Document v1nJkO0pr258dnmddO52pYovE

From: Sent: To: Cc: Subject: Attach: Bruce Jarnot <jarnotb@api.org> Wednesday, July 14,2004 12:36 PM (GMT) benzconsort-tc@listserve.api.org benzconsort-oc@listserve.api.org BHRC-TC... Mid-Year Progress Report: Case Control Study CC Progress Report 07-14-2004.doc BHRC Technical Committee - Attached for your review and consideration is Otto Wong's mid-year progress report for the Shanghai Case Control study. We expect to receive Richard's mid-year Disease Progression & Molecular Epidemiology progress report later this month. Best Regards - Bruce. ***** Bruce M. Jarnot, PhD., DABT American Petroleum Institute Regulatory and Scientific Affairs 1220 L Street, NW (Suite 900) Washington, DC 20005-4070 phone: (202) 682-8473 fax: -8031 email: jarnotb@api.org SHELL-MCCLURG-052189 Progress Report AML and NHL Case-control Study Activities through June 2004 Prepared by: Otto Wong, SC.D. Applied Health Sciences, Inc. 181 Second Avenue, Suite 628 San Mateo, CA 94401 USA Tel: 1 (650) 347-7898 USA Fax: 1 (650) 344-6887 USA ottowong@aol.com July 14,2004 Patient Enrollment: Patient enrolment is the responsibility of the designated Clinical Coordinator at each participating hospital. For AML cases and controls, the Clinical Coordinators (mostly hematologists) are under the direction of Dr. LIN Guiwei of the Huashan Hospital. Dr. LIN is not only an experienced hematologist but also a trained epidemiologist (at the University of Pennsylvania). For NHL cases and controls, the Clinical Coordinators (mostly pathologists) are under the direction of Dr. Zhu Xiongzeng of the Tumor Hospital. Patients with preliminary diagnoses of AML or NHL were referred to the Joint Clinical and Molecular Laboratory (JCML) for diagnostic confirmation. Only JCML-confirmed AML or NHL cases are eligible for participation in the case-control study. As of mid-June, approximately 103 JCML-confirmed AML have been enrolled in the case-control study. These patients were diagnosed between mid-August 2003 and mid-June 2004, covering an interval of9.5 months. The estimated annual accrual rate of AML patients is, therefore, 138, which is slightly higher than the assumed rate of 120 in the proposal. Based on this accrual rate, we estimate that by the end of 2006 would have approximately 460 cases of AML, which is slightly lower than the targeted sample size of 500. However, the trend of the accrual rate has been going up recently. Taking the trend into account, we estimate the number of AML cases by the end of2006 would exceed 500. As of mid-June, there were approximately 60 cases of JCML-confirmed NHL (as defined by ICD 9) in the case-control study. The estimated annual accrual rate is approximately 85, which is lower than the assumed rate of 120 in the proposal. 1 SHELL-MCCLURG-052190 Based on this accrual rate, we estimate that by the end of 2006, we would have approximately 285 cases ofNHL, which is markedly lower than the targeted sample size of 500. Taking the recent upward trend into consideration, the best estimate at this point is that we will have between 300 and 350 NHL cases by the end of2006. There are two major reasons for the deficit ofNHL patients. First, patient enrollment was a year behind schedule. Second, reporting ofNHL patients was incomplete at some hospitals. Meetings with responsible pathologists at participating hospitals were held in June to ensure that reporting of cases will be more complete in the future. The most important issue appeared to be related to the efforts to triage cases of non-malignant lymphoproliferative disease by recruiting patients only after an initial review of biopsy materials. This procedure had not worked well and had resulted in a relatively high rate of refusals and cases lost to follow-up. We have decided to recruit all potential candidates of NHL at the first presentation rather then to wait until we have confirmation. We estimate that this will result in an increase of 20%. Selection of Controls Control selection for AML cases presented no problem. For NHL cases, however, some irregularities at a few hospitals were discovered. Most of the NHL cases came from the Tumor Hospital and many were outpatients. According to the study protocol, controls were matched to cases with respect to outpatientlinpatient status. Through a review of the patient records, I discovered that some of the NHL outpatient controls were not "real" patients at the Tumor Hospital. Once an outpatient NHL case was identified, the nurses or doctors looked for someone who would fit the matching variables (i.e., age, sex) among their friends, relatives or neighbors. I noticed that quite a few controls lived at or near the Community Center (.@~~) at 1200 Xietu Road ( #~ ~ ) ,which is close to the Tumor Hospital. These people were not sick. The motivation to participate in the study was purely financial. Each person got 240 RMB for participation. After being "selected" as a control into the study, then the control registered at the hospital as an outpatient, which costs 6 RMB. In the JCML database, these controls did not have any diagnosis. A similar problem was also discovered at No. 6 Hospital. (Please see the attached memorandum "Control Selection at Certain Hospitals" dated 5 May 2004.) Several meetings with the responsible Clinical Coordinators were held, and the importance of maintaining the scientific integrity of the protocol was explained to them. We also emphasized to them that we would closely monitor the control selection at these hospitals. To ensure that in the future all controls are actually patients, we further require that all controls be selected from inpatients only. We do not believe that restricting controls to inpatients will introduce any bias, whereas controls selected from the Clinical Coordinators' neighbors or friends will likely result in bias. 2 SHELL-MCCLURG-052191  We will continue to monitor the selection of controls in the future. Exposure Assessment: By June 2004, we have identified 48 patients exposed to both benzene and other substances, and detailed exposure profiles have been developed for 28 patients. In addition, 360 patients were identified to have been exposed to other chemicals. Employment and exposure histories were obtained from the patients through a questionnaire interview. General employment and exposure information is obtained through the use of a "primary" questionnaire, and detailed exposurespecific information through the use of "secondary" industry/occupation-specific questionnaires. Primary sources for benzene exposure information include the following: the exposure database at the Shanghai Municipal Institute for Public Health Supervision (IPHS), Chinese occupational medicine literature, and ad hoc industrial hygiene sampling. For additional details of exposure assessment, please see Mr. Tom Armstrong's report on exposure assessment. Project and Budget Management: To manage the project properly, it is necessary to devote more time than originally estimated, which demands greater physical presence in Shanghai. During the past 6 months, I have made more and longer trips to Shanghai than originally budgeted for. Fortunately, I was able to take advantage of my trips to Hong Kong, which were paid for by the universities there. I anticipate that for the second half of the year, I will have to make 3 to 4 trips to Shanghai. 3 SHELL-MCCLURG-052192 Control Selection at Certain Hospitals Prepared by Otto Wong and Rob Schnatter, 5 May 2004 The selection of controls at each hospital is the responsibility of the Clinical Coordinator at the hospital. The Clinical Coordinators were given a copy of the following instruction: Instruction for selecting controls in the AMLINHL case-control study English Selection of controls (1 case - 2 controls) 1. Same gender 2. Age 5 years 3. No disease of the lymph or blood system 4. Closest admission date 5. Same hospital 6. If the case is an inpatient, controls will be inpatients as well. If the case is an outpatient, controls will be outpatients as well. ~3t :x~ ~JH..I9~:t~ (ll'fpH~~ - 21~~:x~ ~,~) 1. ttj3U*1E] 2. ~1M'5 ~ 3. :FujtHgs.\t.on~~U"tc~~ 4. A~Jr: S ~:QUili - 5. IE] -1~HJr: 6. :!lO~~1~~~11~Jr:~A, :x~~,~m~11~Jr:~A. :!lO~~1~~~nit~A, :x~~,~m~nit~A. If a control cannot be found, relax age to 10 years. jlD~:t~1'UX'.t ~JUJ~*,~~~ 10 ~. If only one control can be found, we will keep both the case and the one control. jlD ~R:t~ U -1-X'.t ~Jt ~in ~Jt1~ iB~1-fpg19U&~1-x'.t ~Jt In February 2004, a review of the questionnaire data of the cases and controls was carried out. Two irregularities were noted: 1. Quite a few controls at the Tumor Hospital lived in the same neighborhood (neighbors or relatives). 2. Several controls at No.6 Hospital were health care workers (nurses or doctors). 4 SHELL-MCCLURG-052193 The numbers of neighbors or relatives (21, 52%) and health care workers (6, 50%) appeared to be higher than one might have expected if the selection of controls was random. All these "suspect" controls were outpatients with some very minor complaints, such as flu or upset stomach. An investigation of the selection procedures at these two hospitals was made in February and March, 2004. At the Tumor Hospital it was found that the Clinical Coordinator relied on one certain nurse for control selection. For some outpatient cases, the nurse "recruited" controls among her relatives or neighbors who fulfilled the gender and age matching criteria. Once an appropriate candidate had been identified, she asked the latter to register as an outpatient at the hospital (for a fee of 6), thus becoming eligible as a potential control who would be entitled to receive the 240 participation fee (equivalent to approximately a department store salesperson's salary for one week). At No.6 Hospital, for some cases the Clinical Coordinator simply "recruited" coworkers (nurses and doctors) who met the matching criteria for gender and age. The same economic gain applied. The selection of controls from non-patients (relatives, neighbors and coworkers) will likely introduce selection bias. For co-workers, this procedure may possibly result in an under-representation of exposure among the controls. For relatives or neighbors, it is difficult to predict whether this selection procedure could bias study results. The primary motivation for this "unorthodox" approach appeared to be the 240 participation fee. In addition to the financial incentive, another motivation might be convenience. Two separate meetings with the Clinical Coordinators at the Tumor Hospital and No.6 Hospital were held to discuss corrective measures. Given the different setups at each hospital and the number of individuals involved, the only "foolproof" method is to require all controls to be selected from inpatients. It is highly unlikely that a non-patient will be willing or able to register as an inpatient, if he or she is not actually sick. Of the 284 total cases in the study as of 20 April 2004, 26 (9%) are outpatients from the Tumor Hospital or No.6 Hospital. Of these, we believe inappropriate controls were selected for 19 (73%) outpatient cases. Overall, inappropriate controls were selected for 7% of the cases (19/284). Our review did not detect any other irregularities in control selection, although we cannot guarantee that other inappropriate controls (possibly friends or relatives) were not selected for other cases. We do feel confident that this problem will be circumvented through the use of inpatient controls. 5 SHELL-MCCLURG-052194 While there may be some slight social class differences in outpatients and inpatients, we don't believe that these slight differences will cause a significant bias in the likelihood of occupational exposure. If such a bias is present, we believe it will be much smaller than the potential bias in selecting neighbors, coworkers, friends, or relatives. There is no ground to suspect that outpatients and inpatients differ substantially in any occupational or lifestyle factor. Dr. Ye Xibiao, the Project Coordinator at Fudan University, provided the following comparison between outpatients and inpatients. There are some minor differences in terms of smoking and age. Age is one of the matching variables, and, therefore, will not be an issue. Smoking will be treated as a confounding variable, and all analyses will be adjusted for smoking. 6 SHELL-MCCLURG-052195 Variables SEX Male Female Types of patients Outpatients Inpatients Total 78 ( 60.5 ) 51 ( 39.5 ) 401 ( 55.6 ) 479 ( 56.4 ) 320 ( 44.4 ) 371 ( 43.6 ) MARTIAL STATUS DNK 0 5 ( 0.7 ) 5 ( 0.6 ) DIVORCED 0 MARRIED 111 ( 86.0 ) NEVER MARRIED 12(9.3) WIDOWED 6 ( 4.7 ) 7 ( 1.0 ) 604 ( 83.8 ) 76 ( 10.5 ) 29 ( 4.0 ) 7 ( 0.8 ) 715 ( 84.1 ) 88 ( 10.4 ) 35 ( 4.1 ) EDUCATION DNK 1 ( 0.8 ) HIGH 37 ( 28.7 ) MIDDLE 35 (27.1 ) NONE 5 ( 3.9 ) POSTGRADUATE 3 ( 2.3 ) PRIMARY 21 ( 16.3 ) UNIVERSITY 27 ( 20.9 ) 3 ( 0.4 ) 196 ( 27.2 ) 228(31.6) 53 ( 7.4 ) 4 ( 0.6 ) 111(15.4) 126 ( 17.5 ) 4 ( 0.5 ) 233 ( 27.4 ) 263 ( 30.9 ) 58 ( 6.8 ) 7 ( 0.8 ) 132 ( 15.5 ) 153 ( 18.0 ) SMOKE* No Yes, but not now Yes, still smoke 72 ( 55.8 ) 16(12.4) 41(31.8) 447 ( 62.0 ) 120 ( 16.6 ) 154 ( 21.4 ) 519(61.1) 136 ( 16.0 ) 195 ( 22.9 ) DRINK DNK No Yes 0 96 ( 74.4 ) 33 (25.6 ) 5 ( 0.7 ) 544 ( 75.5 ) 172 (23.9) 5 ( 0.6 ) 640 ( 75.3 ) 205 (24.1 ) CITY Shanghai Out of Shanghai 99 ( 76.7 ) 30 ( 23.3 ) 586(81.3) 685 ( 80.6 ) 135 ( 18.7 ) 165 ( 19.4 ) AGE(yrs)* 18354555- 24 ( 18.6 ) 25 ( 19.4 ) 32 (24.8 ) 28 ( 21.7 ) 131 ( 18.2 ) 88(12.2) 173 (24.0) 121 ( 16.8 ) 155 ( 18.2 ) 113 ( 13.3 ) 205 (24.1 ) 149 ( 17.5 ) 7 SHELL-MCCLURG-052196 65- * p<O.OS 20 ( 15.5 ) 208 ( 28.8) 228 ( 26.8 ) 8 SHELL-MCCLURG-052197