be developed into a valuable medical imaging tool. We anticipate that PCT will be utilized for medical breast imaging in the near future with the advantage that it could provide better contrast than conventional X-ray absorption imaging. The unique properties of synchrotron X-ray sources such as high coherence, energy tunability, and high brightness are particularly well-suited for generating PCT data using very short exposure times on the order of less than 1 min. The coherence of synchrotron radiation allows for phase-contrast imaging with superior sensitivity to small differences in soft-tissue density. Here we also compare the results of PCT using two different detectors, as these unique source characteristics need to be complemented with a highly efficient detector. Moreover, the application of phase retrieval for PCT image reconstruction enables the use of noisier images, potentially significantly reducing the total dose received by patients during acquisition. This work is part of ongoing research into innovative tomographic methods aimed at the introduction of 3D X-ray medical imaging at the IMBL to improve the detection and diagnosis of breast cancer. Major progress in this area at the IMBL includes the characterization of a large number of mastectomy samples, both normal and cancerous, which have been scanned at

Published
2021

15. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Author

Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Martin, RM, Lewis, SJ, Kazmi, N, Robinson, TM, Albanes, D, Aleksandrova, K, Berndt, SI, Bishop, DT, Brenner, H, Buchanan, DD, Bueno-de-Mesquita, B, Campbell, PT, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Ellingjord-Dale, M, Figueiredo, JC, Gallinger, SJ, Giles, GG, Giovannucci, E, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harlid, S, Harrison, TA, Hoffmeister, M, Hopper, JL, Hsu, L, Maria Huerta, J, Huyghe, JR, Jenkins, MA, Keku, TO, Kuehn, T, La Vecchia, C, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Lynch, B, Markowitz, SD, Masala, G, May, AM, Milne, R, Monninkhof, E, Moreno, L, Moreno, V, Newcomb, PA, Offit, K, Perduca, V, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Riboli, E, Sanchez, M-J, Schmit, SL, Schoen, RE, Severi, G, Sieri, S, Slattery, ML, Song, M, Tangen, CM, Thibodeau, SN, Travis, RC, Trichopoulou, A, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gunter, MJ, Murphy, N, Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Martin, RM, Lewis, SJ, Kazmi, N, Robinson, TM, Albanes, D, Aleksandrova, K, Berndt, SI, Bishop, DT, Brenner, H, Buchanan, DD, Bueno-de-Mesquita, B, Campbell, PT, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Ellingjord-Dale, M, Figueiredo, JC, Gallinger, SJ, Giles, GG, Giovannucci, E, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harlid, S, Harrison, TA, Hoffmeister, M, Hopper, JL, Hsu, L, Maria Huerta, J, Huyghe, JR, Jenkins, MA, Keku, TO, Kuehn, T, La Vecchia, C, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Lynch, B, Markowitz, SD, Masala, G, May, AM, Milne, R, Monninkhof, E, Moreno, L, Moreno, V, Newcomb, PA, Offit, K, Perduca, V, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Riboli, E, Sanchez, M-J, Schmit, SL, Schoen, RE, Severi, G, Sieri, S, Slattery, ML, Song, M, Tangen, CM, Thibodeau, SN, Travis, RC, Trichopoulou, A, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gunter, MJ, and Murphy, N

Abstract

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

Published
2020

17. Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Author

Walker, GJ, Harrison, JW, Heap, GA, Voskuil, MD, Andersen, V, Anderson, CA, Ananthakrishnan, AN, Barrett, JC, Beaugerie, L, Bewshea, CM, Cole, AT, Cummings, FR, Daly, MJ, Ellul, P, Fedorak, RN, Festen, EAM, Florin, TH, Gaya, DR, Halfvarson, J, Hart, AL, Heerasing, NM, Hendy, P, Irving, PM, Jones, SE, Koskela, J, Lindsay, JO, Mansfield, JC, McGovern, D, Parkes, M, Pollok, RCG, Ramakrishnan, S, Rampton, DS, Rivas, MA, Russell, RK, Schultz, M, Sebastian, S, Seksik, P, Singh, A, So, K, Sokol, H, Subramaniam, K, Todd, A, Annese, V, Weersma, RK, Xavier, R, Ward, R, Weedon, MN, Goodhand, JR, Kennedy, NA, Ahmad, T, Holden, AL, Andrews, J, Auth, M, Babu, S, Bampton, P, Banim, P, Barnes, T, Basude, D, Beckly, J, Bell, A, Bell, S, Bhandari, P, Bloom, S, Border, D, Bredin, F, Brookes, MJ, Brown, M, Calvert, C, Campbell, D, Chanchlani, N, Chaudhary, B, Chaudhary, R, Chung-Faye, G, Colleypriest, B, Connor, S, Cooney, R, Cooper, S, Creed, TJ, Croft, N, Cullen, S, D'Amato, M, Dalal, H, Daneshmend, TK, Das, D, Delaney, M, Desilva, S, Dhar, A, Dharmasiri, S, Direkze, N, Dunckley, P, Elphick, D, Everett, SM, Feeney, M, Fell, J, Foley, S, Franke, A, Gavin, D, Gee, I, Ghosh, D, Goldsmith, C, Gorard, D, Gordon, JN, Gore, S, Green, J, Grimes, D, Hamill, G, Harbord, M, Hart, J, Hawkey, C, Iqbal, T, Ireland, A, Johnson, M, Jones, C, Kanegasundaram, S, Karban, A, Katsanos, KH, Kiparissi, F, Kirkham, S, Lal, S, Langlands, S, Lawrance, IC, Lees, CW, Lev-Tzion, R, Levison, S, Lewis, SJ, Li, A, Limdi, J, Lin, S, Lobo, A, Lockett, M, Loehry, J, MacDonald, C, MacFaul, G, Mahmood, T, Mann, S, Mawdsley, J, Mazhar, Z, McGovern, JF, McNair, A, Modi, A, Monahan, K, Moran, A, Morris, M-A, Mortimore, M, Mowat, C, Muhammed, R, Murray, CDR, Olivier, H, Orchard, TR, Panter, S, Patel, V, Phillips, R, Prasad, N, Preston, C, Radford-Smith, G, Rajasekhar, P, Roy, D, Saich, R, Satsangi, J, Schreiber, S, Sen, S, Shah, N, Shenderay, R, Shenoy, A, Shutt, J, Silverberg, M, Simmons, A, Simmons, J, Singh, S, Smith, M, Snook, JA, Sonwalker, S, Stevens, CR, Sturniolo, G, Subramanian, S, Thomas, A, Tighe, M, Torrente, F, Tremelling, M, Tsianos, E, Vani, D, Walsh, A, Watermeyer, G, Watts, D, Watts, G, Weaver, S, Wesley, E, Willmott, A, Yearsley, K, Zambar, V, Zeissig, S, University of Helsinki, Broad Institute, University of Helsinki, Complex Disease Genetics, Institute for Molecular Medicine Finland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Simmons, A

Subjects
Male, PREDICTOR, AZATHIOPRINE, Azathioprine, Genome-wide association study, CHILDREN, S-METHYLTRANSFERASE, SUSCEPTIBILITY, Gastroenterology, THERAPY, Leukocyte Count, 0302 clinical medicine, Crohn Disease, Interquartile range, Medicine, Exome, Pyrophosphatases, 11 Medical and Health Sciences, 0303 health sciences, Thiopurine methyltransferase, biology, IBD Pharmacogenetics Study Group, General Medicine, 3. Good health, Editorial Commentary, Cohort, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, Adolescent, MERCAPTOPURINE INTOLERANCE, European Continental Ancestry Group, 3121 Internal medicine, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Young Adult, Medicine, General & Internal, Internal medicine, General & Internal Medicine, MANAGEMENT, Humans, POLYMORPHISMS, 030304 developmental biology, ACUTE LYMPHOBLASTIC-LEUKEMIA, Science & Technology, business.industry, Case-control study, Odds ratio, Methyltransferases, Sequence Analysis, DNA, Haplotypes, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, biology.protein, Colitis, Ulcerative, business, Pharmacogenetics, Genome-Wide Association Study
Abstract

Funding Information: reported serving as a consultant for AbbVie UK; receiving honoraria from Falk and AbbVie UK; receiving grants from Crohn’s & Colitis UK and Tillott’s Pharmaceuticals; having a fellowship from the UK National Institute for Health Research; and receiving travel reimbursement from Merck Sharp & Dohme and Norgine. Dr Heap reported receiving travel reimbursement from AbbVie; and being a current employee of AbbVie and owning stock in the company. Dr Andersen reported receiving personal fees from Merck Sharp & Dohme and Janssen. Dr Ananthakrishnan reported receiving a grant from Pfizer; and receiving personal fees from Takeda. Dr Beaugerie reported receiving advisory board fees from Allergan, Janssen, and Pfizer; receiving a grant from Hospira; and receiving grants and honoraria from AbbVie, Merck Sharp & Dohme, Ferring, Takeda, and Tillott’s Pharmaceuticals. Dr Cummings reported receiving personal fees from AbbVie, Takeda, Biogen, Janssen, Merck Sharp & Dohme, Amgen, Hakim Pharmaceuticals, and Pfizer/Hospira; and receiving grants from Takeda, Biogen, AstraZeneca, and Pfizer/Hospira. Dr Halfvarson reported receiving personal fees from AbbVie, Hospira, Janssen, Medivir, Merck Sharp & Dohme, Pfizer, RenapharmaVifor, Takeda, Tillott’s Pharmaceuticals, Celgene, Sandoz, and Shire; and receiving grants from Janssen, Merck Sharp & Dohme, and Takeda. Dr Hart reported receiving advisory board fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Janssen, Merck Sharp & Dohme, Pfizer, Shire, and Takeda; receiving honoraria from Falk and Ferring; and receiving a grant from Takeda. Dr Irving reported receiving personal fees from Janssen, AbbVie, Takeda, Ferring, Pfizer, Lilly, Merck Sharp & Dohme, Samsung, and Sandoz; and receiving grants from Takeda and Merck Sharp & Dohme. Dr Lindsay reported receiving advisory board fees from Atlantic Health, AbbVie UK/global, Merck Sharp & Dohme, Shire UK, Vifor Pharma, Ferring International, Celltrion, Takeda, Napp, Pfizer, and Janssen; serving as a consultant for AbbVie UK/global, Takeda, and Pfizer; receiving grants from Shire UK, AbbVie UK/global, Warner Chilcott, Funding Information: Takeda, Hospira, Ferring International, and Merck Sharp & Dohme; receiving honoraria from Takeda, Cornerstones US, Tillott’s Pharmaceuticals, Napp, Shire International, Janssen, AbbVie, and Pfizer; and receiving travel reimbursement from AbbVie UK, Merck Sharp & Dohme, Warner Chilcott, Takeda, and Shire International. Dr McGovern reported receiving grants from the National Institutes of Health, Helmsley Charitable Trust, and Janssen; and serving as a consultant for Pfizer, Q Biologics, Cidara, Gilead, and Janssen. Dr Seksik reported receiving advisory board fees from Astellas; receiving honoraria from Takeda, AbbVie, and Ferring; and receiving grants from Merck Sharp & Dohme and Biocodex. Dr Sokol reported receiving grants from Biocodex, Danone, and BiomX; serving as a consultant for Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, Bristol-Myers Squibb, Astellas, Merck Sharp & Dohme, Novartis, Tillott’s Pharmaceuticals, and Biose; and being the co-founder of Nextbiotix. Dr Annese reported receiving advisory board fees from Takeda, AbbVie, and Medtronic; and receiving honoraria from Janssen, Takeda, AbbVie, and Medtronic. Dr Weersma reported receiving grants from Takeda, Ferring, and Tramedico; and receiving personal fees from AbbVie. Dr Goodhand reported receiving honoraria from Falk, AbbVie, and Shield Therapeutics. Dr Kennedy reported serving as a consultant for Falk; receiving honoraria from Falk, Allergan, Pharmacosmos, and Takeda; and being a deputy editor of Alimentary Pharmacology & Therapeutics. Dr Ahmad reported receiving unrestricted grants, advisory board fees, speaker honoraria, and support to attend international meetings from AbbVie, Merck Sharp & Dohme, Janssen, Takeda, Ferring, Tillott’s Pharmaceuticals, Ferring, Pfizer, Napp, Celltrion, and Hospira. No other disclosures were reported. Funding Information: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California), Alistair McNair, PhD (Queen Elizabeth Hospital, London, UK), Anita Modi, MD (Luton and Dunstable University Hospital, Luton, UK), Kevin Monahan, PhD (West Middlesex University Hospital, Middlesex, UK), Alex Moran, MD (Northern Devon Healthcare Trust, Barnstaple, UK), Mary-Anne Morris, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marianne Mortimore, MBBS (Mater Research Institute, University of Queensland, South Brisbane, Australia), Craig Mowat, MD (Ninewells Hospital, NHS Tayside, Dundee, UK), Rafeeq Muhammed, MD (Birmingham Children's Hospital, Birmingham, UK), Charles D. R. Murray, PhD (Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK), Hanlie Olivier (IBD Pharmacogenetics Group, University of Exeter, Exeter, UK), Timothy R. Orchard, DM (Imperial College Healthcare NHS Trust, London, UK), Simon Panter, MD (South Tyneside District Hospital, South Tyneside, UK), Vinod Patel, MBBS (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rosemary Phillips, MD (Princess Alexandra Hospital, Essex, UK), Neeraj Prasad, MSc (Wrightington Hospital, Wrightington, UK), Cathryn Preston, MBChB (Bradford Royal Infirmary, Bradford, UK), Graham Radford-Smith, PhD (Royal Brisbane and Women’s Hospital, Brisbane, Australia), Praveen Rajasekhar, MD (Northumbria NHS Trust, Tyne and Wear, UK), Dipak Roy, PhD (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rebecca Saich, PhD (Basingstoke and North Hampshire Hospital, Basingstoke, UK), Jack Satsangi, PhD (Western General Hospital, NHS Lothian, Edinburgh, UK), Stefan Schreiber, PhD (Kiel University, Kiel, Germany), Sandip Sen, MD (Royal Stoke University Hospital, Stoke-on-Trent, UK), Neil Shah, MD (Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK), Richard Shenderay, MBBS (Airedale NHS Foundation Trust, Keighley, UK), Acuth Shenoy, MD (Colchester Hospital University NHS Foundation Trust, Colchester, UK), James Shutt, DM (Dorset County Hospital NHS Foundation Trust, Dorchester, UK), Mark Silverberg, PhD (Mount Sinai Hospital, Toronto, Ontario, Canada), Alison Simmons, PhD (Oxford University Hospitals, Oxford, UK), Jonathan Simmons, DM (Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, UK), Salil Singh, PhD (Bolton NHS Foundation Trust, Bolton, UK), Malcolm Smith, MBChB (Aberdeen Royal Infirmary, Aberdeen, UK), Mark Smith, MD (Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK), Melissa Smith, MB (Royal Sussex County Hospital, Brighton, UK), Jonathon A. Snook, DPhil (Poole Hospital NHS Foundation Trust, Poole, UK), Sunil Sonwalker, MD (Calderdale Royal Hospital, Halifax, UK), Christine R. Stevens, PhD (Broad Institute, Harvard University, Cambridge, Massachusetts), Giacomo Sturniolo, PhD (Univerita di Padova, Padova, Italy), Sreedhar Subramanian, MD (Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK), Amanda Thomas, MBBS (Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK), Mark Tighe, BM (Poole Hospital NHS Foundation Trust, Poole, UK), Franco Torrente, MD (Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), Mark Tremelling, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Epameinondas Tsianos, PhD (University Hospital of Ioannina, Ioannina, Greece), Deven Vani, MD (Mid Yorkshire Hospitals NHS Trust, Wakefield, UK), Alissa Walsh, MBBS (St Vincent’s Hospital, Sydney, Australia), Gillian Watermeyer, MBChB (Groote Schuur Hospital, Cape Town, South Africa), David Watts, MBChB (Forth Valley Royal Hospital, Larbert, UK), Gill Watts, MD (Wythenshawe Hospital, South Manchester, UK), Sean Weaver, PhD (Royal Bournemouth General Hospital, Bournemouth, UK), Emma Wesley, MBBS (Musgrove Park Hospital, Taunton and Somerset NHS Hospitals, Taunton, UK), Anne Willmott, MBChB (Leicester Royal Infirmary-Paediatric, Leicester, UK), Karen Yearsley, BM (Nevill Hall Hospital, Abergavenny, UK), Veena Zambar, MBBS (Leeds General Infirmary, Leeds, UK), and Sebastian Zeissig, MD (University Medical Center Schleswig-Hostein, Kiel, Germany). These individuals identified and recruited patient s to the study and provided comments on a draft of the manuscript. Funding Information: Adverse Events Consortium funded the sample collection and genotyping at the Broad Institute. The UK National Institute for Health Research provided research nurse support to facilitate recruitment at all UK research sites. Crohn’s & Colitis UK and forCrohns provided funding support and publicized this study to their members. The Exeter National Institute for Health Research Clinical Research Facility provided DNA storage and management. Institutional strategic support award WT097835MF from Wellcome Trust supported the management of the study. Samples from Cedars-Sinai were collected and processed through the MIRIAD biobank that was funded by grant P01DK046763 from the National Institutes of Health. Publisher Copyright: © 2019 American Medical Association. All rights reserved. IMPORTANCE Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTS Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM. MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 x 10(-9)). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 x 10(-8)), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10(-7)) of TIM, independent of TPMT genotype and thiopurine dose. CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Published
2019

18. Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)

Author

Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Al Olama, AA, Schumacher, FR, Ingles, SA, Govindasami, K, Benlloch, S, Berndt, SI, Albanes, D, Koutros, S, Muir, K, Stevens, VL, Gapstur, SM, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Wolk, A, West, C, Mucci, L, Kraft, P, Cancel-Tassin, G, Sorensen, KD, Maehle, L, Grindedal, EM, Strom, SS, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Bensen, JT, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, LA, Pandha, H, Thibodeau, SN, Schaid, DJ, Wiklund, F, Chanock, SJ, Easton, DF, Eeles, RA, Kote-Jarai, Z, Conti, DV, Haiman, CA, Henderson, BE, Stern, MC, Thwaites, A, Guy, M, Whitmore, I, Morgan, A, Fisher, C, Hazel, S, Livni, N, Cook, M, Fachal, L, Weinstein, S, Freeman, LEB, Hoover, RN, Machiela, MJ, Lophatananon, A, Carter, BD, Goodman, P, Moya, L, Srinivasan, S, Kedda, M-A, Yeadon, T, Eckert, A, Eklund, M, Cavalli-Bjoerkman, C, Dunning, AM, Sipeky, C, Hakansson, N, Elliott, R, Ranu, H, Giovannucci, E, Turman, C, Hunter, DJ, Cussenot, O, Orntoft, TF, Lane, A, Lewis, SJ, Davis, M, Key, TJ, Brown, P, Kulkarni, GS, Zlotta, AR, Fleshner, NE, Finelli, A, Mao, X, Marzec, J, MacInnis, RJ, Milne, R, Hopper, JL, Aguado, M, Bustamante, M, Castano-Vinyals, G, Gracia-Lavedan, E, Cecchini, L, Stampfer, M, Ma, J, Sellers, TA, Geybels, MS, Park, H, Zachariah, B, Kolb, S, Wokolorczyk, D, Lubinski, J, Kluzniak, W, Nielsen, SF, Weisher, M, Cuk, K, Vogel, W, Luedeke, M, Logothetis, CJ, Paulo, P, Cardoso, M, Maia, S, Silva, MP, Steele, L, Ding, YC, De Meerleer, G, De Langhe, S, Thierens, H, Lim, J, Tan, MH, Ong, AT, Lin, DW, Kachakova, D, Mitkova, A, Mitev, V, Parliament, M, Jenster, G, Bangma, C, Schroder, FH, Truong, T, Koudou, YA, Michael, A, Kierzek, A, Karlsson, A, Broms, M, Wu, H, Aukim-Hastie, C, Tillmans, L, Riska, S, McDonnell, SK, Dearnaley, D, Spurdle, A, Gardiner, R, Hayes, V, Butler, L, Taylor, R, Papargiris, M, Saunders, P, Kujala, P, Talala, K, Taari, K, Bentzen, S, Hicks, B, Vogt, A, Hutchinson, A, Cox, A, George, A, Toi, A, Evans, A, Van der Kwast, TH, Imai, T, Saito, S, Zhao, S-C, Ren, G, Zhang, Y, Yu, Y, Wu, Y, Wu, J, Zhou, B, Pedersen, J, Lobato-Busto, R, Manuel Ruiz-Dominguez, J, Mengual, L, Alcaraz, A, Pow-Sang, J, Herkommer, K, Vlahova, A, Dikov, T, Christova, S, Carracedo, A, Tretarre, B, Rebillard, X, Mulot, C, Adolfsson, J, Stattin, P, Johansson, J-E, Martin, RM, Thompson, IM, Chambers, S, Aitken, J, Horvath, L, Haynes, A-M, Tilley, W, Risbridger, G, Aly, M, Nordstrom, T, Pharoah, P, Tammela, TLJ, Murtola, T, Auvinen, A, Burnet, N, Barnett, G, Andriole, G, Klim, A, Drake, BF, Borre, M, Kerns, S, Ostrer, H, Zhang, H-W, Cao, G, Lin, J, Ling, J, Li, M, Feng, N, Li, J, He, W, Guo, X, Sun, Z, Wang, G, Guo, J, Southey, MC, FitzGerald, LM, Marsden, G, Gomez-Caamano, A, Carballo, A, Peleteiro, P, Calvo, P, Szulkin, R, Llorca, J, Dierssen-Sotos, T, Gomez-Acebo, I, Lin, H-Y, Ostrander, EA, Bisbjerg, R, Klarskov, P, Roder, MA, Iversen, P, Holleczek, B, Stegmaier, C, Schnoeller, T, Bohnert, P, John, EM, Ost, P, Teo, S-H, Gamulin, M, Kulis, T, Kastelan, Z, Slavov, C, Popov, E, Van den Broeck, T, Joniau, S, Larkin, S, Esteban Castelao, J, Martinez, ME, Van Schaik, RHN, Xu, J, Lindstrom, S, Riboli, E, Berry, C, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Freedman, M, Cenee, S, Sanchez, M, and Commission of the European Communities

Subjects
Multidisciplinary Sciences, Science & Technology, MD Multidisciplinary, Science & Technology - Other Topics, PRACTICAL Consortium
Abstract

Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.

Published
2019

19. Blood lipids and prostate cancer: a Mendelian randomization analysis

Author

Bull, CJ, Bonilla, C, Holly, JM, Perks, CM, Davies, N, Haycock, P, Yu, OH, Richards, JB, Eeles, R, Easton, D, Kote-Jarai, Z, Amin Al Olama, A, Benlloch, S, Muir, K, Giles, GG, MacInnis, RJ, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Neal, D, Pashayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Micheal, A, Pandha, H, Smith, GD, Lewis, SJ, and Martin, RM

Subjects
Male, Polymorphism, Single Nucleotide, statins, Quantitative Trait, Heritable, Meta-Analysis as Topic, Mendelian randomization, Odds Ratio, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Original Research, Neoplasm Staging, Clinical Cancer Research, Genetic Variation, Prostatic Neoplasms, Mendelian Randomization Analysis, prostate cancer, Lipids, Cholesterol, Case-Control Studies, Population Surveillance, lipids (amino acids, peptides, and proteins), ICEP, Neoplasm Grading, Genome-Wide Association Study
Abstract

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (

Published
2016

20. Circulating vitamin D concentration and risk of seven cancers: a Mendelian randomization study

Author

Dimitrakopoulou, VI, Tsilidis, KK, Haycock, PC, Dimou, NL, Al-Dabhani, K, Martin, RM, Lewis, SJ, Gunter, MJ, Mondul, A, Shui, IM, Theodoratou, E, Nimptsch, K, Lindström, S, Albanes, D, Kühn, T, Key, TJ, Travis, RC, Vimaleswaran, KS, GECCO Consortium, PRACTICAL Consortium, GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO), Kraft, P, Pierce, BL, and Schildkraut, JM

Subjects
Male, 25-HYDROXYVITAMIN D, Lung Neoplasms, SUSCEPTIBILITY LOCI, Breast Neoplasms, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Risk Assessment, COLORECTAL-CANCER, 1117 Public Health and Health Services, Neuroblastoma, Medicine, General & Internal, General & Internal Medicine, Neoplasms, BREAST-CANCER, Humans, PRACTICAL Consortium, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Vitamin D, METAANALYSIS, GECCO Consortium, Ovarian Neoplasms, Science & Technology, Incidence, GENETIC-VARIATION, Genetic Variation, Prostatic Neoplasms, 1103 Clinical Sciences, Mendelian Randomization Analysis, Vitamin D Deficiency, PREVENTION, PROSTATE-CANCER, Pancreatic Neoplasms, Case-Control Studies, Female, GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO), Colorectal Neoplasms, Life Sciences & Biomedicine, Genome-Wide Association Study
Abstract

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. Design Mendelian randomisation study. Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform). Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls. Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined. Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated. Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

Published
2017

21. Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial

Author

Mowat, C, Arnott, I, Cahill, A, Smith, M, Ahmad, T, Subramanian, S, Travis, S, Morris, J, Hamlin, J, Dhar, A, Nwokolo, C, Edwards, C, Creed, T, Bloom, S, Yousif, M, Thomas, L, Campbell, S, Lewis, SJ, Sebastian, S, Sen, S, Lal, S, Hawkey, C, Murray, C, Cummings, F, Goh, J, Lindsay, JO, Arebi, N, Potts, L, McKinley, AJ, Thomson, JM, Todd, JA, Collie, M, Dunlop, MG, Mowat, A, Gaya, DR, Winter, J, Naismith, GD, Ennis, H, Keerie, C, Lewis, S, Prescott, RJ, Kennedy, NA, Satsangi, J, and TOPPIC Study Group

Abstract

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.

Published
2017

22. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization:Genetic variants as instruments for circulating levels

Author

Bonilla, C, Lewis, SJ, Rowlands, MA, Gaunt, TR, Davey Smith, G, Gunnell, D, Palmer, T, Donovan, JL, Hamdy, F, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Grönberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Martin, RM, and Holly, JM

Subjects
Male, insulin‐like growth factor‐binding proteins, insulin-like growth factor-binding proteins, Polymorphism, Single Nucleotide, PRACTICAL, insulin‐like growth factors, single nucleotide polymorphisms, Somatomedins, insulin-like growth factors, Mendelian randomization, Journal Article, Humans, Longitudinal Studies, Aged, Neoplasm Staging, Prostatic Neoplasms, Mendelian Randomization Analysis, Middle Aged, ALSPAC, prostate cancer, United Kingdom, UKHLS, Insulin-Like Growth Factor Binding Proteins, IGFBP3, Case-Control Studies, ProtecT, Neoplasm Grading, Cancer Epidemiology, Genome-Wide Association Study
Abstract

Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker., What's New? Circulating insulin‐like growth factors (IGF) and their binding proteins have been associated with prostate cancer risk in observational epidemiological studies but it is not clear whether there is a causal relationship with disease. To address this question, the authors used Mendelian randomization, a method that uses genetic variants as proxies for measured exposures. Their results implicate the IGF pathway in general in prostate cancer development but specific biomarkers remain to be determined.

Published
2016

23. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: genetic variants as instruments for circulating levels

Author

Wrightson, RC, Bonilla, C, Lewis, SJ, Rowlands, MA, Hamdy, FC, Neal, DE, and Travis, RC

Abstract

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ~700 men without prostate cancer and two replication cohorts (N~900 and ~9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs high (≥ 7) Gleason grade, localised vs advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (~265 ng/ml) on risk of high vs low grade disease as 1.14 (95% CI 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Published
2016

24. Prenatal alcohol exposure and offspring cognition and school performance. A 'Mendelian randomization' natural experiment

Author

Zuccolo, L, Lewis, SJ, Smith, GD, Sayal, K, Draper, ES, Fraser, R, Barrow, M, Alati, R, Ring, S, Macleod, J, Golding, J, Heron, J, and Gray, R

Abstract

BACKGROUND: There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. METHODS: We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N=4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N=6268), contributed to the analyses. RESULTS: Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers' genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. CONCLUSIONS: Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.

Published
2016

25. Effect of smoking on physical and cognitive capability in later life: a multicohort study using observational and genetic approaches

Author

Cooper, Rachel, North, TL, Palmer, TM, Lewis, SJ, Cooper, R, Power, C, Pattie, A, Starr, JM, Deary, IJ, Martin, RM, Aihie, Sayer A, Kumari, M, Cooper, C, Kivimaki, M, Kuh, D, Ben-Shlomo, Y, and Day, IN

Abstract

Objectives The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature. Setting 9 British cohorts belonging to the HALCyon collaboration. Participants Individual participant data on N=26 692 individuals of European ancestry (N from earliest phase analysed per study) of mean ages 50–79 years were available for inclusion in observational meta-analyses of the primary outcomes. Primary outcomes Physical capability, cognitive capability and cognitive decline. The smoking exposures were cigarettes per day, current versus ex-smoker, current versus never smoker and ever versus never smoker. Results In observational analyses current and ever smoking were generally associated with poorer physical and cognitive capability. For example, current smokers had a general fluid cognition score which was 0.17 z-score units (95% CI −0.221 to −0.124) lower than ex-smokers in cross-sectional analyses. Current smokers had a walk speed which was 0.25 z-score units lower than never smokers (95% CI −0.338 to −0.170). An MR instrumental variable approach for current versus ex-smoker and number of cigarettes smoked per day produced CIs which neither confirmed nor refuted the observational estimates. The number of genetic associations stratified by smoking status were consistent with type I error. Conclusions Our observational analysis supports the hypothesis that smoking is detrimental to physical and cognitive capability. Further studies are needed for a suitably powered MR approach.

Published
2015

30. Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort

Author

Bonilla, C, Lewis, SJ, Martin, RM, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, Cook, M, Morga, A, Lophatananon, A, Fisher, C, Leongamornlert, D, Saunders, EJ, Sawyer, EJ, Govindasami, K, Tymrakiewicz, M, Guy, M, Livni, N, Wilkinson, R, Jugurnauth-Little, S, Hazel, S, Dadaev, T, Southey, MC, Fitzgerald, LM, Pedersen, J, Hopper, J, Karlsson, A, Cavalli-Bjoerkman, C, Johansson, JE, Adolfson, J, Aly, M, Broms, M, Stattin, P, Henderson, BE, Schumacher, F, Auvinen, A, Taari, K, Maeaettaenen, L, Kujala, P, Murtola, T, Tammela, TLJ, Sipeky, C, Roder, MA, Iversen, P, Klarskov, P, Nielsen, SF, Weischer, M, Bonilla, C, Lewis, SJ, Martin, RM, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, Cook, M, Morga, A, Lophatananon, A, Fisher, C, Leongamornlert, D, Saunders, EJ, Sawyer, EJ, Govindasami, K, Tymrakiewicz, M, Guy, M, Livni, N, Wilkinson, R, Jugurnauth-Little, S, Hazel, S, Dadaev, T, Southey, MC, Fitzgerald, LM, Pedersen, J, Hopper, J, Karlsson, A, Cavalli-Bjoerkman, C, Johansson, JE, Adolfson, J, Aly, M, Broms, M, Stattin, P, Henderson, BE, Schumacher, F, Auvinen, A, Taari, K, Maeaettaenen, L, Kujala, P, Murtola, T, Tammela, TLJ, Sipeky, C, Roder, MA, Iversen, P, Klarskov, P, Nielsen, SF, and Weischer, M

Abstract

© 2016 Bonilla et al. Background: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.

Published
2016

31. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels

Author

Bonilla, C, Lewis, SJ, Rowlands, M-A, Gaunt, TR, Smith, GD, Gunnell, D, Palmer, T, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Groenberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Martin, RM, Holly, JMP, Bonilla, C, Lewis, SJ, Rowlands, M-A, Gaunt, TR, Smith, GD, Gunnell, D, Palmer, T, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Groenberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Martin, RM, and Holly, JMP

Abstract

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Published
2016

32. The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Author

Davies, NM, Gaunt, TR, Lewis, SJ, Holly, J, Donovan, JL, Hamdy, FC, Kemp, JP, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Neal, D, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, Martin, RM, Davies, NM, Gaunt, TR, Lewis, SJ, Holly, J, Donovan, JL, Hamdy, FC, Kemp, JP, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Neal, D, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, and Martin, RM

Abstract

BACKGROUND: Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. METHODS: We conducted a case-control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man's number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. RESULTS: The genetic risk scores explained 6.31 and 1.46% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95% CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95% CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). CONCLUSIONS: We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with inc

Published
2015

33. … ABOUT ALCOHOLISM

Author

Lewis Sj and Messner R

Subjects
Advanced and Specialized Nursing, History, Mythology, Assessment and Diagnosis, Emergency Nursing, LPN and LVN, Critical Care Nursing, Epistemology
Published
1994

43. Upper instrumented vertebral fractures in long lumbar fusions: what are the associated risk factors?

Author

Lewis SJ, Abbas H, Chua S, Bacon S, Bronstein Y, Goldstein S, Magana S, Sullivan K, Dold AP, Bodrogi A, Lewis, Stephen J, Abbas, Harith, Chua, Sooyong, Bacon, Sarah, Bronstein, Yigal, Goldstein, Sergey, Magana, Sofia, Sullivan, Kelly, Dold, Andrew P, and Bodrogi, Andrew

Abstract

Study Design: A retrospective comparative study. Objective: To investigate the risk factors associated with upper instrumented vertebral (UIV) fractures in adult lumbar deformity. Summary Of Background Data: Long segment lumbar fusions may lead to junctional failures. The purpose of this study was to determine factors associated with junctional failures. Methods: Twenty-seven consecutive patients from 2001 to 2008 with minimum 4 levels fused, lower instrumented vertebra (LIV) of L5 or S1, upper instrumented vertebra of T10 or distal, and no previous surgery proximal to the instrumentation were retrospectively reviewed. We describe the UIV angle, the sagittal angle of the upper instrumented vertebra with the horizontal. Patients were divided into 3 groups: group 1, 7 patients with UIV fractures; group 2, 6 patients with other proximal failures; and group 3, 14 patients with no proximal complications. Results: The mean number of levels fused was 5.7 (4-7), 5.2 (4-8), and 6.2 (4-8); mean age was 64.1, 61.8, and 64.1, and mean body mass index was 33.5, 30.0, and 31.6 for groups 1, 2, and 3, respectively (P > 0.05). Osteotomies were performed in 5 of 7 in group 1, 1 of 6 in group 2, and 5 of 14 in group 3. Mean follow-up was 26.3 months. The average intraoperative UIV angle (UIV0) and immediate postoperative UIV angle (UIV1) were 18.6°/15.4° for group 1, 5.7°/5.3° for group 2, and 10.3°/7.1° for group 3 (P < 0.05). Surgical revision rates were higher in group 1 (71%) compared with groups 2 (50%) and 3 (43%). Eight of 11 (73%) patients with upper instrumented vertebra of L1 or L2 had either UIV fracture or other proximal failure compared with 5 of 16 (31%) in patients with upper instrumented vertebra of T10, T11, or T12. Conclusion: Our series of long lumbar fusions had a high long-term complication and revision rate. A high UIV angle on intraoperative lateral radiograph was strongly associated with UIV fractures. UIVs of L1 or L2 had a higher rate of adjacent segment or UIV failure. [ABSTRACT FROM AUTHOR]

Published
2012
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44. Posterior column reconstruction with autologous rib graft after en bloc tumor excision.

Author

Lewis SJ, Kulkarni AG, Rampersaud YR, Jhaveri S, Quraishi N, Bacon SA, Magana SP, Lewis, Stephen J, Kulkarni, Arvind G, Rampersaud, Yoga Raja, Jhaveri, Subir, Quraishi, Nasir, Bacon, Sarah A, and Magana, Sofia P

Abstract

Study Design: Retrospective review of consecutive case series. Objective: To evaluate the efficacy of using autologous rib graft for fusion across long posterior column defects. Summary Of Background Data: Achieving fusion across large posterior column defects after en bloc tumor resection can be difficult. Rib graft can be harvested from the local wound, and its shape and structural properties are well suited for reconstruction of thoracic posterior column deficits. Methods: After Research Ethics Board approval, a retrospective review of the charts of 17 consecutive patients undergoing posterior column reconstruction after en bloc tumor resections was carried out. Autologous vascularized and nonvascularized rib grafts were utilized in 8 and 9 cases, respectively; 14 patients with malignant tumors and 3 with benign etiology. After surgery, patients underwent routine clinical and radiographic follow-up, with a computed tomographic scan performed at a minimum of 6 months in all surviving patients. Clinical and radiographic films were analyzed. Results: Computed tomographic scans at a minimum of 6 months demonstrated graft incorporation in all surviving cases. There was no obvious difference at 6-month imaging to differentiate vascularized from nonvascularized grafts. There were no cases of graft dislodgement or fracture. Graft site morbidity was difficult to isolate from the morbidity of these large procedures. No complications related to the graft were identified. Conclusion: The use of autologous rib graft with a proximal step-cut and distal saddle-cut supplemented with posterior instrumentation allowed immediate stabilization of the posterior column defect created by the en bloc tumor resection. This technique of fashioning the graft and taking advantage of its natural curved structure for immediate press-fit was associated with graft incorporation in our cases. [ABSTRACT FROM AUTHOR]

Published
2012
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45. Reduced mismatch negativity in mild cognitive impairment: associations with neuropsychological performance.

Author

Mowszowski L, Hermens DF, Diamond K, Norrie L, Hickie IB, Lewis SJ, Naismith SL, Mowszowski, Loren, Hermens, Daniel F, Diamond, Keri, Norrie, Louisa, Hickie, Ian B, Lewis, Simon J G, and Naismith, Sharon L

Abstract

Mild cognitive impairment (MCI) refers to a transitory state between healthy aging and dementia. Biomarkers are needed to facilitate early identification of MCI and predict progression to dementia. One potential neurophysiological biomarker, mismatch negativity (MMN), is an event-related potential reflecting fundamental, pre-attentive cognitive processes. MMN is reduced in normal aging and dementia and in neuropsychiatric samples and is associated with verbal memory deficits and poor executive functioning. This study aimed to investigate auditory MMN and its relationship to neuropsychological performance in MCI. Twenty-eight MCI participants and fourteen controls, aged ≥50 years, underwent neurophysiological and neuropsychological assessment, and completed questionnaires pertaining to disability. Relative to controls, the MCI group demonstrated reduced temporal MMN amplitude (p < 0.01). Reduced right temporal MMN was significantly associated with poorer verbal learning (r = 0.496; p < 0.01) and reduced left temporal MMN was significantly associated with increased self-reported disability (r = -0.419; p < 0.05). These results indicate that patients with MCI exhibit altered pre-attentive information processing, which in turn is associated with memory and psychosocial deficits. These findings overall suggest that MMN may be a viable neurophysiological biomarker of underlying disease in this 'at risk' group. [ABSTRACT FROM AUTHOR]

Published
2012
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46. Intraoperative multimodality monitoring in adult spinal deformity: analysis of a prospective series of one hundred two cases with independent evaluation.

Author

Quraishi NA, Lewis SJ, Kelleher MO, Sarjeant R, Rampersaud YR, and Fehlings MG

Abstract

STUDY DESIGN: A retrospective analysis of prospectively collected data of 102 consecutive adult patients who underwent intraoperative neurophysiological monitoring (IOM) during spinal deformity corrective surgery. OBJECTIVE: To report the sensitivity and specificity of combined IOM in this study population using the postoperative neurologic examination as the 'gold standard.' SUMMARY OF BACKGROUND DATA: IOM is recommended during corrective spinal surgery and has been widely used in the pediatric deformity population. However, there are limited data describing the application of IOM in adults undergoing spinal deformity corrective surgery. METHODS: The study group consisted of 102 patients undergoing spinal deformity corrective surgery between 2001 and 2004. Patients were monitored using at least 2 or more electrophysiological methods including somatosensory-evoked potentials (SSEP), motor-evoked potentials (MEP), and electromyography (EMG). RESULTS: The mean age of patients was 41.5 years (+/-17). The majority of the operative procedures involved instrumented fusion from thoracic to lumbar/sacral spine (n = 55), thoracic-pelvis fusion (n = 26), and a combined total of 32 osteotomies (including 25 pedicle subtraction osteotomies and 7 Smith-Peterson osteotomies). SSEPs were recorded successfully in 101 (99%), EMGs in 89 of 102 (87%), and MEPs in 12 of 16 (75%). Five cases were true positives (4.95%), and these were all detected by combined monitoring (2-SSEP, 2-EMG, 1-MEP). There were no false positives with SSEPs, but EMG resulted in 30 of 89 (34%) false positives. There were 4 false negatives with SSEPs, which reduced its sensitivity to 33%. There was 1 false negative with EMG, and 0 with MEPs. When these results were collated, the overall sensitivity of combined multimodality IOM in this adult deformity series was 100%, specificity 84.3%, PPV 13.9%, and NPV 97%. The combined sensitivity in the osteotomy group (n = 32) was 67%, specificity 98%, PPV 80%, and NPV 96%. In comparison, there were no IOM abnormalities in those patients who had in situ/minor corrective procedures (n = 18; largely adult degenerative scoliosis). CONCLUSION: Multimodality IOM of spinal cord sensory and motor function during surgical correction of adult spinal deformity is feasible and provides useful neurophysiological data with an overall sensitivity of 100% and a specificity of 84.3% (67% and 98%, respectively in patients undergoing major deformity correction). [ABSTRACT FROM AUTHOR]

Published
2009
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47. Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study.

Author

Wenger NK, Lewis SJ, Welty FK, Herrington DM, Bittner V, and TNT Steering Committee and Investigators

Abstract

OBJECTIVE: To examine by secondary analysis of the Treating to New Targets (TNT) study whether the benefits of intensive versus standard levels of lipid lowering are equally applicable to women. METHODS: A total of 10 001 patients (1902 women) with stable coronary heart disease (CHD) were randomised to double-blind treatment with atorvastatin 10 or 80 mg/day for a median follow-up of 4.9 years. RESULTS: In women and men, intensive treatment with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events compared with atorvastatin 10 mg. Among women, the relative and absolute reductions were 27% and 2.7%, respectively (hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.54 to 1.00, p = 0.049). In men, the corresponding rate reductions were 21% and 2.2% (HR = 0.79, 95% CI 0.69 to 0.91, p = 0.001). The number needed to treat value (to prevent one cardiovascular event over 4.9 years compared with patients treated with atorvastatin 10 mg) for atorvastatin 80 mg was 29 for women and 30 for men. Rates of death of non-cardiovascular origin in the atorvastatin 80 mg and atorvastatin 10 mg were 3.6% and 1.6%, respectively (p = 0.004) among women, and 2.8% and 3.1% (p = 0.47) among men. CONCLUSION: Intensive lipid-lowering treatment with atorvastatin 80 mg produced significant reductions in relative risk for major cardiovascular events compared with atorvastatin 10 mg in both women and men with stable CHD. [ABSTRACT FROM AUTHOR]

Published
2008

48. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease.

Author

Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, Treating to New Targets Study Steering Committee and Investigators, Wenger, Nanette K, Lewis, Sandra J, Herrington, David M, Bittner, Vera, and Welty, Francine K

Abstract

Background: Increased life expectancy is associated with an increase in the burden of chronic cardiovascular disease.Objective: To assess the efficacy and safety of high-dose atorvastatin in patients 65 years of age or older.Design: A prespecified secondary analysis of the Treating to New Targets study, a randomized, double-blind clinical trial.Setting: 256 sites in 14 countries participating in the Treating to New Targets study.Participants: 10,001 patients (3809 patients > or =65 years of age) with coronary heart disease (CHD) and low-density lipoprotein cholesterol levels less than 3.4 mmol/L (<130 mg/dL).Intervention: Patients were randomly assigned to receive atorvastatin, 10 or 80 mg/d.Measurements: The primary end point was the occurrence of a first major cardiovascular event (death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke).Results: In patients 65 years of age or older, absolute risk was reduced by 2.3% and relative risk by 19% for major cardiovascular events in favor of the high-dose atorvastatin group (hazard ratio, 0.81 [95% CI, 0.67 to 0.98]; P = 0.032). Among the components of the composite outcome, the mortality rates from CHD, nonfatal non-procedure-related myocardial infarction, and fatal or nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were all lower in older patients who received high-dose atorvastatin, although the difference was not statistically significant for each individual component. The improved clinical outcome in patients 65 years of age or older was not associated with persistent elevations in creatine kinase levels.Limitation: Because the study was a secondary analysis, the findings should be interpreted within the context of the main study results.Conclusions: The analysis suggests that additional clinical benefit can be achieved by treating older patients with CHD more aggressively to reduce low-density lipoprotein cholesterol levels to less than 2.6 mmol/L (<100 mg/dL). The findings support the use of intensive low-density lipoprotein cholesterol-lowering therapy in high-risk older persons with established cardiovascular disease. Click here for related information on atorvastatin. [ABSTRACT FROM AUTHOR]

Published
2007
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