briefly , we used the british columbia linked health databases ( bclhd ) , which includes administrative health claims , demographic data , and information from the bc cancer agency from 1 april 1996 through 31 march 2006 , to identify a retrospective cohort of individuals > 30 years of age with incident type 2 diabetes ( n = 185,100 ) . a cohort of the same size was selected as control subjects from individuals who had not been identified as having diabetes as of 31 march 2006 , with one - to - one matching on birth year and sex . the date of type 2 diabetes diagnosis was assigned as the index date for each matched pair . to protect patient confidentiality , ethics approval from the university of british columbia behavioral research ethics board and the university of alberta health research ethics board was obtained . type 2 diabetes was identified with the previously validated case definition ( 13 ) used by the canadian national diabetes surveillance system ( 14 ) and defined as the earlier of 1 ) a hospital admission for diabetes ( icd-9 code 250 ) or 2 ) the second of two medical fee - for - service claims coded with icd-9 code 250 within a 2-year period . individuals who met this definition before 1 april 1996 and women with gestational diabetes ( icd-9 code 648.8 ) were excluded . after exclusion of individuals with any cancer diagnosis in the 2 years before the index date , we identified incident cases of bladder cancer ( icd - o-3 code c67.x ) diagnosed after the index date . individuals were censored at the earlier of the end of the study ( 31 march 2006 ) or departure from bclhd ( i.e. , from british columbia ) , and the follow - up was terminated at death . we first calculated unadjusted bladder cancer incidence rates during the following time windows after the index date : < 1.0 , 1.02.0 , 2.03.0 , and 3.010.0 years . we then used cox regression to estimate adjusted time - varying hazard ratios ( hrs ) for developing bladder cancer during the time windows , with time since the index date as the time scale and the nondiabetes cohort as the reference group . all models were adjusted for age , sex , index year , and socioeconomic status . to represent socioeconomic status , median neighborhood income quintiles were derived from 2006 canadian census data and assigned according to postal code of residence , with a sixth missing information category also included . to explore potential detection bias , we hypothesized that the risk of bladder cancer would differ by the frequency of visits to physicians in the 2 years before the index date . rate of physician visits has recently been reported as a strong indicator for potential observational bias and is associated with illness adjustment ( 15 ) . physician visits in the 2 years before the index date were categorized in tertiles as 12 visits ( low ) , 1324 visits ( medium ) , and 25 visits ( high ) . we tested an interaction term between diabetes status and number of physician visits . finding a statistically significant interaction , we then stratified the incidence rate calculations and regression models by the physician visit categories . to graphically display changes in bladder cancer risk over time , we used a lowess curve to smooth the plotted representation of the time - varying bladder cancer risk in each category . all analyses were conducted with stata / se 11 ( statacorp , college station , tx ) statistical software ; graphs were created in r ( 16 ) . we first calculated unadjusted bladder cancer incidence rates during the following time windows after the index date : < 1.0 , 1.02.0 , 2.03.0 , and 3.010.0 years . we then used cox regression to estimate adjusted time - varying hazard ratios ( hrs ) for developing bladder cancer during the time windows , with time since the index date as the time scale and the nondiabetes cohort as the reference group . all models were adjusted for age , sex , index year , and socioeconomic status . to represent socioeconomic status , median neighborhood income quintiles were derived from 2006 canadian census data and assigned according to postal code of residence , with a sixth missing information category also included . to explore potential detection bias , we hypothesized that the risk of bladder cancer would differ by the frequency of visits to physicians in the 2 years before the index date . rate of physician visits has recently been reported as a strong indicator for potential observational bias and is associated with illness adjustment ( 15 ) . physician visits in the 2 years before the index date were categorized in tertiles as 12 visits ( low ) , 1324 visits ( medium ) , and 25 visits ( high ) . we tested an interaction term between diabetes status and number of physician visits . finding a statistically significant interaction , we then stratified the incidence rate calculations and regression models by the physician visit categories . to graphically display changes in bladder cancer risk over time , adjusted hrs were calculated and plotted at regular intervals throughout follow - up . we used a lowess curve to smooth the plotted representation of the time - varying bladder cancer risk in each category . all analyses were conducted with stata / se 11 ( statacorp , college station , tx ) statistical software ; graphs were created in r ( 16 ) . the cohort comprised 185,100 individuals with incident type 2 diabetes and 775,398 person - years ( py ) of follow - up and 185,100 matched individuals without diabetes and 795,167 py of follow - up ( table 1 ) . fifty - four percent were male , and the mean ( sd ) age at the time of diabetes diagnosis ( or index date for the control cohort ) was 60.7 ( 13.5 ) years . individuals with incident type 2 diabetes were more likely to have a low socioeconomic status , with 23% in the lowest socioeconomic quintile vs. 16% in the highest quintile compared with 19 and 21% , respectively , in the nondiabetes cohort . the incident type 2 diabetes and nondiabetes cohorts had an approximately equal median ( interquartile range [ iqr ] ) duration of cancer - free years in the database before the index date ( 4.0 [ 1.86.7 ] vs. 4.1 [ 1.96.8 ] , respectively ) . follow - up length after the index date was similar in both cohorts ( 3.8 [ 1.76.5 ] vs. 3.9 [ 1.86.6 ] years in the diabetes and nondiabetes cohorts , respectively ) ( table 1 ) . population characteristics at index date during the entire follow - up period , 603 ( 0.33% ) individuals with incident type 2 diabetes and 568 ( 0.31% ) nondiabetic individuals were given a diagnosis of bladder cancer . individuals who were eventually given a diagnosis of bladder cancer were older at the index date ( mean 69.5 ( sd 10.0 ) vs. 60.7 ( 13.5 ) years ) , were more often male ( 81 vs. 54% ) , and had more physician visits ( median 22 [ iqr 1239 ] vs. 19 [ 934 ] ) in the 2 years before the index date than those who were not given a diagnosis of bladder cancer ( table 1 ) . the overall incidence of diagnosed bladder cancer over the duration of follow - up was 77.8 ( 95% ci 71.784.2 ) per 100,000 py for those with diabetes vs. 71.4 ( 65.777.6 ) per 100,000 py for those without . in adjusted analyses , diabetes was significantly associated with an increased risk of bladder cancer ( adjusted hr 1.13 [ 95% ci 1.011.26 ] , p = 0.04 ) . in the first year following the index date , the incidence rates of bladder cancer in the diabetes and nondiabetes cohorts were 85.3 ( 95% ci 72.0100.4 ) and 66.1 ( 54.579.4 ) per 100,000 py , respectively ( adjusted hr 1.30 [ 95% ci 1.021.67 ] , p = 0.03 ) . diabetes was not associated with an increased risk of bladder cancer in any subsequent time window ( table 2 ) , and the overall risk of bladder cancer , when excluding the first year of follow - up , was 1.08 ( 0.951.23 ) ( p = 0.24 ) ( fig . 1 and table 2 ) . unadjusted bladder cancer irs in newly diagnosed t2 dm and no dm cohorts and ahrs by time since t2 dm diagnosis and number of physician visits in the 2 years before the index date ( t2 dm diagnosis ) risk of bladder cancer by frequency of physician visits 2 years before the index date . adjusted hrs for each physician visit category ( 12 , 1324 , and 25 visits ) were calculated at multiple points throughout follow - up and plotted (  connected by dashed line ) . the time - varying risk of bladder cancer is estimated with the solid trend lines . the 95% ci for the overall ( i.e. , nonstratified ) effect is shaded in gray ( trend line for overall risk not shown ) . the incident type 2 diabetes cohort had a greater number of physician visits in the 2 years before the index date ( i.e. , diabetes diagnosis ) than the nondiabetes cohort ( median 23 [ iqr 1339 ] vs. 16 [ 730 ] ) . we observed a statistically significant interaction between diabetes status and the frequency of physician visits in the 2 years before the index date in the time windows of 01 year ( p = 0.017 ) and 12 years ( p = 0.012 ) . therefore , we stratified regression models according to the number of physician visits before the index date ( table 2 ) . in the first year of follow - up , the significantly elevated risk of bladder cancer was confined to those who had the fewest previous physician visits ( adjusted hr 2.14 [ 95% ci 1.293.55 ] vs. 1.27 [ 0.821.97 ] vs. 0.99 [ 0.681.43 ] for 12 , 1324 , and 25 visits , respectively , p = 0.018 for trend ) ( table 2 ) . in subsequent time periods , estimates in all physician visit frequency categories approached the null and were not statistically significant ( fig . 1 and table 2 ) . during the entire follow - up period , 603 ( 0.33% ) individuals with incident type 2 diabetes and 568 ( 0.31% ) nondiabetic individuals were given a diagnosis of bladder cancer . individuals who were eventually given a diagnosis of bladder cancer were older at the index date ( mean 69.5 ( sd 10.0 ) vs. 60.7 ( 13.5 ) years ) , were more often male ( 81 vs. 54% ) , and had more physician visits ( median 22 [ iqr 1239 ] vs. 19 [ 934 ] ) in the 2 years before the index date than those who were not given a diagnosis of bladder cancer ( table 1 ) . the overall incidence of diagnosed bladder cancer over the duration of follow - up was 77.8 ( 95% ci 71.784.2 ) per 100,000 py for those with diabetes vs. 71.4 ( 65.777.6 ) per 100,000 py for those without . in adjusted analyses , diabetes was significantly associated with an increased risk of bladder cancer ( adjusted hr 1.13 [ 95% ci 1.011.26 ] , p = 0.04 ) . in the first year following the index date , the incidence rates of bladder cancer in the diabetes and nondiabetes cohorts were 85.3 ( 95% ci 72.0100.4 ) and 66.1 ( 54.579.4 ) per 100,000 py , respectively ( adjusted hr 1.30 [ 95% ci 1.021.67 ] , p = 0.03 ) . diabetes was not associated with an increased risk of bladder cancer in any subsequent time window ( table 2 ) , and the overall risk of bladder cancer , when excluding the first year of follow - up , was 1.08 ( 0.951.23 ) ( p = 0.24 ) ( fig . 1 and table 2 ) . unadjusted bladder cancer irs in newly diagnosed t2 dm and no dm cohorts and ahrs by time since t2 dm diagnosis and number of physician visits in the 2 years before the index date ( t2 dm diagnosis ) risk of bladder cancer by frequency of physician visits 2 years before the index date . adjusted hrs for each physician visit category ( 12 , 1324 , and 25 visits ) were calculated at multiple points throughout follow - up and plotted (  connected by dashed line ) . the time - varying risk of bladder cancer is estimated with the solid trend lines . the 95% ci for the overall ( i.e. , nonstratified ) effect is shaded in gray ( trend line for overall risk not shown ) . the incident type 2 diabetes cohort had a greater number of physician visits in the 2 years before the index date ( i.e. , diabetes diagnosis ) than the nondiabetes cohort ( median 23 [ iqr 1339 ] vs. 16 [ 730 ] ) . we observed a statistically significant interaction between diabetes status and the frequency of physician visits in the 2 years before the index date in the time windows of 01 year ( p = 0.017 ) and 12 years ( p = 0.012 ) . therefore , we stratified regression models according to the number of physician visits before the index date ( table 2 ) . in the first year of follow - up , the significantly elevated risk of bladder cancer was confined to those who had the fewest previous physician visits ( adjusted hr 2.14 [ 95% ci 1.293.55 ] vs. 1.27 [ 0.821.97 ] vs. 0.99 [ 0.681.43 ] for 12 , 1324 , and 25 visits , respectively , p = 0.018 for trend ) ( table 2 ) . in subsequent time periods , estimates in all physician visit frequency categories approached the null and were not statistically significant ( fig . 1 and table 2 ) . overall , we observed a statistically significant 13% relative increase in the risk of developing bladder cancer over a period of up to 10 years after the diagnosis of type 2 diabetes . however , our more detailed analyses suggest that the increased risk of bladder cancer occurred in the first year after type 2 diabetes diagnosis and predominantly among individuals who previously accessed physician services the least . indeed , we found no significant increased risk of bladder cancer among those with type 2 diabetes in time periods of 2 years , regardless of controlling for detection bias ( i.e. , the frequency of previous physician visits ) . there is a growing body of observational studies on the risk of various cancer in people with type 2 diabetes , including an estimated 43% increased risk of bladder cancer among those with diabetes of any duration ( 6,7,17,18 ) . consistent with evidence from several other cancers in people with diabetes ( 7,8 ) , the present results show a significantly elevated overall risk of bladder cancer that when split into follow - up time windows shows a highly elevated risk of bladder cancer in the months immediately following type 2 diabetes diagnosis . bladder cancer is not routinely screened for during a regular physician s visit and often is discovered incidentally during routine urinalyses ( 19 ) . approximately 1 in 10 cases of hematuria are caused by an underlying bladder cancer ( 20 ) . individuals who previously visited the physician infrequently , and thus had less opportunity for investigation of potential symptoms , may be more likely to have an undiagnosed bladder cancer at the time of diabetes diagnosis than those who had more frequent physician contact , suggesting a mechanism for potential detection bias . similarly , among individuals with fewer ( 12 ) physician visits in the 2 years before diabetes diagnosis , the below - the - null rebound of bladder cancer risk observed in this group during the second year after diabetes diagnosis ( index date ) suggests that cases that would have been detected in year 2 were shifted to the first year , thereby depleting these susceptible individuals from the subsequent time point . we observed no difference in bladder cancer risk between individuals with and without diabetes in the highest physician visit category . in this category , frequent physician visits may be driven by serious and/or multiple health problems ; in this group , diabetes status may no longer differentially affect the likelihood of discovering bladder cancer . alternatively , frequent physician visits may reflect health - seeking behavior ( i.e. , regular exercise , eating a healthy diet , not smoking ) ; such behaviors may have prevented the otherwise potentially elevated bladder cancer risk in the diabetes group . despite some strengths , this work has several important limitations . first , we lacked potentially important clinical information , such as smoking ( a known risk factor for bladder cancer and , thus , a potential confounder ) or frequency of urinalyses ( to further explore the detection bias hypothesis ) . we did , however , adjust for socioeconomic status , which is correlated with smoking status . confounding by smoking is unlikely to be time dependent and , thus , the time - specific findings may not be subject to this limitation . second , the follow - up period of up to 10 years ( median 4 years ) may not have been long enough to capture latent bladder cancer risk when the estimated latency period may extend up to 30 years ( 21 ) . third , diagnoses of diabetes were based entirely on claims data , and given the number of individuals with undiagnosed diabetes in the community , it is almost certain that there were individuals with diabetes in the control group . given that the diagnostic workup for a diagnosis of diabetes is associated with a ( short - term ) increased risk of a bladder cancer diagnosis , undiagnosed diabetes in the nondiabetes cohort would not influence the findings in an important way because individuals in this group would not have received this workup . if our hypotheses are correct , other new diagnoses , such as of hypothyroidism or chronic obstructive pulmonary disease , could also lead to spuriously increased diagnoses of new cancers because of detection bias . we observed a significantly increased risk of bladder cancer in individuals with newly diagnosed type 2 diabetes compared with individuals without diabetes . however , this increased risk in the type 2 diabetes population was limited to the first year following diabetes diagnosis and only among individuals with the fewest ( 12 ) physician visits in the previous 2 years . subsequent to the first year following diabetes diagnosis , the risk of bladder cancer was equal to that of individuals without diabetes . this pattern suggests a potential detection bias of bladder cancer in those with type 2 diabetes . studies that fail to account for time since diabetes diagnosis and frequency of physician visits may overestimate the long - term risk of bladder cancer in these individuals . moreover , the present findings suggest that associations between diabetes ( and possibly other newly diagnosed conditions ) and risk of other cancers might , at least in part , be a result of detection biases . with the recent interest in the potential association between pioglitazone use and bladder cancer ( 9,11,12 ) and given the potential bias visiting the physician has on bladder cancer detection , this study begs the question of whether seeing the physician more frequently ( e.g. , to intensify or switch glucose - lowering agents ) may bias the discovery of clinically present , but undiagnosed bladder cancer . there is a growing body of observational studies on the risk of various cancer in people with type 2 diabetes , including an estimated 43% increased risk of bladder cancer among those with diabetes of any duration ( 6,7,17,18 ) . consistent with evidence from several other cancers in people with diabetes ( 7,8 ) , the present results show a significantly elevated overall risk of bladder cancer that when split into follow - up time windows shows a highly elevated risk of bladder cancer in the months immediately following type 2 diabetes diagnosis . bladder cancer is not routinely screened for during a regular physician s visit and often is discovered incidentally during routine urinalyses ( 19 ) . approximately 1 in 10 cases of hematuria are caused by an underlying bladder cancer ( 20 ) . individuals who previously visited the physician infrequently , and thus had less opportunity for investigation of potential symptoms , may be more likely to have an undiagnosed bladder cancer at the time of diabetes diagnosis than those who had more frequent physician contact , suggesting a mechanism for potential detection bias . similarly , among individuals with fewer ( 12 ) physician visits in the 2 years before diabetes diagnosis , workup at the time of diagnosis may allow bladder cancer to be detected sooner . the below - the - null rebound of bladder cancer risk observed in this group during the second year after diabetes diagnosis ( index date ) suggests that cases that would have been detected in year 2 were shifted to the first year , thereby depleting these susceptible individuals from the subsequent time point . we observed no difference in bladder cancer risk between individuals with and without diabetes in the highest physician visit category . in this category , frequent physician visits may be driven by serious and/or multiple health problems ; in this group , diabetes status may no longer differentially affect the likelihood of discovering bladder cancer . alternatively , frequent physician visits may reflect health - seeking behavior ( i.e. , regular exercise , eating a healthy diet , not smoking ) ; such behaviors may have prevented the otherwise potentially elevated bladder cancer risk in the diabetes group . first , we lacked potentially important clinical information , such as smoking ( a known risk factor for bladder cancer and , thus , a potential confounder ) or frequency of urinalyses ( to further explore the detection bias hypothesis ) . we did , however , adjust for socioeconomic status , which is correlated with smoking status . confounding by smoking is unlikely to be time dependent and , thus , the time - specific findings may not be subject to this limitation . second , the follow - up period of up to 10 years ( median 4 years ) may not have been long enough to capture latent bladder cancer risk when the estimated latency period may extend up to 30 years ( 21 ) . third , diagnoses of diabetes were based entirely on claims data , and given the number of individuals with undiagnosed diabetes in the community , it is almost certain that there were individuals with diabetes in the control group . given that the diagnostic workup for a diagnosis of diabetes is associated with a ( short - term ) increased risk of a bladder cancer diagnosis , undiagnosed diabetes in the nondiabetes cohort would not influence the findings in an important way because individuals in this group would not have received this workup . if our hypotheses are correct , other new diagnoses , such as of hypothyroidism or chronic obstructive pulmonary disease , could also lead to spuriously increased diagnoses of new cancers because of detection bias . we observed a significantly increased risk of bladder cancer in individuals with newly diagnosed type 2 diabetes compared with individuals without diabetes . however , this increased risk in the type 2 diabetes population was limited to the first year following diabetes diagnosis and only among individuals with the fewest ( 12 ) physician visits in the previous 2 years . subsequent to the first year following diabetes diagnosis , the risk of bladder cancer was equal to that of individuals without diabetes . this pattern suggests a potential detection bias of bladder cancer in those with type 2 diabetes . studies that fail to account for time since diabetes diagnosis and frequency of physician visits may overestimate the long - term risk of bladder cancer in these individuals . moreover , the present findings suggest that associations between diabetes ( and possibly other newly diagnosed conditions ) and risk of other cancers might , at least in part , be a result of detection biases . with the recent interest in the potential association between pioglitazone use and bladder cancer ( 9,11,12 ) and given the potential bias visiting the physician has on bladder cancer detection , this study begs the question of whether seeing the physician more frequently ( e.g. , to intensify or switch glucose - lowering agents ) may bias the discovery of clinically present , but undiagnosed bladder cancer .
objectiveto investigate whether the risk of bladder cancer in individuals with newly diagnosed type 2 diabetes is influenced by the frequency of physician visits before diagnosis as a measure of detection bias.research design and methodswith the use of linked administrative databases from 1996 to 2006 , we established a cohort of 185,100 adults from british columbia , canada , with incident type 2 diabetes matched one to one with nondiabetic individuals on age , sex , and index date . 
 incidence rates and adjusted hazard ratios ( ahrs ) for bladder cancer were calculated during annual time windows following the index date . 
 analyses were stratified by number of physician visits in the 2 years before diabetes diagnosis and adjusted for age , sex , year of cohort entry , and socioeconomic status.resultsthe study population was 54% men and had an average age of 60.7  13.5 years ; 1,171 new bladder cancers were diagnosed over a median follow - up of 4 years . in the first year after diabetes diagnosis , bladder cancer incidence in the diabetic cohort was 85.3 ( 95% ci 72.0100.4 ) per 100,000 person - years and 66.1 ( 54.579.4 ) in the control cohort ( ahr 1.30 [ 1.021.67 ] , p = 0.03 ) . 
 this first - year increased bladder cancer risk was limited to those with the fewest physician visits 2 years before the index date ( 12 visits , ahr 2.14 [ 1.293.55 ] , p = 0.003 ) . 
 after the first year , type 2 diabetes was not associated with bladder cancer.conclusionsthe results suggest that early detection bias may account for an overestimation in previously reported increased risks of bladder cancer associated with type 2 diabetes .