***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: Background : The number of Mendelian r and omization analyses including large numbers of genetic variants is rapidly increasing . This is due to the proliferation of genome-wide association studies , and the desire to obtain more precise estimates of causal effects . However , some genetic variants may not be valid instrumental variables , in particular due to them having more than one proximal phenotypic correlate ( pleiotropy ) . Methods : We view Mendelian r and omization with multiple instruments as a meta- analysis , and show that bias caused by pleiotropy can be regarded as analogous to small study bias . Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry . Egger regression , a tool to detect small study bias in meta- analysis , can be adapted to test for bias from pleiotropy , and the slope coefficient from Egger regression provides an estimate of the causal effect . Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant ( not via the exposure ) , Egger ’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables . Results : We illustrate the use of this approach by re-analysing two published Mendelian r and omization studies of the causal effect of height on lung function , and the causal effect of blood pressure on coronary artery disease risk .  The conservative nature of this approach is illustrated with these examples . Conclusions : An adaption of Egger regression ( which we call MR-Egger ) can detect some violations of the st and ard instrumental variable assumptions , and provide an effect estimate which is not subject to these violations . The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian r and omization investigation Adult height has been found in some but not all studies to be associated positively with overall cancer incidence as well as several site-specific cancers . The Physicians ' Health Study ( PHS ) , a r and omized trial of beta-carotene and aspirin in the primary prevention of cancer and cardiovascular disease in men , provided an opportunity to examine the association between height and total malignant neoplasms ( excluding non-melanoma skin cancer ) , as well as site-specific cancers including prostate , colorectal , and lung cancer . The PHS is comprised of 22,071 US male physicians in the United States , a population homogeneous for adult socioeconomic status , aged 40 to 84 years in 1982 . Participants were classified into five height categories at study entry . After an average follow-up of over 12 years , there were 2,566 cases of incident total malignant neoplasms , including 1,047 prostate , 341 colorectal , and 170 lung cancer cases . Height was associated positively with both total malignant neoplasms and prostate cancer . Compared with men in the shortest category(≤ 67 inches ) , relative risks and 95 percent confidence intervals (CI)for total malignant neoplasms for men whose height ( in inches ) was 68 - 69,70 - 71 , 72 , and 73 + were , respectively : 1.13 ( CI = 0.99 - 1.28 ) , 1.15 ( CI = 1.02 - 1.30 ) , 1.29 ( CI = 1.12 - 1.49 ) , and 1.21 ( CI = 1.05 - 1.39 ) , P trend 0.001,adjusted for age , r and omized treatment assignments , body mass index ( wt/ht2 ) , cigarette smoking , alcohol use , and exercise frequency . For prostatecancer , the corresponding RR values were 1.23 ( CI = 1.00 - 1.51 ) , 1.26 ( CI = 1.04 - 1.54 ) , 1.59 ( CI = 1.27 - 1.98 ) , and 1.26 ( CI = 1.00 - 1.59 ) , P trend 0.005.For colorectal cancer , in some but not all height categories compared with the shortest , there were elevated RRs without a significant linear trend : RR= 1.51 ( CI = 1.06 - 2.14 ) , 1.14 ( CI = 0.80 - 1.62 ) , 1.19 ( CI = 0.79 - 1.80 ) , and 1.53 ( CI = 1.04 - 2.25 ) , P trend 0.23 . In contrast , there was no evidence of an association of height with lung cancer . These data indicate a positive association between height and risk of total malignant neoplasms , as well as of prostate cancer and , possibly , colorectal cancer Objectives : Few risk factors for prostate cancer are known , but both endocrine changes and dietary factors have been implicated in the etiology of the disease . Anthropometry may therefore provide a tool in the search for carcinogenic mechanisms connected to these suggested causal components . Methods : We have studied the association between body size and prostate cancer risk in a prospect i ve study of 22,248 Norwegian men . During 12 years of follow-up , 642 men developed cancer of the prostate . A possible association between anthropometry ( height , weight , body mass index ( BMI ) , and lean body mass ( LBM ) ) and prostate cancer risk was assessed using Cox regression analysis . Results : Overall , we observed no significant trend for any of the variables studied , although an excess risk of prostate cancer with increasing height was suggested by an age-adjusted relative risk of 1.2 ( 95 % CI=0.9–1.6 ) for the tallest compared to the shortest quintile of men . None of the other three variables ( weight , BMI , and LBM ) displayed any consistent relation with the risk of prostate cancer . Conclusions : We conclude that these results do not indicate a strong association between anthropometric factors and risk of prostate cancer Background High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential " reverse causality " where undetected disease modifies cholesterol prior to diagnosis . Methods We conducted a prospect i ve cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007 . We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade -specific prostate cancer incidence . We excluded cancers detected within at least 5 years of cholesterol assay . Results 650 men developed prostate cancer in up to 37 years ' follow-up . Baseline plasma cholesterol was positively associated with hazard of high grade ( Gleason score≥8 ) prostate cancer incidence ( n = 119 ) . The association was greatest among men in the 2nd highest quintile for cholesterol , 6.1 to < 6.69 mmol/l , Hazard Ratio 2.28 , 95 % CI 1.27 to 4.10 , compared with the baseline of < 5.05 mmol/l . This association remained significant after adjustment for body mass index , smoking and socioeconomic status . Conclusions Men with higher cholesterol are at greater risk of developing high- grade prostate cancer but not overall risk of prostate cancer . Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer Most common human traits and diseases have a polygenic pattern of inheritance : DNA sequence variants at many genetic loci influence the phenotype . Genome-wide association ( GWA ) studies have identified more than 600 variants associated with human traits , but these typically explain small fractions of phenotypic variation , raising questions about the use of further studies . Here , using 183,727 individuals , we show that hundreds of genetic variants , in at least 180 loci , influence adult height , a highly heritable and classic polygenic trait . The large number of loci reveals patterns with important implication s for genetic studies of common human diseases and traits . First , the 180 loci are not r and om , but instead are enriched for genes that are connected in biological pathways ( P = 0.016 ) and that underlie skeletal growth defects ( P < 0.001 ) . Second , the likely causal gene is often located near the most strongly associated variant : in 13 of 21 loci containing a known skeletal growth gene , that gene was closest to the associated variant . Third , at least 19 loci have multiple independently associated variants , suggesting that allelic heterogeneity is a frequent feature of polygenic traits , that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified . Fourth , associated variants are enriched for likely functional effects on genes , being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes . Our data explain approximately 10 % of the phenotypic variation in height , and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16 % of phenotypic variation ( approximately 20 % of heritable variation ) . Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully , our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways As with other instrumental variable ( IV ) analyses , Mendelian r and omization ( MR ) studies rest on strong assumptions . These assumptions are not routinely systematic ally evaluated in MR applications , although such evaluation could add to the credibility of MR analyses . In this article , the authors present several methods that are useful for evaluating the validity of an MR study . They apply these methods to a recent MR study that used fat mass and obesity-associated ( FTO ) genotype as an IV to estimate the effect of obesity on mental disorder . These approaches to evaluating assumptions for valid IV analyses are not fail-safe , in that there are situations where the approaches might either fail to identify a biased IV or inappropriately suggest that a valid IV is biased . Therefore , the authors describe the assumptions upon which the IV assessment s rely . The methods they describe are relevant to any IV analysis , regardless of whether it is based on a genetic IV or other possible sources of exogenous variation . Methods that assess the IV assumptions are generally not conclusive , but routinely applying such methods is nonetheless likely to improve the scientific contributions of MR studies Purpose To assess the association between height and risk of cancer and cancer death .  Methods The metabolic syndrome and cancer project is a prospect i ve pooled cohort study of 585,928 participants from seven cohorts in Austria , Norway , and Sweden .  Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for cancer incidence and death were estimated in height categories and per 5-cm increment for each cancer site using Cox proportional hazards model . Results During a mean follow-up of 12.7 years ( SD = 7.2 ) , 38,862 participants were diagnosed with cancer and 13,547 participants died of cancer . Increased height ( per 5-cm increment ) was associated with an increased overall cancer risk in women , HR 1.07 ( 95 % CI 1.06–1.09 ) , and in men , HR 1.04 ( 95 % CI 1.03–1.06 ) . The highest HR was seen for malignant melanoma in women , HR 1.17 ( 95 % CI 1.11–1.24 ) , and in men HR 1.12 ( 95 % CI 1.08–1.19 ) . Height was also associated with increased risk of cancer death in women , HR 1.03 ( 95 % CI 1.01–1.16 ) , and in men , HR 1.03 ( 95 % CI 1.01–1.05 ) . The highest HR was observed for breast cancer death in postmenopausal women ( > 60 years ) , HR 1.10 ( 95 % CI 1.00–1.21 ) , and death from renal cell carcinoma in men , HR 1.18 ( 95 % CI 1.07–1.30 ) . All these associations were independent of body mass index . Conclusion Height was associated with risk of cancer and cancer death indicating that factors related to height such as hormonal and genetic factors stimulate both cancer development and progression Background : The relationship between prostate cancer and height is uncertain . Methods : We prospect ively examined the association of height with prostate cancer among 34268 men in the prostate , lung , colorectal , and ovarian cancer trial .  Anthropometry  was assessed at baseline and 2144 incident prostate cancer cases were identified upto 8.9 years of follow-up . Results : Overall , tallness was not associated with the risk of prostate cancer or with the risk of non-aggressive disease , but the risk for aggressive prostate cancer tended to be greater in taller men ( Gleason score ⩾7 or stage ⩾III ; P trend=0.05 ; relative risk ( RR ) for 190 cm+ vs ⩽170 cm=1.39 , 95 % confidence interval ( 95 % CI ) : 0.96–2.01 ) . This association was largely limited to men below the age of 65 years ( P trend=0.008 ; RR for 190 cm+ vs ⩽170 cm=1.76 , 95 % CI : 1.06–2.93 ; P for interaction=0.009 ) , although the number of cases was small and risk estimates were somewhat unstable . Conclusion : The results of this large prospect i ve prostate cancer screening trial suggest that tallness is associated with increased risk for younger onset aggressive prostate cancer Studies of colon cancer risk in males have reported strong positive associations with obesity , particularly with central adiposity . The association has been weaker and less consistent for women . 
    Output:
    
Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers