Figures and data in Multi-syndrome, multi-gene risk modeling for individuals with a family history of cancer with the novel R package PanelPRO

Figures
Tables
Additional files

11 figures, 7 tables and 1 additional file

Figures

Figure 1

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Figure 2

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*test_fam_1* sample pedigree as included in the PanelPRO package, plotted using the external visPed package.

The colors refer to cancer diagnoses in the legend. The age of diagnosis is shown below the individual if it is known.

Figure 3

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The sample pedigree err_fam_1 which contains a pedigree loop, due to the mating pattern of the siblings aged 59 and 55 with the siblings aged 60 and 62, respectively.

The two circles linked by a dotted line represent the same individual.

Figure 4

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Figure 5 with 3 supplements

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Figure 5—figure supplement 1

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PanelPRO output with *test_fam_5* as pedigree input.

Graphical output from the visRisk function in PanelPRO for *test_fam_5*.

Figure 5—figure supplement 2

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BRCAPRO output with *test_fam_5* as pedigree input.

Text output from the BRCAPRO model for *test_fam_5*.

Figure 5—figure supplement 3

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IBIS output with *test_fam_5* as pedigree input.

Screenshot of output from IBIS for *test_fam_5*.

Figure 6 with 5 supplements

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Figure 6—figure supplement 1

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PanelPRO output with *test_fam_6* as pedigree input.

Graphical output from the visRisk function in PanelPRO for *test_fam_6*.

Figure 6—figure supplement 2

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BRCAPRO output with *test_fam_6* as pedigree input.

Text output from the BRCAPRO model for *test_fam_6*.

Figure 6—figure supplement 3

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MMRPRO output with *test_fam_6* as pedigree input.

Text output from the MMRPRO model for *test_fam_6*.

Figure 6—figure supplement 4

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IBIS output with *test_fam_6* as pedigree input.

Screenshot of output from IBIS for *test_fam_6*.

Figure 6—figure supplement 5

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PREMM-5 output with *test_fam_6* as pedigree input.

Screenshot of output from PREMM-5 for *test_fam_6*.

Figure 7 with 3 supplements

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Figure 7—figure supplement 1

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PanelPRO output with *test_fam_7* as pedigree input.

Graphical output from the visRisk function in PanelPRO for *test_fam_7*.

Figure 7—figure supplement 2

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MMRPRO output with *test_fam_7* as pedigree input.

Text output from the MMRPRO model for *test_fam_7*.

Figure 7—figure supplement 3

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PREMM-5 output with *test_fam_7* as pedigree input.

Screenshot of output from PREMM-5 for *test_fam_7*.

Figure 8 with 5 supplements

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Figure 8—figure supplement 1

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PanelPRO output with *test_fam_10* as pedigree input.

Graphical output from the visRisk function in PanelPRO for *test_fam_10*.

Figure 8—figure supplement 2

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BRCAPRO output with *test_fam_10* as pedigree input.

Text output from the BRCAPRO model for *test_fam_10*.

Figure 8—figure supplement 3

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MMRPRO output with *test_fam_10* as pedigree input.

Text output from the MMRPRO model for *test_fam_10*.

Figure 8—figure supplement 4

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IBIS output with *test_fam_1* as pedigree input.

Screenshot of output from IBIS for *test_fam_10*.

Figure 8—figure supplement 5

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PREMM-5 output with test_fam_10 as pedigree input.

Screenshot of output from PREMM-5 for test_fam_10.

Figure 9 with 5 supplements

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Figure 9—figure supplement 1

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PanelPRO output with test_fam_11 as pedigree input.

Graphical output from the visRisk function in PanelPRO for test_fam_11.

Figure 9—figure supplement 2

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BRCAPRO output with test_fam_11 as pedigree input.

Text output from the MMRPRO model for test_fam_11.

Figure 9—figure supplement 3

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MMRPRO output with test_fam_11 as pedigree input.

Text output from the MMRPRO model for test_fam_11.

Figure 9—figure supplement 4

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IBIS output with test_fam_11 as pedigree input.

Screenshot of output from IBIS for test_fam_11.

Figure 9—figure supplement 5

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PREMM-5 output with test_fam_11 as pedigree input.

Screenshot of output from PREMM-5 for test_fam_11

Figure 10

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Sample run-times for *test_fam_1* evaluated by PanelPRO on the default settings, as a function of the number of genes considered.

The paring parameter is set to 2. These run time experiments were performed on a 2020 Linux machine with an 11th Gen Intel(R) i7-1165G7 chip at 2.80 GHz.

Appendix 1—figure 1

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Tables

Table 1

Pedigree structure in PanelPRO.

Column	Definition	Value
ID	Unique numeric identifier of each individual	Non-repeated strictly positive integer
MotherID	ID of one’s mother	Strictly positive integer or NA (missing)
FatherID	ID of one’s father	Strictly positive integer or NA (missing)
Sex	Sex of the individual: 1 for male, 0 for female	One of {0, 1}
isProband	Indicates the proband or counselee by 1 and 0 otherwise – multiple probands can be specified	One of {0, 1)
CurAge	Age of censoring: either the current age or death age, depending on isDead status	Positive integer or NA (missing)
isAff*	Affection status of cancer *	One of {0, 1}
Age*	Affection age of cancer *	Positive integer or NA (missing)
isDead	Whether someone has died	One of {0, 1, NA}
race	Race of individual (used to modify penetrance)	One of All_Races, AIAN, Asian, Black, White, Hispanic, WH, WNH, NA
Ancestry	Ancestry of individual (used to modify allele frequencies)	One of AJ, nonAJ, Italian, NA
Twins	Identifies siblings who are identical twins or multiple births	Each set is identified by a unique integer, and 0 otherwise
riskmod	Preventative interventions which modify penetrance	List, combination of "mastectomy", "hysterectomy", and "oophorectomy"
InterAge	Age of each preventative interventions	List, combination of integers
Gene name from GENE_TYPES	Germline testing result	One of {0, 1, NA}
Marker name from CK14, CK5.6, ER, PR, HER2, MSI	Marker testing result	One of {0, 1, NA}

Table 2

List of model options that the user can pass to PanelPRO, along with their defaults.

Option	Default value	Possible values	Description
max.mut	NULL	Integers up to the number of genes	Number of maximum simultaneous mutations, also known as the paring parameter. If no integer has been input, it re-defaults to 2.
iterations	20	Integers from 1 upwards	In case of missing current or cancer ages in the pedigree, this is the number of times those ages will be imputed.
parallel	TRUE	TRUE or FALSE	If age imputations are needed, this parameter can be set to utilize multiple cores on one’s machine.
net	FALSE	TRUE or FALSE	Determines whether net or crude penetrances are used to compute future risk of cancer. Net penetrances exclude all other causes of death, apart from the affected cancer.
age.by	5	Integers from one upwards	The intervals of age used to report the future risk of cancer.

Table 3

List of main functions in PanelPRO.

Category	Name	Description
Pre-processing	checkFam	Checks family structure as defined by the user. The inputs are a data.frame specifying the pedigree and a built database returned by buildDatabase. The output is a modified data.frame pedigree and list of imputed ages, if missing ages were imputed (see the Missing Data section).
Pre-processing	buildDatabase	Subsets the internal database PanelPRODatabase depending on the cancers and genes selected. The input is the list PanelPRODatabase. The output is another list which is a subset of PanelPRODatabase.
Algorithm	PanelPROCalc	Estimates the posterior carrier probabilities and future risks of the proband. The inputs are the outputs of checkFam. The outputs are lists of posterior probabilities and future risks for the proband.
Main function	PanelPRO	Runs main function. The inputs are the user-specified pedigree, a vector of cancers in the model, a vector of genes in the model, and other optional parameters. The output is a list of estimates of posterior carrier probabilities for each genotype, along with future cancer risks and ranges for each of these.

Table 4

Comparison between supported cancers and genes in PanelPRO and other platforms.

Model or platform name	Version	Supported cancer input types	Supported gene carrier probability outputs	Supported future cancer risk outputs
PanelPRO	0.2.0	Brain, breast, cervical, colorectal, endometrial, gastric, kidney, leukemia, melanoma, ovarian, osteosarcoma, pancreatic, small intestine, soft tissue sarcoma, thyroid, urinary bladder, hepatobiliary	APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53	same as cancer inputs
BRCAPRO	2.1–7	Breast, ovarian	BRCA1, BRCA2	same as cancer inputs
MMRPRO	2.1–7	Colorectal, endometrial	MLH1, MSH2, MSH6	same as cancer inputs
IBIS	0.8b	Breast	NA	Breast
CanRisk	1.2.3	Breast, contralateral breast, ovarian, prostate, pancreatic	BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D, RAD51C, BRIP1	Breast, ovarian
PREMM-5	NA	Colorectal, endometrial, other (group of ovarian, stomach, small intestine, urinary tract/bladder/kidney, bile ducts, brain, pancreas, sebaceous gland skin)	MLH1, MSH2, MSH6, PMS2, EPCAM	NA

Table 5

Notation for Mendelian Modeling for a model with $K$ genes and $R$ cancers and a family of $I$ members.

The subscript $i$ denotes the $i$ th family member.

Variable and notation	Description	R object from user input, if applicable
Genotypes
$𝐆_{i} = {(G_{k i})}_{k = 1}^{K}$	Genotype of individual $i$ , where $G_{k i}$ is the binary indicator for carrying a deleterious mutation in the $k$ th gene
$𝐆 = {(𝐆_{i})}_{i = 1}^{I}$	Genotypes of all family members $i = 1, \dots, I$
Sex
$U_{i}$	Binary indicator that individual $i$ is male	Sex
$𝐔 = {(U_{i})}_{i = 1}^{I}$	Binary male indicators for all family members $i = 1, \dots, I$
Cancer history
$T_{r i}$	Age of diagnosis of the $r$ th cancer for individual $i$	AgeXX
$C_{i}$	Individual i’ s censoring age (current age or age of death)	CurAge
$δ_{r i} = I (T_{r i} \leq C_{i})$	Binary indicator that cancer $r$ occurs before the censoring age for individual $i$
$𝐇_{r i} = {\begin{matrix} (C_{i}, δ_{r i}) & if δ_{r i} = 0 \\ (C_{i}, δ_{r i}, T_{r i}) & if δ_{r i} = 1 \end{matrix}$	Observed history of the $r$ th cancer for individual $i$ , not including risk modifiers and interventions
$𝐇_{i} = {(𝐇_{r i})}_{r = 1}^{R}$	All observed history for individual $i$
$𝐇 = {(𝐇_{i})}_{i = 1}^{I}$	Observed histories for all family members $i = 1, \dots, I$
$T_{d, r i}$	Individual $i$ ’s age of death from causes other than cancer $r$
$T_{r i}^{*} = \min (T_{r i}, T_{d, r i})$	Individual $i$ ’s age of first outcome, either cancer $r$ or death from causes other than cancer $r$
$J_{r i} = I (T_{r i}^{*} = T_{r i})$	Binary indicator that individual $i$ develops the $r$ th cancer	isAffXX

Appendix 1—table 1

Abbreviations of cancers in PanelPRO.

Short name	Long name	Short name	Long name
BRA	Brain	OC	Ovarian
BC	Breast	OST	Osteosarcoma
CER	Cervical	PANC	Pancreas
COL	Colorectal	PROS	Prostate
ENDO	Endometrial	SI	Small Intestine
GAS	Gastric	STS	Soft Tissue Sarcoma
KID	Kidney	THY	Thyroid
LEUK	Leukemia	UB	Urinary Bladder
MELA	Melanoma	HEP	Heptobiliary

Appendix 1—table 2

Summary of sample pedigrees provided within the package.

Pedigree name	Number of family members	Cancers present
test_fam_1	19	BC, OC
test_fam_2	25	ENDO, PANC, SI
test_fam_3	50	BRA, BC, COL, ENDO, GAS, KID, MELA, OC, PANC, PROS, SI
test_fam_4	9	BC, OC, BRA, COL, PROS, ENDO, SI,
test_fam_5	17	BC, MELA
test_fam_6	19	BC, ENDO, MELA, PANC
test_fam_7	19	COL, ENDO
test_fam_8	20	COL, PROS
test_fam_9	19	BC, PROS
test_fam_10	21	BC, COL
test_fam_11	16	BC, ENDO, OC, PANC, SI
test_fam_12	21	all cancers in Appendix 1—table 1
err_fam_1	10	BC, PANC