Table 3.

Follow-up methods and results of loss to follow-up, ascertainment type and completeness, classification issues, and potential for bias in 26 low-dose radiation epidemiological studies

Study name (reference)	Method of follow-up: active vs linkage	Loss to follow-up*	Likelihood of Differential ascertainment Incomplete ascertainment False negative outcomes False positive outcomes	Other classification issues	Comment	Potential for bias (Y/N possible)
Environmental
Chernobyl-exposed children (1)	NA*	NA	NA Unlikely Unlikely Unlikely	Expert hematologists reviewed each case	Authors state: high degree of completeness of case ascertainment but no further details; Ukraine component had higher percent of controls than cases from less contaminated regions	No
TMI residents (2)	Linkage	1.6% lost to follow-up; annual follow-up via post office address change	No Unlikely Unlikely Unlikely	TMI population registry matched annually with PA state cancer registry from 1982 onward	Population-based cancer registry not established until 3 y after accident: possible incomplete ascertainment of leukemia	No
Chinese background (3)	Active	Villages visited annually to assess cancer mortality; 1.6% lost to follow-up in higher background radiation and 2.8% in lower background radiation regions, both mostly due to emigration	Possible; older mean attained age in lower background than in higher background radiation regions; tuberculosis mortality lower in higher background than in lower background radiation regions; slightly lower cancer mortality rate in higher background than in lower background radiation regions Likely ↓ Likely Unlikely	Basis of diagnosis of variable quality	No national mortality registers. Some diagnoses from hospital records, but others from interviews of village doctors, family, or next of kin; thus, ascertainment of cancer incidence and mortality, particularly for leukemia, likely incomplete, potentially greater in the lower background radiation region.	Possible for both solid cancers and leukemia. Uncertain direction of bias because false negatives could be substantial in both higher and lower background radiation regions.
GB background (4)	Linkage	NA	No; birth register controls linked to National Registry of Childhood Tumors Unlikely Unlikely Unlikely	Specialized pediatric cancer registry used; cases classified using ICCC		No
Swiss children background (5)	Linkage	NK*†; 1.7% excluded due to uncertain residence	No Possible ↓ Possible Possible	<4% Potential false positives; >400 cancers not linked that are potentially false negatives; ≤7% linkages resulted in false matches	Authors state: no evidence that false negatives differed from linked cases in radiation exposure	No
Techa River residents (6)	Active: case ascertainment from oncology clinics, medical records, and death certificates (latter percent declined over time)	NK‡; outcome available on 73% of cohort; 21% periodically lived outside study region; 5.7% nonmigrants lost to follow-up	No Possible ↓ Likely Possible	20% incident cancers were death certificate diagnoses	Authors state: no indication that migration confounds results, although other studies suggest that healthier persons more likely to emigrate	No
Finnish background (7)	Linkage	NA; very small numbers of exclusions (0.0036% prohibited use of data; residence data incomplete for 3.3-4.4%)	No; population register provided information about residences for 94% cases, 95% controls Unlikely Unlikely Unlikely			No
Taiwanese residents (8)	Linkage	NK§; residential history based on interview; loss to follow-up not stated	No Possible ↓ Possible Unlikely	Improving quality of cancer registry over time; ICD-O first edition used	Incomplete and missing occupancy data	No
Medical
Cardiovascular imaging patients (9)	Linkage	NK‖; loss to follow-up not reported	Possible; those undergoing diagnostic or therapeutic procedures with imaging more likely to have cancer outcomes detected Likely ↑ Possible Likely	No estimates provided for total cancers, total solid cancers, or leukemia. Nonstandard anatomic site groupings used to report outcomes.		Possible. Increased risk of solid cancer may have been observed in those exposed due to increased imaging
French pediatric CT (10)	Linkage	NK¶; loss to follow-up not reported	No Unlikely Unlikely Unlikely			No
UK pediatric CT (11)	Linkage and medical record review	Unlikely to bias results	No; detailed clinical review undertaken following initial report. No indication of differential by exposure status (ever CT vs never CT), but availability of detailed additional clinical information was lower for noncancer cases (40% available) than cancer cases (90% available). Unlikely Likely (brain tumors only) Unlikely		15.7% of potentially eligible patients identified in Radiology Information Systems database were excluded because could not be traced using National Health Services Central Register, but unlikely to differ by exposure status	No
PIRATES (low dose) (12)	Pooled analysis: outcomes for 4 cohort outcomes identified via linkage; 4 cohorts through active follow-up; 1 cohort (a-bomb) via linkage from 1958 onward	NK**; loss to follow-up not reported	No Possible ↓ Possible Possible	No major changes in classification of total thyroid cancer over lengthy follow-up period; histologic confirmation required for cases		No
Occupational
Korean radiation workers (13)	Linkage	NK††; loss to follow-up not reported	Possible; medical surveillance required for radiation workers but not for general population or worker comparison group (motor vehicle manufacturing) Possible ↑ Unlikely Possible	Use of a modification of ICD-10 that is closer to ICD-9 for hematopoietic neoplasms	Follow-up (mortality: 1992–2004; incidence: 2000–2005) began several years after dose monitoring was initiated	Possible. Increased solid cancer and leukemia risks due to required medical surveillance of those exposed, whereas not required in unexposed
Belarus, Russia, and Baltic CL (14)	Linkage	NA	NA; authors state: underascertainment likely but little reason that any underascertainment would be related to dose level Likely ↓; authors noted this limitation, particularly for Russia component Unlikely Unlikely	Expert hematopathologists reviewed each case		No
UKNRRW NW (15)	Linkage	Unlikely to bias results	No Unlikely Unlikely Unlikely		Refusal rate for participation approximately 1%	No
Korean male NP NW (16)	Linkage	NK‡‡; loss to follow-up not reported	No; unmonitored workers were those who worked in same nuclear power facilities as radiation-monitored workers Unlikely Unlikely Unlikely	None; ICD10 used	Follow-up (1992–2005) began 14 y after dose monitoring initiated	No
Rocketdyne NW (17)	Linkage	Unlikely to bias results; 0.6% loss to follow-up	No Unlikely Possible Unlikely	ICD9		No
Japanese male NW (18)	Linkage	NK§§; 27.4% loss to follow-up for period before prospective follow-up (1986–1991) but 0.3% subsequently (1991–1997)	Yes; retrospective follow-up included higher proportion of young, newly employed workers than did prospective follow-up; early loss to follow-up likely related to higher dose Likely; excess risks for certain gastrointestinal cancers likely explained by selection bias characterizing retrospective follow-up and confounding by lifestyle factors Possible Unlikely	ICD9	Loss to follow-up was higher in early years when doses were higher	Possible. Incomplete assessment of risks of solid cancers and leukemia due to loss to follow-up of early workers
Canadian NW (19)	Linkage	97.6% vital status ascertainment	No Unlikely Unlikely Unlikely	ICD9 used to recode underlying cause of death from original ICD code in use at time of death	Cause known for 99.9% of deaths; a subset of workers (AECL) had problematic dosimetry and were therefore excluded.	No
Ukrainian CL (20)	Medical facility follow-up before 2001, linkage after	NA	No; case ascertainment procedures changed: cases identified from local health-care facilities before 2001 and subsequently through linkage with Ukrainian Cancer Registry Possible ↓; nationwide coverage by Ukrainian Cancer Registry not complete until 1997 Unlikely Unlikely	Expert hematopathologists reviewed each case	Reflects high level of medical surveillance: unexpected similar radiation-related risks for CLL and non-CLL leukemias. Unexpectedly high proportion of CLL cases in study (58%) compared with 40–44% in general populations of European descent in other countries	No
German NP NW (21)	Follow-up through linkage of last known residence with vital status	NK‖‖; low loss to follow-up (0.7%)	No Possible ↓ Possible; 4% of death certificates requested not obtained Unlikely	ICD9 and ICD10	Follow-up (1991–2008) began 25 y after dose monitoring initiated	No
US NW (22)	Linkage	1.1% lost to follow-up	No; cause of death unavailable for 1.1% of decedents Unlikely Possible Unlikely	Used mortality/cause of death ascertained in earlier follow-up. Confirmed vital status with SSA Death Master File, cause of death from the NDI, and newly identified deaths coded to the latest ICD revision.		No
INWORKS NW (23, 24)	Linkage	Loss to follow-up not described for pooled cohorts	No Unlikely Possible Unlikely	See French nuclear workers below. Ascertained vital status through linkage of participating French, UK, and US cohorts with employer and SSA records. Identified cause of death through linkage with national and regional cancer registries.	Certain outcomes (smoking- and asbestos-related cancers) may have reflected confounding of radiation-related dose response by these exposures	No
US atomic veterans (25)	Linkage	Vital status determined for 95.3%	No; cause of death unavailable for 3% of decedents Unlikely Possible Unlikely		Follow-up (1957–2010) began 12 y after first exposure; deaths occurring pre 1957 not identified. Findings for certain malignant and nonmalignant outcomes and lack of healthy worker effect observed among participants in 1 test (designated SMOKY) but not others.	No
USRT (26–28)	Linkage to national mortality register; questionnaire-based ascertainment of incidence	NK¶¶; <0.2% loss to follow-up	No; internal analysis used exclusively for dose-response risk assessment; no evidence of differential ascertainment by level of radiation exposure Breast, skin incidence likely↓ because source of ascertainment is questionnaire-based self-report. Brain tumor mortality: possible ↓ Breast, skin incidence: possible Brain tumor mortality: possible Breast, skin incidence: possible Brain tumor mortality: possible	Some misclassification of breast and skin cancer is likely due to ascertainment from questionnaire self-report despite efforts to confirm these outcomes with medical records. Self-report compared with medical record diagnoses have shown only a small percent misclassified. Use of death certificates as only source for primary brain tumors likely has resulted in some misclassification, but no validation has been performed.		No
French NW (29)	Linkage	NK***; 0.2% of workers lost to follow-up	No; cause of death unavailable for 2.3% of decedents Possible ↓; cause of death information not available before 1968 Possible Unlikely	Causes of death were coded to ICD revision in effect at time of death.	French National Death Registry established1968; prior deaths not identified. Potential confounding by socioeconomic status. Many contractor workers not included because of poor follow-up, incomplete company records, problematic identifying information, and incomplete dosimetry reconstruction.	No

Notes: In the fourth column (differential/incomplete ascertainment and false negatives or positives), definitions of the terms used include: likely = evidence there was a problem; unlikely = evidence there was no problem; possible = could not rule out a problem; downward arrows = evidence of notable reduced ascertainment; upward arrows = evidence of notably increased ascertainment of clinically nonapparent or precancer neoplasms. The basis of these qualitative assessments is described in the sixth column (comments). In the seventh column (potential for bias), definitions of the terms used include: yes = potential for bias is evident; no = potential for bias is not evident; possible = could not rule out the potential for bias. Estimates of differential or incomplete ascertainment, false negative, or false positive outcomes are qualitative and somewhat subjective. Quantification of these elements is not possible for almost all of the studies due to absence of critical information about methods.

^*AECL = Atomic Energy of Canada Limited; CL = Chernobyl liquidators; CLL = chronic lymphocytic leukemia; GB = Great Britain; ICCC = International Childhood Cancer Classification; ICD = International Classification of Diseases; ICD-O = International Classification of Diseases for Oncology; INWORKS = International Nuclear Workers Study; NK = not known; NP = nuclear power; NW = nuclear workers; TMI = Three Mile Island; UK = United Kingdom; UKNRRW = United Kingdom National Registry for Radiation Workers; US = United States; USRT = US Radiologic Technologists.

^† NK: Swiss children background cohort identified and residence determined from 1990 and 2000 national censuses and linked with the Swiss Childhood Cancer Registry (the latter estimated >90% complete). Unclear residential history between censuses because active follow-up was not undertaken, but the Swiss National Cancer Registry includes all residences from diagnosis back to birth and is therefore potentially more complete.

^‡ NK: Techa River residents study had loss to follow-up of 15% in 2007 publication that declined to 5.7% in the current publication; results from studies of migrants suggest that migration wqas more likely by healthier persons, although the authors explicitly indicated it was unlikely that migration acts as a confounding factor.

^§ NK: Taiwan residents’ cohort was established in 1992, interviewed in 1995–2000 to reconstruct residential history from 1983 onward; incomplete and missing occupancy data resulted in exclusion of 1020 cohort members from 7262 registered as living in the building.

^‖ NK: Quebec (Canada) patients newly diagnosed with myocardial infarction (77% undergoing diagnostic or therapeutic procedures involving radiation exposure) were not actively followed-up for cancer and deaths; linkage for outcomes was limited to Quebec insurance databases for which no information was provided about level of completeness; no information about loss to follow-up or emigration.

^¶ NK: French pediatric CT population followed-up using vital status register designated medium quality; loss to follow-up not stated.

^**NK: PIRATES, likely highly complete identification of thyroid cancer incidence from four cohorts linked with high-quality nationwide population-based and cancer registries and the a-bomb survivors from 1958 onward when high-quality cancer registries were available; likely underascertainment for four cohorts with other methods of follow-up and before 1958 for the a-bomb survivors.

^†† NK: Korean radiation workers were defined as all workers under medical surveillance because of ionizing radaition exposures as required by law, but there was little information about the source and completeness of this cohort. Follow-up began at the date of first exposure surveillance (as early as January 1984 or later) or January 1992, whichever was later. Hence, outcomes that ocurred before 1992 were not considered.

^‡‡ NK: Korean nuclear power industry workers radiation workers were defined as those who were issued with a dosimeter at nuclear power facilities until 2005. Follow-up for cancer incidence was undertaken for male nuclear power industry workers who were compared with unmonitored workers from the same facilities during the period 1992–2005. Outcomes that occurred before 1992 were not considered.

^§§ NK: Japanese nuclear workers were characterized by 27.4% loss to follow-up during 1986–1991 due to incorrect address information provided by nuclear facility or lack of availability of residential addresses, which were only maintained for 5 years; only 0.3% loss to follow-up during 1991–2002 because follow-up was initiated in 1991 and residential addresses were fully available during the 1991–2002 follow-up.

^‖‖ NK: German nuclear workers were followed-up by search of the regional population registry based on the last known address to determine vital status. No information about loss to follow-up or inability to identify workers in the regional population registries. Dose monitoring was initiated 25 years before follow-up was launched. Deaths occurring before 1991 were not identified.

^¶¶ NK: For the USRT, annual individual dose estimates were reconstructed for the period 1926–1997, although follow-up did not commence until completion of a baseline questionnaire (eg, 1983–1989 or 1994–1998, depending on which “baseline” questionnaire patients completed). The historical dose reconstruction required incorporation of questionnaire (work history, work procedures, radiation protection) information because badge doses were missing for a substantial fraction of technologists, particularly for the period before 1977.

^***NK: In the French nuclear workers, dose monitoring was initiated 18 years before follow-up was possible because a national death register was only available from 1968 onward. Deaths before 1968 were not systematically identified, but an earlier analysis revealed that the standardized mortality ratio for the period 1946–2004 was similar to that for the period 1968–2004 (49).