Medical and dietary interventions for preventing recurrent urinary stones in children

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

This review aims to look at the benefits and harms of medical and dietary interventions for the prevention of idiopathic urinary stones in children aged from one to 18 years.

Background

Description of the condition

Although more frequent in adults, urinary tract stones (urolithiasis) occur in children, with reported incidence of 2% to 3% and a male to female ratio of 1:1 (Malek 1975; Pietrow 2002). Urinary tract stones in children account for 1/1000 to 1/7600 hospital admissions, according to data from the 1970s to 1990s (Nimkin 1992; Troup 1972; Walther 1980). However, recent reports suggest that urinary calculi are being recognised at an increasing frequency in children (Dwyer 2012; Trinchieri 1996; VanDervoort 2007).

In the US there are over 2 million outpatient visits annually for renal colic at an estimated annual cost of $2 billion (Pearle 2005). Recent studies have also found an 86% increase in emergency department visits secondary to kidney stones in children from 1999 to 2008 (Kairam 2013). There is a 27% to 50% risk of developing a recurrent stone within the first five years of the initial stone episode and approximately 70% of children who form stones will continue with recurrent stone disease during childhood and adulthood (Kocvara 1999; Milliner 1993). Thus, most of these children have chronic, painful and debilitating disease that erratically interrupts their education and the work life of their parents and carers. Because of these factors, prevention of future episodes is critical.

Excluding genetic and secondary causes of stone disease (i.e. medication induced or intestinal malabsorption), there are many nutritional risk factors for the formation of idiopathic nephrolithiasis as the composition of urine is largely determined by diet( Heilberg 2013). For example, high dietary sodium intake decreases proximal tubular sodium reabsorption which reduces renal calcium reabsorption causing hypercalciuria secondary to increased calcium excretion (Heilberg 2013). High animal protein intake, a source of purines, contributes to hyperuricosuria as well as leads to hypercalciuria secondary to increased bone resorption and lower tubular calcium reabsorption (Heilberg 2013). On the other hand, dietary modifications are also protective against stone disease. Citrates increase the solubility of stone-forming calcium salts and inhibit calcium oxalate crystal growth as well as induce a systemic alkalisation which reduces calcium excretion (Heilberg 2013). In addition, as metabolic acidosis results increased in bone resorption, increased citrate intake may also improve bone mineral density (Arrabal-Polo 2013). Potassium may also be protective as decreased potassium intake increases calcium excretion and citrate reabsorption, and ingested potassium will accompany organic ions such as citrate that will be metabolized to bicarbonate (Saxena 2010). Finally, low urinary volume is a well-known risk factor for stone disease and increased water intake results in excretion of a less saturated and higher volume of urine, which benefits all types of stone-formers (Borghi 1996).

Description of the intervention

After the initial acute stone event, long-term management of urinary stone disease focuses on the prevention of recurrent or new urinary stones. Urinary stones may be composed of a variety of constituents including calcium oxalate, calcium phosphate, uric acid, and struvite. The prevention of recurrent stones focuses on improving the balance between the crystal-forming and crystal-inhibiting substances in the urine (Fink 2013). The most basic interventions are dietary and include increasing water intake, restricting consumption of animal protein and salt, and increasing ingestion of fibre, calcium, and potassium (Kocvara 1999). Pharmacologic interventions include thiazide diuretics, potassium salts, allopurinol, and phosphate.

How the intervention might work

Prevention of urinary stones revolves around improving the concentration of various substances in the urine to prevent the precipitation of salts which form into stones. This can be achieved with a variety of dietary and pharmacologic interventions. Simply increasing water intake causes an increase in urine volume. This should in turn decrease the concentration of calcium, oxalate, phosphorus and uric acid in the urine, and thus subsequently reduce the saturation of the salts that form stones (Borghi 1996). An increase in urine volume to > 2.5 L/d has been previously shown in adults to decrease the time to and total number of stone recurrences (Borghi 1996).

With regard to specific diets, it has been hypothesised that excess animal protein intake increases urinary calcium, oxalate and uric acid, and decreases urinary citrate (Dussol 2008). In addition, a high fibre diet also may decrease urinary calcium (Dussol 2008). Oversaturation of urine with calcium is one of the most important risk factors for calcium nephrolithiasis and paradoxically, studies have shown that diets low in calcium actually have increased risks for stone disease possibly secondary to an increase in urinary oxalate (Heilberg 2013). As expected, urinary oxalate excretion increases as dietary oxalate intake increases and thus a low oxalate diet is also thought to be protective (Heilberg 2013). High sodium intake reduces renal tubular calcium reabsorption and thus increases calcium excretion and the risk for stone formation (Heilberg 2013). Citrate is protective against the formation of urinary tract stones because urinary citrate increases the solubility of stone-forming calcium salts and so inhibits calcium oxalate crystal growth (Heilberg 2013).

There are also a variety of medications that can alter the urinary parameters and are hypothesised to prevent urinary stones. Thiazide diuretics cause enhanced calcium reabsorption in the distal renal tubule and decrease the urinary concentration of calcium (Escribano 2009). Because urinary citrate inhibits stone formation, the administration of citrate salts is also hypothesised to prevent recurrent stone disease. Allopurinol, a xanthine oxidase inhibitor, reduces uric acid synthesis and lowers urinary uric acid, has proven to be effective in reducing recurrence of uric acid and calcium stones which form via heterogeneous nucleation (Escribano 2009). Finally, neutral phosphates, sodium/potassium phosphate or both may be used as urinary chelators to reduce stone formation.

Why it is important to do this review

Urinary tract stone disease is a major public health issue; one in 33 children will be affected. Given the increasing incidence of urinary tract stones in children any treatments aimed at preventing recurrent disease will diminish pain and distress, surgical interventions, and medical health costs. To date, there have been very few small studies that have explored the use of any pharmacologic or dietary interventions for prevention of recurrent urinary tract stone disease in children. It is anticipated that this review will stimulate further studies in interventions for the prevention of urinary tract stones in children.

Objectives

This review aims to look at the benefits and harms of medical and dietary interventions for the prevention of idiopathic urinary stones in children aged from one to 18 years.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) of children treated with medical or dietary interventions for the prevention of recurrent urinary stones will be included. In addition, RCTs and quasi-RCTs that included both adults and children participants will be included when separate analyses were reported for adult and child study populations or when the number of children was 10 or more. If very few or no RCTs or quasi-RCTs are found with meet the inclusion criteria, high quality descriptive studies will be considered.

Types of participants

Inclusion criteria
  • Male and female children aged from one to 18 years

  • Participants with a history of urinary stones as documented on imaging by either ultrasound, KUB (kidney, ureter and bladder radiography), or computer tomography (CT) scan.

Exclusion criteria
  • Pregnancy

  • Males and females aged < one year or > 18 years

  • Primary bladder stones

  • Genetically defined stone diseases such as cysteine stones, primary hyperoxaluria, inherited disorders of uric acid metabolism, APRT deficiency, or genetic disorders which may cause hypercalciuria such as Dent disease, or claudin mutations

  • Patients with secondary causes of calcium oxalate stones (e.g. inflammatory bowel disease)

  • Patients on diet/medications predisposing to stones (e.g. ketogenic diet, Topamax, acetazolamide)

  • Hyperparathyroidism.

Types of interventions

We will include interventions with a minimum duration of treatment of 12 months. Examples of pharmacologic interventions include thiazide diuretics, citrate salts, medications that reduce uric acid such as allopurinol, and consumption of calcium supplements before meals. Examples of dietary interventions may include low protein diets, low sodium diets, low oxalate diets, and high citrate diets (e.g. the lemonade diet (Seltzer 1996)).

  1. Any pharmacological intervention versus placebo

  2. Any pharmacological intervention versus no treatment

  3. Any pharmacological intervention versus standard of care (hydration)

  4. Comparison of any two pharmacological interventions

  5. Comparison of any amount, frequency, duration, or mode of administration of a type of pharmacologic intervention

  6. Any dietary intervention versus placebo

  7. Any dietary intervention versus no treatment

  8. Any dietary intervention versus standard of care (hydration)

  9. Comparison of any dietary and pharmacologic intervention.

Types of outcome measures

Primary outcomes

The primary outcome is the proportion of participants who develop a new urinary stone (recurrence rate/patient/year) after initiation of intervention as documented by ultrasound, X-ray, or CT imaging.

Secondary outcomes
  1. Serum electrolytes (calcium, sodium, potassium, phosphate, and uric acid) between treatment and control groups

  2. 24-hour urinary collection parameters (calcium, oxalate, citrate, uric acid, pH, sodium, potassium) between treatment and control groups as well as creatinine (mg/kg/24 h) to affirm adequate collection

  3. Proportion of participants with adverse events (e.g. hypokalaemia, hyperkalaemia, allergic reaction such as skin rash, abdominal pain, nausea, vomiting, hypotension, and elevations in serum uric acid)

  4. Time to new stone formation (days): note that this is a censored outcome (i.e. not all participants will develop a stone and cannot contribute data to this outcome). This is considered a time-to-event outcome and will be analysed with hazard ratio (HR)

  5. Proportion of patients retreated (emergency department visits or stone-related procedures/surgeries) for recurrent stone disease (incidence/patient/y).

Search methods for identification of studies

Electronic searches

We will search the Cochrane Renal Group's Specialised Register through contact with the Trials Search Coordinator using search terms relevant to this review. The Cochrane Renal Groups Specialised Register contains studies identified from the following sources.

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of review articles, relevant studies and clinical practice guidelines.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Non-randomised studies

As suggested in the Cochrane Handbook for Systematic Reviews of Interventions, (section 13.5, Higgins 2011) the Newcastle-Ottawa scale for assessing risk of bias of non-randomised studies will be used (Wells 2012). Although the score does not classify the studies according to study quality, the most appropriate scale – the Newcastle-Ottawa Scale for Cohort studies (Appendix 3; Appendix 4) identifies issues with three domains. These three domains looking at selection (or representativeness of cohorts), comparability (of cohorts due to design or analysis) and outcomes (assessment and follow-up) are further subdivided into eight questions. In the scale, a high-quality choice is represented by a star. The selection, comparability and outcome domains have four, one and three possible stars respectively.

Measures of treatment effect

For dichotomous outcomes (recurrence rate of urinary stones, adverse effects, retreatment) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (serum electrolytes, urinary parameters, time to formation of new stone), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. For continuous variables missing standard deviations (SD), SD will be imputed from published statistics that enable calculation or estimation of the standard deviation such as P values or standard error.

Unit of analysis issues

In the case of a cluster-randomised study design, data will be analysed by the unit of randomisation, for example, the hospital centre or treating physician. Only the first period of cross-over studies will be included because the effects of the initial treatment may affect the outcome of any secondary intervention. In the case of multiple intervention groups (e.g. high and low dose intervention groups), data from each dose group will be combined into one treatment group which will be compared against the non-intervention group.

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing or writing to corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates, for example drop-outs, losses to follow-up and withdrawals will be investigated. Issues of missing data and imputation methods (e.g. last-observation-carried-forward) will be critically appraised (Higgins 2011).

Assessment of heterogeneity

Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to moderate, substantial, and considerable levels of heterogeneity.

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity (type of stone - calcium versus uric acid; type of pharmacologic intervention - thiazide versus potassium citrate; and type of dietary intervention - low protein versus low sodium). Heterogeneity among participants could be related to age; some studies may include children and adults as well as dose and duration of pharmacologic therapy. In the studies that included both child and adult participants in which data were not reported separately for children and adults, we will contact study investigators for child-specific subgroup data. If the subjects were analysed separately by age (≤ 18 versus > 18 years), only child-specific subgroup data will be included. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on treatment effects.

  • Repeating the analysis excluding unpublished studies

  • Repeating the analysis taking account of studies with high risk of bias, as specified

  • Repeating the analysis excluding any large studies to establish how much they dominate the results

  • Repeating the analysis excluding the studies which included both adult and child subjects

  • Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country of origin.

Acknowledgements

We would like to thank the referees for their comments and feedback during the preparation of this protocol, and acknowledge the Cochrane Renal Group for their support.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. urolithiasis:ti,ab,kw

  2. nephrolithiasis:ti,ab,kw

  3. ureterolithiasis:ti,ab,kw

  4. ((kidney* or renal or urin* or ureter*) near/25 (lithiasis or stone* or calcul*)):ti,ab,kw

  5. {or #1-#4}

  6. (diet or dietary):ti,ab,kw

  7. ((restrict* or low or lower* or reduc* or decreas*) near/3 (salt or sodium or oxalate* or protein)):ti,ab,kw

  8. ((restrict* or low or lower* or reduc* or decreas*) near/3 (soft drink* or soda or pop or cola or carbonated)):ti,ab,kw

  9. ((increas* or high* or rich) near/3 (fibre or fiber or potassium)):ti,ab,kw

  10. ((increas* or therapy) near/2 (fluid or fluids or water or drink*)):ti,ab,kw

  11. (hydrat* or rehydrat*):ti,ab,kw

  12. antiurolithiasis next agent*:ti,ab,kw

  13. allopurinol:ti,ab,kw

  14. thiazide*:ti,ab,kw

  15. chlorthalidone:ti,ab,kw

  16. indapamide:ti,ab,kw

  17. hydrochlorothiazide:ti,ab,kw

  18. bendroflumethiazide:ti,ab,kw

  19. trichlormethiazide:ti,ab,kw

  20. magnesium hydroxide:ti,ab,kw

  21. hydroxamic acid*:ti,ab,kw

  22. acetohydroxamic acid:ti,ab,kw

  23. "citric acid":ti,ab,kw

  24. citrate near/1 potassium:ti,ab,kw

  25. citrate near/1 calcium:ti,ab,kw

  26. (high near/3 ("citric acid" or citrate*)):ti,ab,kw

  27. lemonade:ti,ab,kw

  28. conservative* near/1 treat*:ti,ab,kw

  29. {or #6-#28}

  30. {and #5, #29}

  31. (child* or infant* or adolescen* or pediatric or paediatric or schoolchild*)

  32. #30 and #31

MEDLINE
  1. exp Urolithiasis/

  2. urolithiasis.tw.

  3. nephrolithiasis.tw.

  4. ureterolithiasis.tw.

  5. ((kidney* or renal or urin* or ureter*) adj25 (lithiasis or stone$ or calcul$)).tw.

  6. or/1-5

  7. Diet/

  8. Diet Therapy/

  9. Diet, Sodium-Restricted/

  10. Diet, Protein Restricted/

  11. diet therapy.tw.

  12. (diet* adj3 (modif* or composition or intervention*)).tw.

  13. ((restrict* or low or lower* or reduc* or decreas*) adj3 (salt or sodium or oxalate* or protein)).tw.

  14. exp Carbonated Beverages/

  15. ((restrict* or low or lower* or reduc* or decreas*) adj3 (carbonated or soft drink* or soda or pop or cola)).tw.

  16. ((increas* or high* or rich) adj3 (fibre or fiber or potassium)).tw.

  17. Fluid Therapy/

  18. (increas* adj3 (fluid or fluids or water or drink*)).tw.

  19. (hydrat* or rehydrat*).tw.

  20. Allopurinol/

  21. allopurinol.tw.

  22. exp Thiazides/

  23. chlorthalidone.tw.

  24. indapamide.tw.

  25. hydrochlorothiazide.tw.

  26. bendroflumethiazide.tw.

  27. trichlormethiazide.tw.

  28. Magnesium Hydroxide/

  29. Hydroxamic Acids/

  30. magnesium hydroxide.tw.

  31. acetohydroxamic acid.tw.

  32. exp Citric Acid/

  33. (high adj3 (citric acid or citrate*)).tw.

  34. lemonade.tw.

  35. potassium citrate*.tw.

  36. calcium citrate*.tw.

  37. conservative treatment.tw.

  38. or/7-37

  39. and/6,38

  40. exp Child/

  41. exp Infant/

  42. Adolescent/

  43. (child* or infant* or adolescen* or paediatric* or pediatric* or schoolchild*).tw.

  44. or/40-43

  45. and/39,44

EMBASE
  1. exp Urolithiasis/

  2. urinary lithiasis.tw.

  3. nephrolithiasis.tw.

  4. ureterolithiasis.tw.

  5. urolithiasis.tw.

  6. ((kidney$ or renal or urin$ or ureter*) adj25 (lithiasis or stone$ or calcul$)).tw.

  7. or/1-6

  8. Diet/

  9. Diet Therapy/

  10. High Fiber Diet/

  11. Protein Restriction/

  12. Sodium Restriction/

  13. Carbonated Beverage/

  14. Carbonated Water/

  15. Drinking Water/

  16. Fluid Therapy/

  17. Oral Rehydration Therapy/

  18. diet therapy.tw.

  19. (diet* adj3 (modif* or composition or intervention*)).tw.

  20. ((restrict* or low or lower* or reduc* or decreas*) adj3 (salt or sodium or oxalate* or protein)).tw.

  21. ((restrict* or low or lower* or reduc* or decreas*) adj3 (carbonated or soft drink* or soda or pop or cola)).tw.

  22. ((increas* or high* or rich) adj3 (fibre or fiber or potassium)).tw.

  23. (increas* adj3 (fluid or fluids or water or drink*)).tw.

  24. (hydrat* or rehydrat*).tw.

  25. Antiurolithiasis Agent/

  26. Allopurinol/

  27. allopurinol.tw.

  28. exp Thiazide Diuretic Agent/

  29. chlorthalidone.tw.

  30. indapamide.tw.

  31. hydrochlorothiazide.tw.

  32. bendroflumethiazide.tw.

  33. trichlormethiazide.tw.

  34. Magnesium Hydroxide/

  35. magnesium hydroxide.tw.

  36. Acetohydroxamic Acid/

  37. acetohydroxamic acid.tw.

  38. Citric Acid/

  39. Citrate Potassium/

  40. citrate calcium/

  41. (high adj3 (citric acid or citrate*)).tw.

  42. lemonade.tw.

  43. potassium citrate*.tw.

  44. calcium citrate*.tw.

  45. (conservative* adj treat*).tw.

  46. or/8-45

  47. and/7,46

  48. exp Child/

  49. exp Adolescent/

  50. exp Adolescence/

  51. (child* or infant* or adolescen* or paediatric* or pediatric* or schoolchild*).tw.

  52. or/48-51

  53. and/47,52

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Appendix 3. Risk of bias assessment - Newcastle Ottawa Scale Form

Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability

Selection

  1. Representativeness of the exposed cohort

    1. truly representative of the average _______________ (describe) in the community *

    2. somewhat representative of the average ______________ in the community *

    3. selected group of users (e.g. nurses, volunteers)

    4. no description of the derivation of the cohort

  2. Selection of the non exposed cohort

    1. drawn from the same community as the exposed cohort *

    2. drawn from a different source

    3. no description of the derivation of the non exposed cohort

  3. Ascertainment of exposure

    1. secure record (e.g. surgical records) *

    2. structured interview *

    3. written self-report

    4. no description

  4. Demonstration that outcome of interest was not present at start of study

    1. yes *

    2. no

Comparability

  1. Comparability of cohorts on the basis of the design or analysis

    1. study controls for _____________ (select the most important factor) *

    2. study controls for any additional factor * (This criteria could be modified to indicate specific control for a second important factor.)

Outcome

  1. Assessment of outcome

    1. independent blind assessment *

    2. record linkage *

    3. self-report

    4. no description

  2. Was follow-up long enough for outcomes to occur

    1. yes (select an adequate follow up period for outcome of interest) *

    2. no

  3. Adequacy of follow-up of cohorts

    1. complete follow-up - all subjects accounted for *

    2. subjects lost to follow-up unlikely to introduce bias - small number lost - <15 % follow-up, or description provided of those lost) *

    3. follow-up rate < 85% and no description of those lost

    4. no statement

Appendix 4. Risk of bias assessment - Newcastle Ottawa Scale

Coding manual for cohort studies

Selection
1. Representativeness of the exposed cohort

Item is assessing the representativeness of exposed individuals in the community, not the representativeness of the sample of women from some general population. For example, subjects derived from groups likely to contain middle class, better educated, health oriented women are likely to be representative of postmenopausal oestrogen users while they are not representative of all women (e.g. members of a health maintenance organisation (HMO) will be a representative sample of oestrogen users. While the HMO may have an under-representation of ethnic groups, the poor, and poorly educated, these excluded groups are not the predominant users users of oestrogen).

Allocation of stars as per rating sheet

2. Selection of the non-exposed cohort

Allocation of stars as per rating sheet.

3. Ascertainment of exposure

Allocation of stars as per rating sheet.

4. Demonstration that outcome of interest was not present at start of study

In the case of mortality studies, outcome of interest is still the presence of a disease/incident, rather than death. That is to say that a statement of no history of disease or incident earns a star.

Comparability
1. Comparability of cohorts on the basis of the design or analysis

A maximum of 2 stars can be allotted in this category. Either exposed and non-exposed individuals must be matched in the design and/or confounders must be adjusted for in the analysis. Statements of no differences between groups or that differences were not statistically significant are not sufficient for establishing comparability. Note; If the relative risk for the exposure of interest is adjusted for the confounders listed, then the groups will be considered to be comparable on each variable used in the adjustment. There may be multiple ratings for this item for different categories of exposure (e.g. ever versus never, current versus previous or never) Age = , Other controlled factors =

Outcome
1. Assessment of outcome

For some outcomes (e.g. fractured hip), reference to the medical record is sufficient to satisfy the requirement for confirmation of the fracture. This would not be adequate for vertebral fracture outcomes where reference to x-rays would be required.

  1. Independent or blind assessment stated in the paper, or confirmation of the outcome by reference to secure records (X-rays, medical records, etc.)

  2. Record linkage (e.g. identified through ICD codes on database records)

  3. Self-report (i.e. no reference to original medical records or X-rays to confirm the outcome)

  4. No description.

2. Was follow-up long enough for outcomes to occur

An acceptable length of time should be decided before quality assessment begins (e.g. 5 yrs. for exposure to breast implants)

3. Adequacy of follow-up of cohorts

This item assesses the follow-up of the exposed and non-exposed cohorts to ensure that losses are not related to either the exposure or the outcome.
Allocation of stars as per rating sheet

Contributions of authors

  1. Draft the protocol: GG, MJ, LB

  2. Study selection: GG, MJ, HM

  3. Extract data from studies: GG, MJ

  4. Enter data into RevMan: GG

  5. Carry out the analysis: GG

  6. Interpret the analysis: GG, MJ, LB

  7. Draft the final review: GG

  8. Disagreement resolution: LB

  9. Update the review: GG, MJ, LB

Declarations of interest

  • Micah A Jacobs: none known

  • Helen Mayo: none known

  • Linda Baker: none known

  • Gwen Grimsby: none known

Sources of support

Internal sources

  • University of Texas Southwestern Medical Center, USA.

External sources

  • No sources of support supplied

Ancillary